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Sample records for activator complex polymorphisms

  1. PPAR Transcriptional Activator Complex Polymorphisms and the Promise of Individualized Therapy for Heart Failure

    PubMed Central

    Mistry, Neville F.; Cresci, Sharon

    2013-01-01

    The PPAR gene pathway consists of interrelated genes that encode transcription factors, enzymes and downstream targets which coordinately act to regulate cellular processes central to glucose and lipid metabolism. The pathway includes the PPAR genes themselves, other class II nuclear hormone receptor transcription factors within the PPAR family, PPAR co-activators, PPAR co-repressors, and downstream metabolic gene targets. This review focuses on the transcription factors that comprise the PPAR transcriptional activator complex – the PPARs (PPARα, PPARβ, or PPARγ), PPAR heterodimeric partners, such as RXRα, and PPAR co-activators, such as PPARγ coactivator 1α (PGC-1α) and the estrogen related receptors (ERRα, ERRβ, and ERRγ). These transcription factors have been implicated in the development of myocardial hypertrophy and dilated cardiomyopathy as well as response to myocardial ischemia/infarction and, by association, ischemic cardiomyopathy. Human expression studies and animal data are presented as the background for a discussion of the emerging field of pharmacogenetics as it applies to these genes and the consequent implications for the individualization of therapy for patients with heart failure. PMID:18998207

  2. PPAR transcriptional activator complex polymorphisms and the promise of individualized therapy for heart failure.

    PubMed

    Mistry, Neville F; Cresci, Sharon

    2010-05-01

    The PPAR gene pathway consists of interrelated genes that encode transcription factors, enzymes, and downstream targets which coordinately act to regulate cellular processes central to glucose and lipid metabolism. The pathway includes the PPAR genes themselves, other class II nuclear hormone receptor transcription factors within the PPAR family, PPAR co-activators, PPAR co-repressors, and downstream metabolic gene targets. This review focuses on the transcription factors that comprise the PPAR transcriptional activator complex--the PPARs (PPARalpha, PPARbeta, or PPARgamma), PPAR heterodimeric partners, such as RXRalpha, and PPAR co-activators, such as PPARgamma coactivator 1alpha (PGC-1alpha) and the estrogen-related receptors (ERRalpha, ERRbeta, and ERRgamma). These transcription factors have been implicated in the development of myocardial hypertrophy and dilated cardiomyopathy as well as response to myocardial ischemia/infarction and, by association, ischemic cardiomyopathy. Human expression studies and animal data are presented as the background for a discussion of the emerging field of pharmacogenetics as it applies to these genes and the consequent implications for the individualization of therapy for patients with heart failure.

  3. BDNF and COMT polymorphisms have a limited association with episodic memory performance or engagement in complex cognitive activity in healthy older adults.

    PubMed

    Stuart, Kimberley; Summers, Mathew James; Valenzuela, Michael J; Vickers, James C

    2014-04-01

    Cognitive decline is a major factor in lowering the quality of life in older populations, and contributes substantially to social, economic, and health costs. As humans age, cognitive function decreases differentially, and individual differences in cognitive ageing are likely attributed to a range of causes, including environmental and genetic influences. The current study included 360 participants (240 females and 120 males) aged between 50 and 79years from the Tasmanian Healthy Brain Project. The brain-derived neurotrophic factor (BDNF) Val66Met and Catechol-O-Methyltransferase (COMT) Val158Met polymorphisms were examined for their association with visual and auditory episodic memory performance. The polymorphisms were also investigated for their association with reported life-long engagement in complex cognitive activity using a retrospective questionnaire. Relative to the demographic variables, the gene variations were found to have no association with episodic memory performance, with the exception of the COMT polymorphism on a single measure of auditory memory (RAVLT). Several other studies also demonstrated that these polymorphisms have no, small, or inconsistent effects on memory function. The BDNF Val66Met and COMT Val158Met polymorphisms were also found to be of little significance to active engagement in complex cognitive activity throughout most of the lifespan. An association was detected between BDNF Val66Met and engagement in cognitive activity in early life (p=.04, d=.23), however this did not reach significance when adjusted for multiple comparisons. The biological mechanisms that underlie engagement in cognitive activity are elusive, thus the potential relationship between BDNF Val66Met genotype and early life cognitive engagement warrants further investigation. Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.

  4. FGF receptor-4 (FGFR4) polymorphism acts as an activity switch of a membrane type 1 matrix metalloproteinase-FGFR4 complex.

    PubMed

    Sugiyama, Nami; Varjosalo, Markku; Meller, Pipsa; Lohi, Jouko; Chan, Kui Ming; Zhou, Zhongjun; Alitalo, Kari; Taipale, Jussi; Keski-Oja, Jorma; Lehti, Kaisa

    2010-09-07

    Tumor cells use membrane type 1 matrix metalloproteinase (MT1-MMP) for invasion and metastasis. However, the signaling mechanisms that underlie MT1-MMP regulation in cancer have remained unclear. Using a systematic gain-of-function kinome screen for MT1-MMP activity, we have here identified kinases that significantly enhance MT1-MMP activity in tumor cells. In particular, we discovered an MT1-MMP/FGF receptor-4 (FGFR4) membrane complex that either stimulates or suppresses MT1-MMP and FGFR4 activities, depending on a tumor progression-associated polymorphism in FGFR4. The FGFR4-R388 allele, linked to poor cancer prognosis, increased collagen invasion by decreasing lysosomal MT1-MMP degradation. FGFR4-R388 induced MT1-MMP phosphorylation and endosomal stabilization, and surprisingly, the increased MT1-MMP in return enhanced FGFR4-R388 autophosphorylation. A phosphorylation-defective MT1-MMP was stabilized on the cell surface, where it induced simultaneous FGFR4-R388 internalization and dissociation of cell-cell junctions. In contrast, the alternative FGFR4-G388 variant down-regulated MT1-MMP, and the overexpression of MT1-MMP and particularly its phosphorylation-defective mutant vice versa induced FGFR4-G388 degradation. These results provide a mechanistic basis for FGFR4-R388 function in cancer invasion.

  5. Purification of polymorphic components of complex genomes

    DOEpatents

    Stodolsky, M.

    1988-01-21

    A method for processing related subject and reference macromolecule composed of complementary strand into their respective subject and reference populations of representative fragments and effectuating purification of unique polymorphic subject fragments. 1 fig.

  6. Purification of polymorphic components of complex genomes

    DOEpatents

    Stodolsky, M.

    1991-07-16

    A method is disclosed for processing related subject and reference macromolecule populations composed of complementary strands into their respective subject and reference populations of representative fragments and effectuating purification of unique polymorphic subject fragments. 1 figure.

  7. Purification of polymorphic components of complex genomes

    DOEpatents

    Stodolsky, Marvin

    1991-01-01

    A method is disclosed for processing related subject and reference macromolecule populations composed of complementary strands into their respective subject and reference populations of representative fragments and effectuating purification of unique polymorphic subject fragments.

  8. Complexity Reduction of Polymorphic Sequences (CRoPS™): A Novel Approach for Large-Scale Polymorphism Discovery in Complex Genomes

    PubMed Central

    van Orsouw, Nathalie J.; Hogers, René C. J.; Janssen, Antoine; Yalcin, Feyruz; Snoeijers, Sandor; Verstege, Esther; Schneiders, Harrie; van der Poel, Hein; van Oeveren, Jan; Verstegen, Harold; van Eijk, Michiel J. T.

    2007-01-01

    Application of single nucleotide polymorphisms (SNPs) is revolutionizing human bio-medical research. However, discovery of polymorphisms in low polymorphic species is still a challenging and costly endeavor, despite widespread availability of Sanger sequencing technology. We present CRoPS™ as a novel approach for polymorphism discovery by combining the power of reproducible genome complexity reduction of AFLP® with Genome Sequencer (GS) 20/GS FLX next-generation sequencing technology. With CRoPS, hundreds-of-thousands of sequence reads derived from complexity-reduced genome sequences of two or more samples are processed and mined for SNPs using a fully-automated bioinformatics pipeline. We show that over 75% of putative maize SNPs discovered using CRoPS are successfully converted to SNPWave® assays, confirming them to be true SNPs derived from unique (single-copy) genome sequences. By using CRoPS, polymorphism discovery will become affordable in organisms with high levels of repetitive DNA in the genome and/or low levels of polymorphism in the (breeding) germplasm without the need for prior sequence information. PMID:18000544

  9. Major histocompatibility complex class I polymorphism in Asiatic lions.

    PubMed

    Sachdev, M; Sankaranarayanan, R; Reddanna, P; Thangaraj, K; Singh, L

    2005-07-01

    Asiatic lions (Panthera leo persica), whose only natural habitat in the world is the Gir forest sanctuary of Gujarat State in India, are highly endangered and are considered to be highly inbred with narrow genetic diversity. An objective assessment of genetic diversity in their immune loci will help in assessing their survivability and may provide vital clues in designing strategies for their scientific management and conservation. We analyzed the comparative sequence polymorphism at exon 2 and exon 3 of major histocompatibility complex (MHC) class I in three groups of lions, i.e. wild Asiatic (from Gir forest), captive-bred Asiatic (from zoological parks in India), and Afro-Asiatic hybrid groups (from zoological parks in India) through polymorphism chain reaction-assisted sequence-based typing. The two exons were amplified, cloned, sequenced, and analyzed for polymorphism at nucleotide and putative translated product level. The analysis revealed extensive sequence polymorphism not only between clones derived from different lions but also the clones derived from a single lion. Furthermore, the wild Asiatic lions of Gir forest exhibited abundant sequence polymorphism at MHC class I comparable with that of Afro-Asiatic hybrid lions and significantly higher than that of captive-bred Asiatic lions. We hypothesize that Asiatic lions of Gir forest are not highly inbred as thought earlier and they possess abundant sequence polymorphism at MHC class I loci. During this study, 52 new sequences of the multigene MHC class I family were also identified among Asiatic lions.

  10. Structural polymorphism of DNA-dendrimer complexes

    NASA Astrophysics Data System (ADS)

    Evans, Heather M.; Ahmad, A.; Ewert, K.; Pfohl, T.; Martin-Herranz, A.; Bruinsma, R. F.; Safinya, C. R.

    2003-08-01

    DNA condensation in vivo relies on electrostatic complexation with small cations or large histones. We report a synchrotron x-ray study of the phase behavior of DNA complexed with synthetic cationic dendrimers of intermediate size and charge. We encounter unexpected structural transitions between columnar mesophases with in-plane square and hexagonal symmetries, as well as liquidlike disorder. The isoelectric point is a locus of structural instability. A simple model is proposed based on competing long-range electrostatic interactions and short-range entropic adhesion by counterion release.

  11. Complexity, polymorphism, and connectivity of mouse Vk gene families.

    PubMed

    Kofler, R; Duchosal, M A; Dixon, F J

    1989-01-01

    To define the polymorphism and extent of the mouse immunoglobulin kappa (Igk) gene complex, we have analyzed restriction-enzyme digested genomic DNA from 33 inbred strains of mice with labeled DNA probes corresponding to 16 Vk protein groups (1 of them previously undescribed) and the Jk/Ck region (V, variable; J, joining; C, constant). These probes detected between 1 and 25 distinct restriction enzyme fragments (REF) that appeared in up to eight polymorphic patterns, thus defining eight mouse Igk haplotypes. The investigated portion of the Vk repertoire was estimated to encompass between 60 and 120 discernable Vk gene-containing REFs. In contrast to mouse VH gene families, several Vk gene families defined by these probes appeared to overlap. This observation has implications for Vk gene analyses by nucleic acid hybridization and raises the possibility that the Vk gene complex is a continuum of related sequences.

  12. Molecular methods for genotyping complex copy number polymorphisms.

    PubMed

    Cantsilieris, Stuart; Baird, Paul N; White, Stefan J

    2013-02-01

    Genome structural variation shows remarkable complexity with respect to copy number, sequence content and distribution. While the discovery of copy number polymorphisms (CNP) has increased exponentially in recent years, the transition from discovery to genotyping has proved challenging, particularly for CNPs embedded in complex regions of the genome. CNPs that are collectively common in the population and possess a dynamic range of copy numbers have proved the most difficult to genotype in association studies. This is in some part due to technical limitations of genotyping assays and the sequence properties of the genomic region being analyzed. Here we describe in detail the basis of a number of molecular techniques used to genotype complex CNPs, compare and contrast these approaches for determination of multi-allelic copy number, and discuss the potential application of these techniques in genetic studies.

  13. Structural characterization of polymorphs and molecular complexes of finasteride

    NASA Astrophysics Data System (ADS)

    Wawrzycka, Irena; Stȩpniak, Krystyna; Matyjaszczyk, Sławomir; Kozioł, Anna E.; Lis, Tadeusz; Abboud, Khalil A.

    1999-01-01

    The molecular structure of finasteride, 17 β-( N-tert-butylcarbamoyl)-4-aza-5 α-androst-1-en-3-one, and structures of three related crystalline forms have been determined by X-ray analysis. The rigid steroid skeleton of the molecule adopts a half-chair/chair/chair/half-chair conformation. Two peptide groups, one cyclic (lactam) in the ring A and a second being a part of the substituent at C17, are the main factors influencing intermolecular contacts. Different hydrogen-bond interactions of these hydrophilic groups are observed in the crystal structures. An infinite ribbon of finasteride molecules is formed between lactam groups in the orthorhombic homomolecular crystal ( 1) obtained from an ethanol solution. The linear molecular complex finasteride-acetic acid ( 1a) is connected by hydrogen bonds between the lactam of finasteride and the carboxyl group of acetic acid. The crystallization from an ethyl acetate solution gives a complex structure of bis-finasteride monohydrate ethyl acetate clathrate ( 1b) with guest molecule disordered in channels. Crystals of a second (monoclinic) finasteride polymorph ( 2) were obtained during thermal decomposition of 1a, and sublimation of 1, 1a and 1b. Two polymorphic forms show different IR spectra.

  14. AMPLIFIED FRAGMENT LENGTH POLYMORPHISM ANALYSIS OF MYCOBACTERIUM AVIUM COMPLEX ISOLATES RECOVERED FROM SOUTHERN CALIFORNIA

    EPA Science Inventory

    Fine-scale genotyping methods are necessary in order to identify possible sources of human exposure to opportunistic pathogens belonging to the Mycobacterium avium complex (MAC). In this study, amplified fragment length polymorphism (AFLP) analysis was evaluated for fingerprintin...

  15. AMPLIFIED FRAGMENT LENGTH POLYMORPHISM ANALYSIS OF MYCOBACTERIUM AVIUM COMPLEX ISOLATES RECOVERED FROM SOUTHERN CALIFORNIA

    EPA Science Inventory

    Fine-scale genotyping methods are necessary in order to identify possible sources of human exposure to opportunistic pathogens belonging to the Mycobacterium avium complex (MAC). In this study, amplified fragment length polymorphism (AFLP) analysis was evaluated for fingerprintin...

  16. Polymorphism complexity and handedness inversion in serum albumin amyloid fibrils.

    PubMed

    Usov, Ivan; Adamcik, Jozef; Mezzenga, Raffaele

    2013-12-23

    Protein-based amyloid fibrils can show a great variety of polymorphic structures within the same protein precursor, although the origins of these structural homologues remain poorly understood. In this work we investigate the fibrillation of bovine serum albumin--a model globular protein--and we follow the polymorphic evolution by a statistical analysis of high-resolution atomic force microscopy images, complemented, at larger length scales, by concepts based on polymer physics formalism. We identify six distinct classes of coexisting amyloid fibrils, including flexible left-handed twisted ribbons, rigid right-handed helical ribbons and nanotubes. We show that the rigid fibrils originate from flexible fibrils through two diverse polymorphic transitions, first, via a single-fibril transformation when the flexible left-handed twisted ribbons turn into the helical left-handed ribbons, to finally evolve into nanotube-like structures, and second, via a double-fibril transformation when two flexible left-handed twisted ribbons wind together resulting in a right-handed twisted ribbon, followed by a rigid right-handed helical ribbon polymorphic conformation. Hence, the change in handedness occurs with an increase in the level of the fibril's structural organization.

  17. A Case Report of Renal Sympathetic Denervation for the Treatment of Polymorphic Ventricular Premature Complexes

    PubMed Central

    Kiuchi, Márcio Galindo; Vitorio, Frederico Puppim; da Silva, Gustavo Ramalho; Paz, Luis Marcelo Rodrigues; Souto, Gladyston Luiz Lima

    2015-01-01

    Abstract Premature ventricular complexes are very common, appearing most frequently in patients with hypertension, obesity, sleep apnea, and structural heart disease. Sympathetic hyperactivity plays a critical role in the development, maintenance, and aggravation of ventricular arrhythmias. Recently, Armaganijan et al reported the relevance of sympathetic activation in patients with ventricular arrhythmias and suggested a potential role for catheter-based renal sympathetic denervation in reducing the arrhythmic burden. In this report, we describe a 32-year-old hypertensive male patient presenting with a high incidence of polymorphic premature ventricular complexes on a 24 hour Holter monitor. Beginning 1 year prior, the patient experienced episodes of presyncope, syncope, and tachycardia palpitations. The patient was taking losartan 100 mg/day, which kept his blood pressure (BP) under control, and sotalol 160 mg twice daily. Bisoprolol 10 mg/day was used previously but was not successful for controlling the episodes. The 24 hour Holter performed after the onset of sotalol 160 mg twice daily showed a heart rate ranging between 48 (minimum)–78 (average)–119 (maximum) bpm; 14,286 polymorphic premature ventricular complexes; 3 episodes of nonsustained ventricular tachycardia, the largest composed of 4 beats at a rate of 197 bpm; and 14 isolated atrial ectopic beats. Cardiac magnetic resonance imaging with gadolinium perfusion performed at rest and under pharmacological stress with dipyridamole showed increased left atrial internal volume, preserved systolic global biventricular function, and an absence of infarcted or ischemic areas. The patient underwent bilateral renal sympathetic denervation. The only drug used postprocedure was losartan 25 mg/day. Three months after the patient underwent renal sympathetic denervation, the mean BP value dropped to 132/86 mmHg, the mean systolic/diastolic 24 hour ambulatory BP measurement was reduced to 128/83

  18. Polymorphism in the spin-crossover ferric complexes [(TPA)Fe(III)(TCC)]PF6.

    PubMed

    Collet, Eric; Boillot, Marie Laure; Hebert, Johan; Moisan, Nicolas; Servol, Marina; Lorenc, Maciej; Toupet, Loïc; Buron-Le Cointe, Marylise; Tissot, Antoine; Sainton, Joelle

    2009-08-01

    We have identified two polymorphs of the molecular complex [(TPA)Fe((III))(TCC)]PF(6) [TPA = tris(2-pyridylmethyl)amine and TCC = 3,4,5,6-tetrachlorocatecholate dianion]: one is monoclinic and the other is orthorhombic. By lowering the temperature both undergo a thermal spin-crossover between a high-spin (S = 5/2) and a low-spin (S = 1/2) state, which we detected by magnetic, optical and X-ray diffraction measurements. The thermal crossover is only slightly shifted between the polymorphs. Their crystalline structures consist of similar cation layers alternating with PF(6) anion layers, packed differently in the two polymorphs. The magnetic and optical properties of the polymorphs are presented.

  19. Decoding the role of regulatory element polymorphisms in complex disease.

    PubMed

    Vockley, Christopher M; Barrera, Alejandro; Reddy, Timothy E

    2017-04-01

    Genetic variation in gene regulatory elements contributes to diverse human diseases, ranging from rare and severe developmental defects to common and complex diseases such as obesity and diabetes. Early examples of regulatory mechanisms of human diseases involve large chromosomal rearrangements that change the regulatory connections within the genome. Single nucleotide variants in regulatory elements can also contribute to disease, potentially via demonstrated associations with changes in transcription factor binding, enhancer activity, post-translational histone modifications, long-range enhancer-promoter interactions, or RNA polymerase recruitment. Establishing causality between non-coding genetic variants, gene regulation, and disease has recently become more feasible with advances in genome-editing and epigenome-editing technologies. As establishing causal regulatory mechanisms of diseases becomes routine, functional annotation of target genes is likely to emerge as a major bottleneck for translation into patient benefits. In this review, we discuss the history and recent advances in understanding the regulatory mechanisms of human disease, and new challenges likely to be encountered once establishing those mechanisms becomes rote. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Solar active region magnetic complexity

    NASA Astrophysics Data System (ADS)

    Nikbakhsh, Shabnam; Tanskanen, Eija; Hackman, Thomas

    2017-04-01

    We have studied the Mount Wilson Classification of solar Active Regions (ARs) for the period from 1996 to 2015. Sunspots are visual indicators of ARs where the solar magnetic field is disturbed. Major manifestations of solar magnetic activity, such as solar flares and Coronal Mass Ejections (CMEs), are associated with solar ARs. There has been so many attempts to classify solar ARs based on their magnetic complexity as a measure of their acitivity. For this study we applied the Mount Wilson Classification which groups ARs in terms of their magnetic complexity from the least complex alpha to the most complex one beta-gamma-delta. We compared the magnetic complexity data to two sets of sunspot number: 1- International Sunspot Number (ISSN) 2- NOAA sunspot number We have been found that the number of more complex structures reach its maximum two years after solar maximum. We also compared the result to our identified geomagnetic storm list. The results showed the more complex ARs are responsible for the strongest geomagnetic storms.

  1. A gain of function polymorphism controlling complex traits and fitness in nature

    PubMed Central

    Prasad, Kasavajhala V. S. K.; Song, Bao-Hua; Olson-Manning, Carrie; Anderson, Jill T.; Lee, Cheng-Ruei; Schranz, M. Eric; Windsor, Aaron J.; Clauss, Maria J.; Manzaneda, Antonio J.; Naqvi, Ibtehaj; Reichelt, Michael; Gershenzon, Jonathan; Rupasinghe, Sanjeewa G.; Schuler, Mary A.; Mitchell-Olds, Thomas

    2013-01-01

    Identifying the causal genes that control complex trait variation remains challenging, limiting our appreciation of the evolutionary processes that influence polymorphisms in nature. We cloned a QTL that controls plant defensive chemistry, damage by insect herbivores, survival, and reproduction in the natural environments where this polymorphism evolved. These ecological effects are driven by duplications in the BCMA loci controlling this QTL and by two selectively favored amino acid changes in the glucosinolate-biosynthetic P450s that they encode. These changes cause a gain of novel enzyme function, modulated by allelic differences in catalytic rate and gene copy number. Ecological interactions in diverse environments likely contribute to the widespread polymorphism of this biochemical function. PMID:22936775

  2. Polymorphism and selection in the major histocompatibility complex DRA and DQA genes in the family Equidae.

    PubMed

    Janova, Eva; Matiasovic, Jan; Vahala, Jiri; Vodicka, Roman; Van Dyk, Enette; Horin, Petr

    2009-07-01

    The major histocompatibility complex genes coding for antigen binding and presenting molecules are the most polymorphic genes in the vertebrate genome. We studied the DRA and DQA gene polymorphism of the family Equidae. In addition to 11 previously reported DRA and 24 DQA alleles, six new DRA sequences and 13 new DQA alleles were identified in the genus Equus. Phylogenetic analysis of both DRA and DQA sequences provided evidence for trans-species polymorphism in the family Equidae. The phylogenetic trees differed from species relationships defined by standard taxonomy of Equidae and from trees based on mitochondrial or neutral gene sequence data. Analysis of selection showed differences between the less variable DRA and more variable DQA genes. DRA alleles were more often shared by more species. The DQA sequences analysed showed strong amongst-species positive selection; the selected amino acid positions mostly corresponded to selected positions in rodent and human DQA genes.

  3. Stability of furosemide polymorphs and the effects of complex formation with β-cyclodextrin and maltodextrin.

    PubMed

    Garnero, Claudia; Chattah, Ana Karina; Longhi, Marcela

    2016-11-05

    The effect of the formation of supramolecular binary complexes with β-cyclodextrin and maltodextrin on the chemical and physical stability of the polymorphs I and II of furosemide was evaluated in solid state. The solid samples were placed under accelerated storage conditions and exposed to daylight into a stability chamber for a 6-month. Chemical stability was monitored by high performance liquid chromatography, while the physical stability was studied by solid state nuclear magnetic resonance, powder X-ray diffraction and scanning electron microscopy. Changes in the physical appearance of the samples were evaluated. The studies showed a significant stabilizing effect of β-cyclodextrin on furosemide form II. Our results suggest that the complex formation is a useful tool for improving the stability of furosemide polymorphs. These new complexes are promising candidates that can be used in the pharmaceutical industry for the preparation of alternative matrices that improve physicochemical properties.

  4. Genetics of complex traits: prediction of phenotype, identification of causal polymorphisms and genetic architecture

    PubMed Central

    Goddard, M. E.; Kemper, K. E.; MacLeod, I. M.; Chamberlain, A. J.; Hayes, B. J.

    2016-01-01

    Complex or quantitative traits are important in medicine, agriculture and evolution, yet, until recently, few of the polymorphisms that cause variation in these traits were known. Genome-wide association studies (GWAS), based on the ability to assay thousands of single nucleotide polymorphisms (SNPs), have revolutionized our understanding of the genetics of complex traits. We advocate the analysis of GWAS data by a statistical method that fits all SNP effects simultaneously, assuming that these effects are drawn from a prior distribution. We illustrate how this method can be used to predict future phenotypes, to map and identify the causal mutations, and to study the genetic architecture of complex traits. The genetic architecture of complex traits is even more complex than previously thought: in almost every trait studied there are thousands of polymorphisms that explain genetic variation. Methods of predicting future phenotypes, collectively known as genomic selection or genomic prediction, have been widely adopted in livestock and crop breeding, leading to increased rates of genetic improvement. PMID:27440663

  5. Polymorphic microsatellite markers in Anthoxanthum (Poaceae) and cross-amplification in the Eurasian complex of the genus1

    PubMed Central

    Lema-Suárez, Irene; Sahuquillo, Elvira; Marí-Mena, Neus; Pimentel, Manuel

    2016-01-01

    Premise of the study: Nonplastid microsatellite primers were developed for the first time in the Euro-Siberian complex of Anthoxanthum (Poaceae), a genus of temperate grasses in which reticulate evolution is common. Methods and Results: A microsatellite-enriched genomic DNA library allowed the detection of 500 fragments containing a microsatellite motif. Fifteen primer pairs were selected for an extended primer test. A preliminary analysis was conducted on the Eurasian diploid lineages of Anthoxanthum, with special emphasis on three populations of the Mediterranean A. aristatum–A. ovatum complex. Thirteen out of 15 markers tested were polymorphic in the complex, with successful cross-amplification in A. odoratum (93% polymorphic loci), A. amarum (73% polymorphic), A. alpinum (73% polymorphic), and A. maderense (60% polymorphic). Conclusions: These microsatellite markers will enable the analysis of evolution and phylogeography in diploid and polyploid lineages of this important genus. PMID:27785386

  6. Polymorphism and Balancing Selection at Major Histocompatibility Complex Loci

    PubMed Central

    Takahata, N.; Satta, Y.; Klein, J.

    1992-01-01

    Amino acid replacements in the peptide-binding region (PBR) of the functional major histocompatibility complex (Mhc) genes appear to be driven by balancing selection. Of the various types of balancing selection, we have examined a model equivalent to overdominance that confers heterozygote advantage. As discussed by A. Robertson, overdominance selection tends to maintain alleles that have more or less the same degree of heterozygote advantage. Because of this symmetry, the model makes various testable predictions about the genealogical relationships among different alleles and provides ways of analyzing DNA sequences of Mhc alleles. In this paper, we analyze DNA sequences of 85 alleles at the HLA-A, -B, -C, -DRB1 and -DQB1 loci with respect to the number of alleles and extent of nucleotide differences at the PBR, as well as at the synonymous (presumably neutral) sites. Theory suggests that the number of alleles that differ at the sites targeted by selection (presumably the nonsynonymous sites in the PBR) should be equal to the mean number of nucleotide substitutions among pairs of alleles. We also demonstrate that the nucleotide substitution rate at the targeted sites relative to that of neutral sites may be much larger than 1. The predictions of the presented model are in surprisingly good agreement with the actual data and thus provide means for inferring certain population parameters. For overdominance selection in a finite population at equilibrium, the product of selection intensity (s) against homozygotes and the effective population size (N) is estimated to be 350-3000, being largest at the B locus and smallest at the C locus. We argue that N is of the order of 10(5) and s is several percent at most, if the mutation rate per site per generation is 10(-8). PMID:1582567

  7. Insertion/deletion-related polymorphisms in the human T cell receptor beta gene complex

    PubMed Central

    1989-01-01

    Insertion/deletion related polymorphisms (IDRP) involving stretches of 15-30 kb within the human TCR-beta gene complex were revealed by pulse- field gel electrophoresis. Two independent IDRP systems were detected by analysis of Sfi I- and Sal I-digested human DNA samples using probes for TCR C and V region gene segments. The allelic nature of these systems was verified in family studies, and mapping data allowed localization of one area of insertion/deletion among the V gene segments and the other near the C region genes. All but one of 50 individuals tested could be typed for the two allelic systems, and gene frequencies for the two allelic forms were 0.37/0.61 and 0.46/0.54, indicating that these polymorphisms are widespread. PMID:2571667

  8. Functionalized active-nucleus complex sensor

    DOEpatents

    Pines, Alexander; Wemmer, David E.; Spence, Megan; Rubin, Seth

    2003-11-25

    A functionalized active-nucleus complex sensor that selectively associates with one or more target species, and a method for assaying and screening for one or a plurality of target species utilizing one or a plurality of functionalized active-nucleus complexes with at least two of the functionalized active-nucleus complexes having an attraction affinity to different corresponding target species. The functionalized active-nucleus complex has an active-nucleus and a targeting carrier. The method involves functionalizing an active-nucleus, for each functionalized active-nucleus complex, by incorporating the active-nucleus into a macromolucular or molecular complex that is capable of binding one of the target species and then bringing the macromolecular or molecular complexes into contact with the target species and detecting the occurrence of or change in a nuclear magnetic resonance signal from each of the active-nuclei in each of the functionalized active-nucleus complexes.

  9. The Same Major Histocompatibility Complex Polymorphism Involved in Control of HIV Influences Peptide Binding in the Mouse H-2Ld System*

    PubMed Central

    Narayanan, Samanthi; Kranz, David M.

    2013-01-01

    Single-site polymorphisms in human class I major histocompatibility complex (MHC) products (HLA-B) have recently been shown to correlate with HIV disease progression or control. An identical single-site polymorphism (at residue 97) in the mouse class I product H-2Ld influences stability of the complex. To gain insight into the human polymorphisms, here we examined peptide binding, stability, and structures of the corresponding Ld polymorphisms, Trp97 and Arg97. Expression of LdW97 and LdR97 genes in a cell line that is antigen-processing competent showed that LdR97 was expressed at higher levels than LdW97, consistent with enhanced stability of self-peptide·LdR97 complexes. To further examine peptide-binding capacities of these two allelic variants, we used a high affinity pep-Ld specific probe to quantitatively examine a collection of self- and foreign peptides that bind to Ld. LdR97 bound more effectively than LdW97 to most peptides, although LdW97 bound more effectively to two peptides. The results support the view that many self-peptides in the Ld system (or the HLA-B system) would exhibit enhanced binding to Arg97 alleles compared with Trp97 alleles. Accordingly, the self-peptide·MHC-Arg97 complexes would influence T-cell selection behavior, impacting the T-cell repertoire of these individuals, and could also impact peripheral T cell activity through effects of self-peptide·Ld interacting with TCR and/or CD8. The structures of several peptide·LdR97 and peptide·LdW97 complexes provided a framework of how this single polymorphism could impact peptide binding. PMID:24064213

  10. Effects of Lead Exposure and Genetic Polymorphisms on ALAD and GPx Activities in Brazilian Battery Workers.

    PubMed

    da Cunha Martins, Airton; Mazzaron Barcelos, Gustavo Rafael; Jacob Ferreira, Anna Laura Bechara; de Souza, Marilesia Ferreira; de Syllos Cólus, Ilce Mara; Antunes, Lusânia Maria Greggi; Bastos Paoliello, Monica Maria; Adeyemi, Joseph A; Barbosa, Fernando

    2015-01-01

    Lead (Pb) is a toxic metal that is widely used by metallurgical industries such as car battery recycling. Exposure to the metal may modify the redox status of the cells and consequently result in changes in activities of important enzymes such as delta-aminolevulinic acid dehydratase (ALAD) and glutathione peroxidase (GPx). Similarly, genetic polymorphisms may modulate the activities of enzymes related to detoxification processes of the metal and may modify Pb body burden. Therefore, the aims of the present study were (i) to evaluate the correlation between blood lead levels (BLL) and activities of the enzymes ALAD and GPx, and (ii) to determine whether activities of these enzymes may be influenced by polymorphisms in ALAD and GPx genes in Brazilian automotive battery workers chronically exposed to Pb, as well as the effects of these polymorphisms on BLL. Our study included 257 participants; BLL were determined by inductively couple plasma-mass spectrometry (ICP-MS), and the activities of the enzymes ALAD and GPx were quantified spectrophotometrically; and genotyping of ALAD (rs1800435) and GPx-1 (rs1800668) polymorphisms was performed by TaqMan assays (real-time polymerase chain reaction, RT-PCR). Significant negative correlations were found between BLL and ALAD activity. Subjects who carried at least one polymorphic allele for ALAD gene displayed markedly lower ALAD activities, while no significant effect was observed regarding GPx-1 polymorphism and activity of the same enzyme. Further, ALAD and GPx-1 polymorphisms exerted no marked influence on BLL. Taken together, our results showed that BLL affected ALAD but not GPx activities, and these were not modulated by polymorphisms in ALAD and GPx gene. Further, the rs1800435 SNP showed a tendency to modulate ALAD activity, while the rs1800668 SNP did not modulate GPx activity in Brazilian automotive battery workers exposed to Pb.

  11. COIL: a methodology for evaluating malarial complexity of infection using likelihood from single nucleotide polymorphism data.

    PubMed

    Galinsky, Kevin; Valim, Clarissa; Salmier, Arielle; de Thoisy, Benoit; Musset, Lise; Legrand, Eric; Faust, Aubrey; Baniecki, Mary Lynn; Ndiaye, Daouda; Daniels, Rachel F; Hartl, Daniel L; Sabeti, Pardis C; Wirth, Dyann F; Volkman, Sarah K; Neafsey, Daniel E

    2015-01-19

    Complex malaria infections are defined as those containing more than one genetically distinct lineage of Plasmodium parasite. Complexity of infection (COI) is a useful parameter to estimate from patient blood samples because it is associated with clinical outcome, epidemiology and disease transmission rate. This manuscript describes a method for estimating COI using likelihood, called COIL, from a panel of bi-allelic genotyping assays. COIL assumes that distinct parasite lineages in complex infections are unrelated and that genotyped loci do not exhibit significant linkage disequilibrium. Using the population minor allele frequency (MAF) of the genotyped loci, COIL uses the binomial distribution to estimate the likelihood of a COI level given the prevalence of observed monomorphic or polymorphic genotypes within each sample. COIL reliably estimates COI up to a level of three or five with at least 24 or 96 unlinked genotyped loci, respectively, as determined by in silico simulation and empirical validation. Evaluation of COI levels greater than five in patient samples may require a very large collection of genotype data, making sequencing a more cost-effective approach for evaluating COI under conditions when disease transmission is extremely high. Performance of the method is positively correlated with the MAF of the genotyped loci. COI estimates from existing SNP genotype datasets create a more detailed portrait of disease than analyses based simply on the number of polymorphic genotypes observed within samples. The capacity to reliably estimate COI from a genome-wide panel of SNP genotypes provides a potentially more accurate alternative to methods relying on PCR amplification of a small number of loci for estimating COI. This approach will also increase the number of applications of SNP genotype data, providing additional motivation to employ SNP barcodes for studies of disease epidemiology or control measure efficacy. The COIL program is available for download

  12. Structure and polymorphisms of the major histocompatibility complex in the Oriental stork, Ciconia boyciana

    PubMed Central

    Tsuji, Hiroki; Taniguchi, Yukio; Ishizuka, Shintaro; Matsuda, Hirokazu; Yamada, Takahisa; Naito, Kazuaki; Iwaisaki, Hiroaki

    2017-01-01

    The major histocompatibility complex (MHC) is highly polymorphic and plays a central role in the vertebrate immune system. Despite its functional consistency, the MHC genomic structure differs substantially among organisms. In birds, the MHCs of Galliformes and the Japanese crested ibis (Pelecaniformes) are well-characterized, but information about other avian MHCs remains scarce. The Oriental stork (Ciconia boyciana, order Ciconiiformes) is a large endangered migrant. The current Japanese population of this bird originates from a few founders; thus, understanding the genetic diversity among them is critical for effective population management. We report the structure and polymorphisms in C. boyciana MHC. One contig (approximately 128 kb) was assembled by screening of lambda phage genomic library and its complete sequence was determined, revealing a gene order of COL11A2, two copies of MHC-IIA/IIB pairs, BRD2, DMA/B1/B2, MHC-I, TAP1/2, and two copies each of pseudo MHC-I and TNXB. This structure was highly similar to that of the Japanese crested ibis, but largely different from that of Galliformes, at both the terminal regions. Genotyping of the MHC-II region detected 10 haplotypes among the six founders. These results provide valuable insights for future studies on the evolution of the avian MHCs and for conservation of C. boyciana. PMID:28211522

  13. Crystal polymorphism of (μ4-O)-body centered adamantanoid Cu(II) complexes

    NASA Astrophysics Data System (ADS)

    Olijnyk, V.; Zarychta, B.

    2016-02-01

    Two novel polymorphs of [Cu4(μ4-O)(μ-Cl)6(DASO)4], (DASO = diallyl sulfoxide; C6H10OS), rhombic (C) and triclinic (D), were obtained and examined by single crystal X-ray diffraction analysis at two temperatures, 295(2) and 100(1) K. This study, in addition to our recent work on the tetragonal (A) and trigonal (B) forms of the title compound, allowed determining the nature of polymorphism and temperature-induced phase transitions. It is stated that both the packing arrangement and the displacive transformation integrate these structures, forming the symmetrically and thermodynamically related series: A,B → C → D. The C3h → C4 distortion of Cu(II) trigonal bipyramidal coordination geometry underlies the static disorder of adamantanoid cage, resulting in the thermal order-disorder phase transition. The square-pyramidal distortion degree as well as the disorder rate may be crucial for anomalous magnetic behaviour of (μ4-O)-body centered adamantanoid Cu(II) complexes.

  14. Structure and polymorphisms of the major histocompatibility complex in the Oriental stork, Ciconia boyciana.

    PubMed

    Tsuji, Hiroki; Taniguchi, Yukio; Ishizuka, Shintaro; Matsuda, Hirokazu; Yamada, Takahisa; Naito, Kazuaki; Iwaisaki, Hiroaki

    2017-02-17

    The major histocompatibility complex (MHC) is highly polymorphic and plays a central role in the vertebrate immune system. Despite its functional consistency, the MHC genomic structure differs substantially among organisms. In birds, the MHCs of Galliformes and the Japanese crested ibis (Pelecaniformes) are well-characterized, but information about other avian MHCs remains scarce. The Oriental stork (Ciconia boyciana, order Ciconiiformes) is a large endangered migrant. The current Japanese population of this bird originates from a few founders; thus, understanding the genetic diversity among them is critical for effective population management. We report the structure and polymorphisms in C. boyciana MHC. One contig (approximately 128 kb) was assembled by screening of lambda phage genomic library and its complete sequence was determined, revealing a gene order of COL11A2, two copies of MHC-IIA/IIB pairs, BRD2, DMA/B1/B2, MHC-I, TAP1/2, and two copies each of pseudo MHC-I and TNXB. This structure was highly similar to that of the Japanese crested ibis, but largely different from that of Galliformes, at both the terminal regions. Genotyping of the MHC-II region detected 10 haplotypes among the six founders. These results provide valuable insights for future studies on the evolution of the avian MHCs and for conservation of C. boyciana.

  15. A complex dominance hierarchy is controlled by polymorphism of small RNAs and their targets.

    PubMed

    Yasuda, Shinsuke; Wada, Yuko; Kakizaki, Tomohiro; Tarutani, Yoshiaki; Miura-Uno, Eiko; Murase, Kohji; Fujii, Sota; Hioki, Tomoya; Shimoda, Taiki; Takada, Yoshinobu; Shiba, Hiroshi; Takasaki-Yasuda, Takeshi; Suzuki, Go; Watanabe, Masao; Takayama, Seiji

    2016-12-22

    In diploid organisms, phenotypic traits are often biased by effects known as Mendelian dominant-recessive interactions between inherited alleles. Phenotypic expression of SP11 alleles, which encodes the male determinants of self-incompatibility in Brassica rapa, is governed by a complex dominance hierarchy(1-3). Here, we show that a single polymorphic 24 nucleotide small RNA, named SP11 methylation inducer 2 (Smi2), controls the linear dominance hierarchy of the four SP11 alleles (S44 > S60 > S40 > S29). In all dominant-recessive interactions, small RNA variants derived from the linked region of dominant SP11 alleles exhibited high sequence similarity to the promoter regions of recessive SP11 alleles and acted in trans to epigenetically silence their expression. Together with our previous study(4), we propose a new model: sequence similarity between polymorphic small RNAs and their target regulates mono-allelic gene expression, which explains the entire five-phased linear dominance hierarchy of the SP11 phenotypic expression in Brassica.

  16. Ancient, highly polymorphic human major histocompatibility complex DQA1 intron sequence

    SciTech Connect

    McGinnis, M.D.; Quinn, D.L.; Lebo, R.V.; Simons, M.J.

    1994-10-01

    A 438 basepair intron 1 sequence adjacent to exon 2 in the human major histocompatibility complex DQA1 gene defined 16 allelic variants in 69 individuals from wide ethnic backgrounds. In contrast, the most variable coding region spanned by the 247 basepair exon 2 defined 11 allelic variants. Our phylogenetic human intron 1 tree derived by the Bootstrap algorithm reflects the same relative allelic relationships as the reported DQA1 exon 2 have cosegregated since divergence of the human races. Comparison of human alleles to a Rhesus monkey DQA1 first intron sequence found only 10 nucleotide substitutions unique to Rhesus, with the other 428 positions (98%) found in at least one human allele. This high degree of homology reflects the evolutionary stability of intron sequences since these two species diverged over 20 million years ago. Because more intron 1 alleles exist than exon 2 alleles, these polymorphic introns can be used to improve tissue typing for transplantation, paternity testing, and forensics and to derive more complete phylogenetic trees. These results suggest that introns represent a previously underutilized polymorphic resource. 42 refs., 3 figs., 1 tab.

  17. Synthesis and polymorphic control for visible light active titania nanoparticles

    NASA Astrophysics Data System (ADS)

    Kaewgun, Sujaree

    Titania (TiO2) is useful for many applications in photocatalysis, antimicrobials, pigment, deodorization, and decomposition of harmful organics and undesirable compounds in the air and waste water under UV irradiation. Among the three phases of TiO2, Rutile, Anatase, and Brookite, studies have been more focused on the anatase and rutile phases. Pure brookite is the most difficult phase to prepare, even under hydrothermal conditions. Predominantly brookite phase TiO2 nanoparticles were prepared by the Water-based Ambient Condition Sol (WACS) process in our laboratory. The objectives of this research were to enhance visible light active (VLA) photocatalytic properties of polymorphic brookite TiO2 by minimizing the lattice defects and narrowing band gap of titania by nitrogen and/or carbon chromophone, and to investigate the deactivation, reusability, and regeneration of the VLA titania in order to design better titania catalysts for organic compound degradation applications. In order to study the influence of hydroxyl content on photocatalytic activities (PCAs) of polymorphic titania nanoparticles, the WACS samples were post-treated by a Solvent-based Ambient Condition Sol (SACS) process in sec-butanol (sec-BuOH). All samples were characterized for phase composition, surface area, hydroxyl contamination, and particle morphology by x-ray diffraction, N2 physisorption, FT-IR, solid state 1H NMR and scanning electron microscopy, and then compared to a commercial titania, Degussa P25. Evaluation of methyl orange (MO) degradation under UV irradiation results showed that the lower lattice hydroxyl content in SACS titania enhanced the PCA. As-prepared titania and SACS samples, which have similar surface areas and crystallinity, were compared in order to prove that the superior PCA came from the reduction in the lattice hydroxyl content. To enhance PCA and VLA properties of WACS, an alternative high boiling point polar solvent, N-methylpyrrolidone (NMP), was utilized in the

  18. Polymorphisms in SIGLEC1 contribute to susceptibility to pulmonary active tuberculosis possibly through the modulation of IL-1ß.

    PubMed

    Souza de Lima, Dhemerson; Nunes, Vinicius C L; Ogusku, Mauricio M; Sadahiro, Aya; Pontillo, Alessandra; Alencar, Bruna de Cunha

    2017-09-28

    Siglec-1/CD169 is a sialoadhesin expressed by macrophages thought to function in cell-to-cell interactions. In the lung, the expression of Siglec-1 is specific for alveolar macrophages and single nucleotide polymorphisms (SNPs) in SIGLEC1 have been recently associated with asthma severity. Taking in account the role of alveolar macrophages in the control of M. tuberculosis and the poor literature about the contribution of SIGLEC1 genetics in M. tuberculosis susceptibility and development of pulmonary active TB, selected SNPs in SIGLEC1 were analysed in a case/control cohort from a TB endemic area of Brazil Amazon. Our findings evidenced for the first time the novel association between SIGLEC1 rs3859664 SNP and active pulmonary TB. Intriguingly, carriers of the polymorphism produced less IL-1ß than non-carriers, suggesting the possible involvement of Siglec-1 signalling pathway with inflammasome complex. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. 4th International Meeting on Single Nucleotide Polymorphism and Complex Genome Analysis. Various uses for DNA variations.

    PubMed

    Brookes, Anthony J

    2002-02-01

    At the 4th International Meeting on Single Nucleotide Polymorphism and Complex Genome Analysis (Stockholm, Sweden, 10th-14th October 2001), approximately 100 scientists from more than 20 nations undertook a probing review of latest developments in the field. Despite impressive and still ongoing activities towards SNP discovery and validation, plus efforts towards haplotype exploitation, it was clear that supporting technologies for genotyping are way behind where they need to be. Innate complexity and large variances in aspects of genome function together pose immense challenges that are difficult to surmount in the human situation. In contrast, studies in simpler organisms and population/evolutionary genetics studies are yielding important new insights. Breakthroughs that are being made in understanding the genetic etiology of complex disease tend to involve genes of larger effect or extremely well merited candidates. Linkage studies and proximal phenotypes are being recommended, though the best way forward is still hotly debated. Consequently, many diverse and ambitious projects are underway, from which the data itself will eventually show what is and is not possible.

  20. Polymorphism Interaction Analysis (PIA): a method for investigating complex gene-gene interactions

    PubMed Central

    Mechanic, Leah E; Luke, Brian T; Goodman, Julie E; Chanock, Stephen J; Harris, Curtis C

    2008-01-01

    Background The risk of common diseases is likely determined by the complex interplay between environmental and genetic factors, including single nucleotide polymorphisms (SNPs). Traditional methods of data analysis are poorly suited for detecting complex interactions due to sparseness of data in high dimensions, which often occurs when data are available for a large number of SNPs for a relatively small number of samples. Validation of associations observed using multiple methods should be implemented to minimize likelihood of false-positive associations. Moreover, high-throughput genotyping methods allow investigators to genotype thousands of SNPs at one time. Investigating associations for each individual SNP or interactions between SNPs using traditional approaches is inefficient and prone to false positives. Results We developed the Polymorphism Interaction Analysis tool (PIA version 2.0) to include different approaches for ranking and scoring SNP combinations, to account for imbalances between case and control ratios, stratify on particular factors, and examine associations of user-defined pathways (based on SNP or gene) with case status. PIA v. 2.0 detected 2-SNP interactions as the highest ranking model 77% of the time, using simulated data sets of genetic models of interaction (minor allele frequency = 0.2; heritability = 0.01; N = 1600) generated previously [Velez DR, White BC, Motsinger AA, Bush WS, Ritchie MD, Williams SM, Moore JH: A balanced accuracy function for epistasis modeling in imbalanced datasets using multifactor dimensionality reduction. Genet Epidemiol 2007, 31:306–315.]. Interacting SNPs were detected in both balanced (20 SNPs) and imbalanced data (case:control 1:2 and 1:4, 10 SNPs) in the context of non-interacting SNPs. Conclusion PIA v. 2.0 is a useful tool for exploring gene*gene or gene*environment interactions and identifying a small number of putative associations which may be investigated further using other statistical methods

  1. Melanin-concentrating hormone receptor 1 polymorphisms are associated with components of energy balance in the Complex Diseases in the Newfoundland Population: Environment and Genetics (CODING) study.

    PubMed

    Fontaine-Bisson, Bénédicte; Thorburn, James; Gregory, Anne; Zhang, Hongwei; Sun, Guang

    2014-02-01

    The melanin-concentrating hormone receptor 1 (MCHR1) is a G protein-coupled receptor that regulates energy balance and body composition in animal models. Inconsistent effects of MCHR1 polymorphisms on energy homeostasis in humans may partly be attributable to environmental factors. We examined the effect of 4 single nucleotide polymorphisms (rs133073, rs133074, rs9611386, and rs882111) in the MCHR1 gene on body composition as well as energy-related lifestyle factors (diet and physical activity). We also examined the effect of gene-lifestyle interactions on body composition. A total of 1153 participants (248 men and 905 women) from the cross-sectional Complex Diseases in the Newfoundland Population: Environment and Genetics (CODING) study were genotyped by using probe-based chemistry validated assays. Diet and physical activity were estimated by using validated frequency questionnaires, and body composition was assessed by using dual-energy X-ray absorptiometry. Three polymorphisms (rs9611386, rs882111, and rs133073) were associated with differences in body-composition measurements (all P < 0.05). There was an interaction between rs9611386 and carbohydrate intake on total mass and waist circumference (both P ≤ 0.01). There was also an interaction between rs9611386 and body mass index categories (normal weight, overweight, and obese) on energy intakes (P = 0.02). A similar interaction was shown with rs882111 (P = 0.02). Interactions were also observed between each of these polymorphisms (rs9611386, rs882111, and rs133073) and physical activity score on body-composition measurements (all P < 0.05). These findings suggest that polymorphisms in the MCHR1 gene are associated with differences in body composition and interact with physiologic and energy-related lifestyle factors.

  2. Bladder exstrophy-epispadias complex and the role of methylenetetrahydrofolate reductase C677T polymorphism: A case control study

    PubMed Central

    Raman, Venkat Shankar; Bajpai, Minu; Ali, Abid

    2016-01-01

    Purpose: The Bladder Exstrophy-Epispadias Complex (BEEC) is the most serious form of midline abdominal malformation. The etiology of BEEC is unknown and is thought to be multifactorial. Methylenetetrahydrofolate reductase (MTHFR) polymorphism C677T is strongly associated with other midline abnormalities such as neural tube defects. No proper case-control study existed comparing MTHFR polymorphism with BEEC. We sought to find an association with MTHFR polymorphism and patients with bladder exstrophy (BE). Materials and Methods: The design of the study was a case-control study, involving 50 children with BEEC and 50 normal healthy school children. Genetic analysis for MTHFR 677 polymorphism was carried out after DNA extraction and polymerase chain reaction amplification. Epidemiological analysis was done by using the birth defect questionnaire on parents of BEEC. Results: Forty-two classical BE, two cloacal exstrophies (CE), four epispadias, and two exstrophy variant patients were a part of this study. Severe variety of BE had a significant association with C667T MTHFR polymorphism as compared to the normal control population (P = 0.01). Conclusion: C677T MTHFR polymorphism has a strong association with severe variety (CE) of BEEC occurrence. PMID:26862292

  3. Active impedance matching of complex structural systems

    NASA Technical Reports Server (NTRS)

    Macmartin, Douglas G.; Miller, David W.; Hall, Steven R.

    1991-01-01

    Viewgraphs on active impedance matching of complex structural systems are presented. Topics covered include: traveling wave model; dereverberated mobility model; computation of dereverberated mobility; control problem: optimal impedance matching; H2 optimal solution; statistical energy analysis (SEA) solution; experimental transfer functions; interferometer actuator and sensor locations; active strut configurations; power dual variables; dereverberation of complex structure; dereverberated transfer function; compensators; and relative power flow.

  4. Polymorphisms in DNA Repair Genes, Recreational Physical Activity and Breast Cancer Risk

    PubMed Central

    McCullough, Lauren E.; Santella, Regina M.; Cleveland, Rebecca J.; Millikan, Robert C.; Olshan, Andrew F.; North, Kari E.; Bradshaw, Patrick T.; Eng, Sybil M.; Terry, Mary Beth; Shen, Jing; Crew, Katherine D.; Rossner, Pavel; Teitelbaum, Susan L.; Neugut, Alfred I.; Gammon, Marilie D.

    2013-01-01

    The mechanisms driving the inverse association between recreational physical activity (RPA) and breast cancer risk are complex. While exercise is associated with increased reactive oxygen species production it may also improve damage repair systems, particularly those that operate on single-strand breaks including base excision repair (BER), nucleotide excision repair (NER) and mismatch repair (MMR). Of these repair pathways, the role of MMR in breast carcinogenesis is least investigated. Polymorphisms in MMR or other DNA repair gene variants may modify the association between RPA and breast cancer incidence. We investigated the individual and joint effects of variants in three MMR pathway genes (MSH3, MLH1 and MSH2) on breast cancer occurrence using resources from the Long Island Breast Cancer Study Project. We additionally characterized interactions between RPA and genetic polymorphisms in MMR, BER and NER pathways. We found statistically significant multiplicative interactions (p<0.05) between MSH2 and MLH1, as well as between postmenopausal RPA and four variants in DNA repair (XPC-Ala499Val, XPF-Arg415Gln, XPG-Asp1104His and MLH1-lle219Val). Significant risk reductions were observed among highly active women with the common genotype for XPC (OR=0.54; 95% CI, 0.36–0.81) and XPF (OR=0.62; 95% CI, 0.44–0.87), as well as among active women who carried at least one variant allele in XPG (OR=0.46; 95% CI, 0.29–0.77) and MLH1 (OR=0.46; 95% CI, 0.30–0.71). Our data show that women with minor alleles in both MSH2 and MLH1 could be at increased breast cancer risk. RPA may be modified by genes in the DNA repair pathway, and merit further investigation. PMID:23852586

  5. Interleukin-21 gene polymorphism rs2221903 is associated with disease activity in patients with rheumatoid arthritis

    PubMed Central

    Malinowski, Damian; Paradowska-Gorycka, Agnieszka; Safranow, Krzysztof

    2017-01-01

    Introduction Interleukin-21 (IL-21) is a cytokine which plays a significant role in the pathogenesis and disease activity of rheumatoid arthritis (RA). Genetic polymorphisms in the IL-21 gene may alter the synthesis of IL-21. The aim of this study was to examine IL-21 and IL-21R polymorphisms in patients with RA. Material and methods We examined 422 patients with RA and 338 healthy controls. Single nucleotide polymorphisms (SNPs) within the IL-21 (rs6822844 G>T, rs6840978 C>T, rs2221903 T>C) and IL-21R (rs2285452 G>A) genes were genotyped using TaqMan genotyping assays. Results There were no statistically significant differences in the distribution of studied genotypes and alleles between RA patients and the control group. To examine whether IL-21 polymorphisms affect disease activity in RA patients, we compared the distribution of IL-21 genotypes between patients with DAS28 ≤ 2.5 (patients with remission of disease symptoms) and patients with DAS28 > 2.5 (patients with active RA). Among patients with DAS28 > 2.5, increased prevalence of rs2221903 CT and CC genotypes was observed (OR = 1.54; 95% CI: 1.04–2.28; p = 0.035). Conclusions The results of this study suggest that IL-21 and IL-21R gene polymorphisms are not risk loci for RA susceptibility, whereas the IL-21 rs2221903 polymorphism is associated with disease activity. PMID:28883856

  6. Interleukin-21 gene polymorphism rs2221903 is associated with disease activity in patients with rheumatoid arthritis.

    PubMed

    Malinowski, Damian; Paradowska-Gorycka, Agnieszka; Safranow, Krzysztof; Pawlik, Andrzej

    2017-08-01

    Interleukin-21 (IL-21) is a cytokine which plays a significant role in the pathogenesis and disease activity of rheumatoid arthritis (RA). Genetic polymorphisms in the IL-21 gene may alter the synthesis of IL-21. The aim of this study was to examine IL-21 and IL-21R polymorphisms in patients with RA. We examined 422 patients with RA and 338 healthy controls. Single nucleotide polymorphisms (SNPs) within the IL-21 (rs6822844 G>T, rs6840978 C>T, rs2221903 T>C) and IL-21R (rs2285452 G>A) genes were genotyped using TaqMan genotyping assays. There were no statistically significant differences in the distribution of studied genotypes and alleles between RA patients and the control group. To examine whether IL-21 polymorphisms affect disease activity in RA patients, we compared the distribution of IL-21 genotypes between patients with DAS28 ≤ 2.5 (patients with remission of disease symptoms) and patients with DAS28 > 2.5 (patients with active RA). Among patients with DAS28 > 2.5, increased prevalence of rs2221903 CT and CC genotypes was observed (OR = 1.54; 95% CI: 1.04-2.28; p = 0.035). The results of this study suggest that IL-21 and IL-21R gene polymorphisms are not risk loci for RA susceptibility, whereas the IL-21 rs2221903 polymorphism is associated with disease activity.

  7. Genomic polymorphism, recombination, and linkage disequilibrium in human major histocompatibility complex-encoded antigen-processing genes

    SciTech Connect

    van Endert, P.M.; Lopez, M.T.; Patel, S.D.; McDevitt, H.O. ); Monaco, J.J. )

    1992-12-01

    Recently, two subunits of a large cytosolic protease and two putative peptide transporter proteins were found to be encoded by genes within the class II region of the major histocompatibility complex (MHC). These genes have been suggested to be involved in the processing of antigenic proteins for presentation by MHC class I molecules. Because of the high degree of polymorphism in MHC genes, and previous evidence for both functional and polypeptide sequence polymorphism in the proteins encoded by the antigen-processing genes, we tested DNA from 27 consanguineous human cell lines for genomic polymorphism by restriction fragment length polymorphism (RFLP) analysis. These studies demonstrate a strong linkage disequilibrium between TAP1 and LMP2 RFLPs. Moreover, RFLPs, as well as a polymorphic stop codon in the telomeric TAP2 gene, appear to be in linkage disequilibrium with HLA-DR alleles and RFLPs in the HLA-DO gene. A high rate of recombination, however, seems to occur in the center of the complex, between the TAP1 and TAP2 genes.

  8. Mineralogical characteristics of the silica polymorphs in relation to their biological activities

    SciTech Connect

    Guthrie, G.D. Jr.; Heaney, P.J.

    1993-10-01

    Numerous aspects of minerals (including the silica polymorphs) can effect their biological activities. These include periodic structures, compositional variations, dissolution characteristics, surface properties, and particle size/shape. In order to understand mineral-induced pathogenesis in a mechanistic way, the links between these properties and biochemical processes must be elucidated. This paper presents some of the basic properties of the silica polymorphs that may relate to pathogenicity and mineralogical strategies for designing biological assays to evaluate these properties.

  9. A molecular perspective on a complex polymorphic inversion system with cytological evidence of multiply reused breakpoints.

    PubMed

    Orengo, D J; Puerma, E; Papaceit, M; Segarra, C; Aguadé, M

    2015-06-01

    Genome sequence comparison across the Drosophila genus revealed that some fixed inversion breakpoints had been multiply reused at this long timescale. Cytological studies of Drosophila inversion polymorphism had previously shown that, also at this shorter timescale, some breakpoints had been multiply reused. The paucity of molecularly characterized polymorphic inversion breakpoints has so far precluded contrasting whether cytologically shared breakpoints of these relatively young inversions are actually reused at the molecular level. The E chromosome of Drosophila subobscura stands out because it presents several inversion complexes. This is the case of the E1+2+9+3 arrangement that originated from the ancestral Est arrangement through the sequential accumulation of four inversions (E1, E2, E9 and E3) sharing some breakpoints. We recently identified the breakpoints of inversions E1 and E2, which allowed establishing reuse at the molecular level of the cytologically shared breakpoint of these inversions. Here, we identified and sequenced the breakpoints of inversions E9 and E3, because they share breakpoints at sections 58D and 64C with those of inversions E1 and E2. This has allowed establishing that E9 and E3 originated through the staggered-break mechanism. Most importantly, sequence comparison has revealed the multiple reuse at the molecular level of the proximal breakpoint (section 58D), which would have been used at least by inversions E2, E9 and E3. In contrast, the distal breakpoint (section 64C) might have been only reused once by inversions E1 and E2, because the distal E3 breakpoint is displaced >70 kb from the other breakpoint limits.

  10. A molecular perspective on a complex polymorphic inversion system with cytological evidence of multiply reused breakpoints

    PubMed Central

    Orengo, D J; Puerma, E; Papaceit, M; Segarra, C; Aguadé, M

    2015-01-01

    Genome sequence comparison across the Drosophila genus revealed that some fixed inversion breakpoints had been multiply reused at this long timescale. Cytological studies of Drosophila inversion polymorphism had previously shown that, also at this shorter timescale, some breakpoints had been multiply reused. The paucity of molecularly characterized polymorphic inversion breakpoints has so far precluded contrasting whether cytologically shared breakpoints of these relatively young inversions are actually reused at the molecular level. The E chromosome of Drosophila subobscura stands out because it presents several inversion complexes. This is the case of the E1+2+9+3 arrangement that originated from the ancestral Est arrangement through the sequential accumulation of four inversions (E1, E2, E9 and E3) sharing some breakpoints. We recently identified the breakpoints of inversions E1 and E2, which allowed establishing reuse at the molecular level of the cytologically shared breakpoint of these inversions. Here, we identified and sequenced the breakpoints of inversions E9 and E3, because they share breakpoints at sections 58D and 64C with those of inversions E1 and E2. This has allowed establishing that E9 and E3 originated through the staggered-break mechanism. Most importantly, sequence comparison has revealed the multiple reuse at the molecular level of the proximal breakpoint (section 58D), which would have been used at least by inversions E2, E9 and E3. In contrast, the distal breakpoint (section 64C) might have been only reused once by inversions E1 and E2, because the distal E3 breakpoint is displaced >70 kb from the other breakpoint limits. PMID:25712227

  11. Use of functional polymorphisms to elucidate the peptide binding site of TAP complexes

    PubMed Central

    Geng, Jie; Pogozheva, Irina D.; Mosberg, Henry I.; Raghavan, Malini

    2015-01-01

    The transporter associated with antigen processing (TAP) translocates peptides from the cytosol to the endoplasmic reticulum (ER) lumen to enable immune surveillance by CD8+ T cells. Peptide transport is preceded by peptide binding to a cytosol-accessible surface of TAP1/TAP2 complexes, but the location of the TAP peptide-binding pocket remains unknown. Guided by the known contributions of polymorphic TAP variants to peptide selection, we combined homology modeling of TAP with experimental measurements to identify several TAP residues that interact with peptides. Models for peptide-TAP complexes were generated, which indicate bent conformation for peptides. The peptide-binding site of TAP is located at the hydrophobic boundary of the cytosolic membrane leaflet, with striking parallels to the glutathione binding site of NaAtm1, a transporter that functions in bacterial heavy metal detoxification. These studies illustrate the conservation of the ligand recognition modes of bacterial and mammalians transporters involved in peptide-guided cellular surveillance. PMID:26324772

  12. Surface character and membranolytic activity of rutile and anatase: two titanium dioxide polymorphs.

    PubMed Central

    Nolan, R P; Langer, A M; Weisman, I; Herson, G B

    1987-01-01

    Biological studies of two titanium dioxide polymorphs, rutile and anatase, have produced conflicting results. Generally, the in vivo and in vitro methods used to evaluate pneumoconiotic dusts have shown the polymorphs to be inert, but occasionally both minerals have been reported to produce effects consistent with biologically active minerals. Many of these reports failed to specify which polymorph was used experimentally. While this limited the value of the data, the problem was further compounded by the variation in the surface properties of each polymorph depending on whether the specimen was a naturally occurring mineral or was made synthetically. Five naturally occurring and 11 synthetically produced titanium dioxide specimens were studied. The physical characterisation of each specimen entailed the determination of the polymorph type(s) by continuous scan x ray diffraction and the size distribution by transmission electron microscopy. The ability of each specimen to lyse erythrocytes was determined and compared with quartz. Only two, both synthetic rutiles, were found to be active. The hydrogen bonding ability of the surfaces of these rutiles were compared with inert rutile and quartz. The binding properties of the active rutile have been found to be consistent with those properties associated with biologically active quartz. The surface properties of rutile are the determinants of its activity. Because natural and synthetic rutiles possess different surface properties, they display different activities. Images PMID:3676122

  13. Polymorphism of a complex resistance gene candidate family in wild populations of common bean (Phaseolus vulgaris) in Argentina: comparison with phenotypic resistance polymorphism.

    PubMed

    De Meaux, J; Cattan-Toupance, I; Lavigne, C; Langin, T; Neema, C

    2003-01-01

    Fifteen populations of wild bean (Phaseolus vulgaris), located in three provinces in Argentina, were analysed for their polymorphism for a complex resistance gene candidate (RGC) family clustered on the genome and for resistance phenotypes to strains of Colletotrichum lindemuthianum. Results indicate that RGC polymorphism is high. Population structure obtained for markers related to resistance was compared to population structure obtained for RAPD markers in order to infer the evolutionary forces driving polymorphism for resistance in wild populations at both molecular and phenotypic levels. Hierarchical analysis of differentiation showed that, within provinces, populations were differentiated for RAPD as well as for molecular and phenotypic markers of resistance. In contrast, provinces were differentiated only for RAPD and RGC markers and not for resistance phenotypes. The discrepancies found between diversity structures for molecular markers (RAPD and RGCs) and for resistance phenotypes suggest an effect of selection and indicate that diversity for resistance may not be driven by the same selective forces at the molecular and phenotypic levels. We further discuss whether specific selective forces are exerted on RGC markers and underline the importance of spatial scale of analysis for demonstrating an impact of selection.

  14. Extensive polymorphism of the major histocompatibility complex DRA gene in Balkan donkeys: perspectives on selection and genealogy.

    PubMed

    Arbanasić, Haidi; Galov, Ana; Ambriović-Ristov, Andreja; Grizelj, Juraj; Arsenos, Georgios; Marković, Božidarka; Dovenski, Toni; Vince, Silvijo; Curik, Ino

    2013-12-01

    The major histocompatibility complex (MHC) contains genes important for immune response in mammals, and these genes exhibit high polymorphism and diversity. The DRA gene, a member of the MHC class II family, is highly conserved across a large number of mammalian species, but it displays exceptionally rich sequence variations in Equidae members. We analyzed allelic polymorphism of the DRA locus in 248 donkeys sampled across the Balkan Peninsula (Albania, Bulgaria, Croatia, Macedonia, Greece and Montenegro). Five known alleles and two new alleles were identified. The new allele Eqas-DRA*0601 was found to carry a synonymous mutation, and new allele Eqas-DRA*0701, a non-synonymous mutation. We further analyzed the historical selection and allele genealogy at the DRA locus in equids. Signals of positive selection obtained by various tests were ambiguous. A conservative conclusion is that DRA polymorphism occurred relatively recently and that positive selection has been acting on the DRA locus for a relatively brief period.

  15. Role of peroxisome proliferator-activated receptors gene polymorphisms in type 2 diabetes and metabolic syndrome.

    PubMed

    Dong, Chen; Zhou, Hui; Shen, Chong; Yu, Lu-Gang; Ding, Yi; Zhang, Yong-Hong; Guo, Zhi-Rong

    2015-05-15

    Metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) are the serious public health problems worldwide. Moreover, it is estimated that MetS patients have about five-fold greater risk of the T2DM development compared with people without the syndrome. Peroxisome proliferator-activated receptors are a subgroup of the nuclear hormone receptor superfamily of ligand-activated transcription factors which play an important role in the pathogenesis of MetS and T2DM. All three members of the peroxisome proliferator-activated receptor (PPAR) nuclear receptor subfamily, PPARα, PPARβ/δ and PPARγ are critical in regulating insulin sensitivity, adipogenesis, lipid metabolism, and blood pressure. Recently, more and more studies indicated that the gene polymorphism of PPARs, such as Leu(162)Val and Val(227)Ala of PPARα, +294T > C of PPARβ/δ, Pro(12)Ala and C1431T of PPARγ, are significantly associated with the onset and progressing of MetS and T2DM in different population worldwide. Furthermore, a large body of evidence demonstrated that the glucose metabolism and lipid metabolism were influenced by gene-gene interaction among PPARs genes. However, given the complexity pathogenesis of metabolic disease, it is unlikely that genetic variation of a single locus would provide an adequate explanation of inter-individual differences which results in diverse clinical syndromes. Thus, gene-gene interactions and gene-environment interactions associated with T2DM and MetS need future comprehensive studies.

  16. Plasminogen activator inhibitor-1 activity and 4G/5G polymorphism in hemodialysis.

    PubMed

    Trimarchi, H; Duboscq, C; Genoud, V; Lombi, F; Muryan, A; Young, P; Schwab, M; Castanon, M; Rodriguez-Reimundes, E; Forrester, M; Pereyra, H; Campolo-Girard, V; Seminario, O; Alonso, M; Kordich, L

    2008-01-01

    Chronic insufficiency alters homeostasis, in part due to endothelial inflammation. Plasminogen activator inhibitor-1 (PAI-1) is increased in renal disease, contributing to vascular damage. We assessed PAI-1 activity and PAI-1 4G/5G polymorphism in hemodialysis (HD) subjects and any association between thrombotic vascular access (VA) events and PAI-1 polymorphism. Prospective, observational study in 36 HD patients: mean age: 66.6 +/- 12.5 yr, males n=26 (72%), time on HD: 28.71 +/- 22.45 months. Vascular accesses: 10 polytetrafluoroethylene grafts (PTFEG), 22 arteriovenous fistulae (AVF), four dual lumen catheters (CAT). Control group (CG): 40 subjects; mean age: 60.0 +/- 15 yrs, males n=30 (75%). Group A (GA): thrombotic events (n=12), and group B (GB): No events (n=24). Groups were no different according to age (69.2 +/- 9.12 vs. 65.3 +/- 14.5 yrs), gender (males: 7; 58.3% vs. 18; 81.8%), time on HD (26.1 +/- 14.7 vs. 30.1 +/- 38.7 months), causes of renal failure. Time to follow-up for access thrombosis: 12 months. PAI-1 levels in HD: 7.21 +/- 2.13 vs. CG: 0.42 +/- 0.27 U/ml (p<0.0001). PAI-1 4G/5G polymorphic variant distribution in HD: 5G/5G: 6 (17%), 4G/5G: 23 (64%); 4G/4G: 7 (19%) and in CG: 5G/5G: 14 (35%); 4G/5G: 18 (45%); 4G/4G: 8 (20%). C-reactive protein (CRP) in HD: 24.5 +/- 15.2 mg/L vs. in CG 2.3 +/- 0.2 mg/L (p<0.0001). PAI-1 4G/5G variants: GA: 5G/5G: 3; 4G/5G: 8; 4G/4G: 1; GB: 5G/5G: 3; 4G/5G: 15; 4G/4G: 6. Thrombosis occurred in 8/10 patients (80%) with PTFEG, 3/22 (9%) in AVF, and 1/4 (25%) in CAT. Among the eight PTFEG patients with thrombosis, seven were PAI 4G/5G. PAI-1 levels were elevated in HD patients, independent of their polymorphic variants, 4G/5G being the most prevalent variant. Our data suggest that in patients with PTFEG the 4G/5G variant might be associated with an increased thrombosis risk.

  17. Genetic polymorphisms and activity of PON1 in a Mexican population

    SciTech Connect

    Rojas-Garcia, A.E.; Solis-Heredia, M.J.; Pina-Guzman, B.; Vega, L.; Lopez-Carrillo, L.; Quintanilla-Vega, B. . E-mail: mquintan@cinvestav.mx

    2005-06-15

    Human paraoxonase (PON1) plays a role in detoxification of organophosphorus (OP) compounds by hydrolyzing the bioactive oxons, and in reducing oxidative low-density lipoproteins, which may protect against atherosclerosis. Some PON1 polymorphisms have been found to be responsible for variations in catalytic activity and expression and have been associated with susceptibility to OP poisoning and vascular diseases. Both situations are of public health relevance in Mexico. Therefore, the aim of this study was to evaluate PON1 phenotype and the frequencies of polymorphisms PON1 -162, -108, 55, and 192 in a Mexican population. The studied population consisted of unrelated individuals (n = 214) of either gender, 18-52 years old. Serum PON1 activity was assayed using phenylacetate and paraoxon as substrates. PON1 variants, -162, 55, and 192, were determined by real-time PCR using the TaqMan System, and PON1 -108 genotype by PCR-RFLP. We found a wide interindividual variability of PON1 activity with a unimodal distribution; the range of enzymatic activity toward phenylacetate was 84.72 to 422.0 U/mL, and 88.37 to 1645.6 U/L toward paraoxon. All four PON1 polymorphisms showed strong linkage disequilibrium (D% >90). PON1 polymorphisms -108, 55, and 192 were independently associated with arylesterase activity; whereas the activity toward paraoxon was related only with PON1 192 polymorphism, suggesting that this polymorphism is determinant to infer PON1 activity. A better understanding of the phenotype and genotypes of PON1 in Mexican populations will facilitate further epidemiological studies involving PON1 variability in OP poisoning and in the development of atherosclerosis.

  18. Polymorphism in the peroxisome proliferator-activated receptor alpha gene influences the risk for Alzheimer's disease.

    PubMed

    Brune, S; Kölsch, H; Ptok, U; Majores, M; Schulz, A; Schlosser, R; Rao, M L; Maier, W; Heun, R

    2003-09-01

    The peroxisome proliferator-activated receptor alpha (PPAR-alpha) is a member of the steroid hormone super family of ligand-inducible transcription factors, involved in glucose and lipid metabolism. We screened for polymorphisms in the PPAR-alpha gene and detected two known polymorphisms located in exon 5 and intron 7. These polymorphisms were investigated for their possible association with Alzheimer's disease (AD) and for their effect in carriers of an insulin gene (INS) polymorphism. The PPAR-alpha C --> G polymorphism in exon 5 (L162V) was associated with AD, in that the V-allele was more frequent in AD patients than in healthy subjects. Further data analysis revealed that carriers of an PPAR-alpha L162V V-allele and an INS-1 allele presented with an increased risk for AD. Cerebrospinal fluid amyloid-beta levels were influenced by PPAR-alpha L162V genotype. These results suggest, that PPAR-alpha polymorphism may be a risk factor for AD.

  19. Polymorphism of alternative splicing of major histocompatibility complex transcripts in wild tiger salamanders.

    PubMed

    Bulut, Zafer; McCormick, Cory R; Bos, David H; DeWoody, J Andrew

    2008-07-01

    Alternative splicing (AS) of mRNA transcripts is increasingly recognized as a source of transcriptome diversity. To date, most AS studies have focused either on comparisons across taxa or on intragenomic comparisons across gene families. We generated a novel data set that represents one of the first population genetic comparisons of AS across individuals. In ambystomatid salamanders, AS of the major histocompatibility complex (MHC) class IIbeta gene (Amti-DAB) produces two transcripts, one full-length and one truncated. The full-length transcript is functional, but the truncated transcript is missing the critical beta1 domain that forms half of the peptide binding region in the intact MHC class II molecule. We captured wild salamander larvae (Ambystoma tigrinum tigrinum) and genotyped them at Amti-DAB via DNA sequencing. From these same larvae, we extracted RNA from gill and spleen and evaluated the relative expression level of Amti-DAB in each tissue. Across individuals, 21% of the transcripts were truncated (alternatively spliced), and the absolute level of alternative transcript expression was higher in gill. The high level of nucleotide variation among seven Amti-DAB alleles provides the ability to detect substitutions (or linked DNA polymorphisms) that might have influenced AS. The data reveal no correlation between AS and haplotype, allele, or zygosity. However, indirect evidence (comparative expression patterns across 3 million years of evolution) suggests that the truncated Amti-DAB transcript may be functional and maintained by natural selection.

  20. Genetics and polymorphism of the mouse prion gene complex: control of scrapie incubation time.

    PubMed Central

    Carlson, G A; Goodman, P A; Lovett, M; Taylor, B A; Marshall, S T; Peterson-Torchia, M; Westaway, D; Prusiner, S B

    1988-01-01

    The mouse prion protein (PrP) gene (Prn-p), which encodes the only macromolecule that has been identified in scrapie prions, is tightly linked or identical to a gene (Prn-i) that controls the duration of the scrapie incubation period in mice. Constellations of restriction fragment length polymorphisms distinguish haplotypes a to f of Prn-p. The Prn-pb allele encodes a PrP that differs in sequence from those encoded by the other haplotypes and, in inbred mouse strains, correlates with long scrapie incubation time (Westaway et al., Cell 51: 651-662, 1987). In segregating crosses of mice, we identified rare individuals with a divergent scrapie incubation time phenotype and Prn-p genotype, but progeny testing to demonstrate meiotic recombination was not possible because scrapie is a lethal disease. Crosses involving the a, d, and e haplotypes demonstrated that genes unlinked to Prn-p could modulate scrapie incubation time and that there were only two alleles of Prn-i among the mouse strains tested. All inbred strains of mice that had the Prnb haplotype were probably direct descendants of the I/LnJ progenitors. We established the linkage relationship between the prion gene complex (Prn) and other chromosome 2 genes; the gene order, proximal to distal, is B2m-II-1a-Prn-Itp-A. Recombination suppression in the B2m-Prn-p interval occurred during the crosses involved in transferring the I/LnJ Prnb complex into a C57BL/6J background. Transmission ratio distortion by Prna/Prnb heterozygous males was also observed in the same crosses. These phenomena, together with the founder effect, would favor apparent linkage disequilibrium between Prn-p and Prn-i. Therefore, transmission genetics may underestimate the number of genes in Prn. Images PMID:3149717

  1. Data describing the effect of DRD4 promoter polymorphisms on promoter activity.

    PubMed

    Tei, Shoin; Mitsuhashi, Hiroaki; Ishiura, Shoichi

    2016-06-01

    This data article tested whether polymorphisms within the dopamine D4 receptor (DRD4) gene promoter can lead to differences in the promoter activity. The variants, a 120-bp variable number tandem repeat (VNTR), -906 T/C, -809 G/A, -616G/C, and -521C/T, were introduced into the DRD4 promoter and the promoter activity was measured in a neural cell line using the luciferase assay. However, no differences were detected among the haplotypes investigated, and the in vitro data obtained from our protocol could not support the involvement of DRD4 promoter polymorphisms in heritable human traits.

  2. Insertion/Deletion Polymorphisms in the ΔNp63 Promoter Are a Risk Factor for Bladder Exstrophy Epispadias Complex

    PubMed Central

    Wilkins, Simon; Zhang, Ke Wei; Mahfuz, Istiak; Quantin, Renaud; D'Cruz, Nancy; Hutson, John; Ee, Michael; Bagli, Darius; Aitken, Karen; Fong, Fion Nga-Yin; Ng, Patrick Kwok-Shing; Tsui, Stephen Kwok-Wing; Fung, Wendy Yin-Wan; Banu, Tahmina; Thakre, Atul; Johar, Kaid; Jaureguizar, Enrique; Li, Long; Cheng, Wei

    2012-01-01

    Bladder exstrophy epispadias complex (BEEC) is a severe congenital anomaly; however, the genetic and molecular mechanisms underlying the formation of BEEC remain unclear. TP63, a member of TP53 tumor suppressor gene family, is expressed in bladder urothelium and skin over the external genitalia during mammalian development. It plays a role in bladder development. We have previously shown that p63−/− mouse embryos developed a bladder exstrophy phenotype identical to human BEEC. We hypothesised that TP63 is involved in human BEEC pathogenesis. RNA was extracted from BEEC foreskin specimens and, as in mice, ΔNp63 was the predominant p63 isoform. ΔNp63 expression in the foreskin and bladder epithelium of BEEC patients was reduced. DNA was sequenced from 163 BEEC patients and 285 ethnicity-matched controls. No exon mutations were detected. Sequencing of the ΔNp63 promoter showed 7 single nucleotide polymorphisms and 4 insertion/deletion (indel) polymorphisms. Indel polymorphisms were associated with an increased risk of BEEC. Significantly the sites of indel polymorphisms differed between Caucasian and non-Caucasian populations. A 12-base-pair deletion was associated with an increased risk with only Caucasian patients (p = 0.0052 Odds Ratio (OR) = 18.33), whereas a 4-base-pair insertion was only associated with non-Caucasian patients (p = 0.0259 OR = 4.583). We found a consistent and statistically significant reduction in transcriptional efficiencies of the promoter sequences containing indel polymorphisms in luciferase assays. These findings suggest that indel polymorphisms of the ΔNp63 promoter lead to a reduction in p63 expression, which could lead to BEEC. PMID:23284286

  3. Epistasis Between Polymorphisms in COMT, ESR1, and GCH1 Influences COMT Enzyme Activity and Pain

    PubMed Central

    Smith, Shad B.; Reenilä, Ilkka; Männistö, Pekka T.; Slade, Gary D.; Maixner, William; Diatchenko, Luda; Nackley, Andrea G.

    2014-01-01

    Abnormalities in the enzymatic activity of catechol-O-methyltransferase (COMT) contribute to chronic pain conditions, such as temporomandibular disorders (TMD). Thus, we sought to determine the effects of polymorphisms in COMT and functionally-related pain genes in the COMT pathway (estrogen receptor 1: ESR1, guanosine-5-triphosphate cyclohydrolase 1: GCH1, methylenetetrahydrofolate reductase: MTHFR) on COMT enzymatic activity, musculoskeletal pain, and pain-related intermediate phenotypes among TMD cases and healthy controls. Results demonstrate that the COMT rs4680 (val158met) polymorphism is most strongly associated with outcome measures, such that individuals with the minor A allele (met) exhibit reduced COMT activity, increased TMD risk, and increased musculoskeletal pain. Epistatic interactions were observed between the COMT rs4680 polymorphism and polymorphisms in GCH1 and ESR1. Among individuals with the COMT met allele, those with two copies of the GCH1 rs10483639 minor G allele exhibit normalized COMT activity and increased mechanical pain thresholds. Among individuals with the COMT val allele, those with two copies of the ESR1 rs3020377 minor A allele exhibit reduced COMT activity, increased bodily pain, and poorer self-reported health. These data reveal that the GCH1 minor G allele confers a protective advantage among met carriers, while the ESR1 minor A allele is disadvantageous among val carriers. Furthermore, these data suggest that the ability to predict the downstream effects of genetic variation on COMT activity is critically important to understanding the molecular basis of chronic pain conditions. PMID:25218601

  4. Epistasis between polymorphisms in COMT, ESR1, and GCH1 influences COMT enzyme activity and pain.

    PubMed

    Smith, Shad B; Reenilä, Ilkka; Männistö, Pekka T; Slade, Gary D; Maixner, William; Diatchenko, Luda; Nackley, Andrea G

    2014-11-01

    Abnormalities in the enzymatic activity of catechol-O-methyltransferase (COMT) contribute to chronic pain conditions, such as temporomandibular disorders (TMD). Thus, we sought to determine the effects of polymorphisms in COMT and functionally related pain genes in the COMT pathway (estrogen receptor 1 [ESR1], guanosine-5-triphosphate cyclohydrolase 1 [GCH1], methylenetetrahydrofolate reductase [MTHFR]) on COMT enzymatic activity, musculoskeletal pain, and pain-related intermediate phenotypes among TMD cases and healthy control subjects. Results show that the COMT rs4680 (val(158)met) polymorphism is most strongly associated with outcome measures, such that individuals with the minor A allele (met) exhibit reduced COMT activity, increased TMD risk, and increased musculoskeletal pain. Epistatic interactions were observed between the COMT rs4680 polymorphism and polymorphisms in GCH1 and ESR1. Among individuals with the COMT met allele, those with 2 copies of the GCH1 rs10483639 minor G allele exhibit normalized COMT activity and increased mechanical pain thresholds. Among individuals with the COMT val allele, those with 2 copies of the ESR1 rs3020377 minor A allele exhibit reduced COMT activity, increased bodily pain, and poorer self-reported health. These data reveal that the GCH1 minor G allele confers a protective advantage among met carriers, whereas the ESR1 minor A allele is disadvantageous among val carriers. Furthermore, these data suggest that the ability to predict the downstream effects of genetic variation on COMT activity is critically important to understanding the molecular basis of chronic pain conditions.

  5. SB subregion of the human major histocompatibility complex: gene organization, allelic polymorphism and expression in transformed cells.

    PubMed

    Okada, K; Prentice, H L; Boss, J M; Levy, D J; Kappes, D; Spies, T; Raghupathy, R; Mengler, R A; Auffray, C; Strominger, J L

    1985-03-01

    The SB region of the human major histocompatibility complex (MHC) has been cloned from cosmid and lambda phage libraries made from the human B-lymphoblastoid cell line Priess (DR4/4, DC4/4, SB3/4). Two alpha genes and two beta genes are encoded in the 100 kb long SB region in the order SB alpha-SB beta-SX alpha-SX beta. The SB alpha and SB beta genes encode the alpha and beta subunits of the SB subset of class II MHC molecules. Both the SX alpha and the SX beta genes are pseudogenes in the haplotype examined. From the isolated clones, the two haplotypes of the Priess cell line, SB3 and SB4, are distinguished by nucleotide sequencing and blot hybridization analyses. Restriction site polymorphisms between the SB3 and SB4 clones were observed only in relatively small regions of the SB beta and SX beta genes. A mouse macrophage cell line was transfected with one of the cosmid clones containing both SB alpha and SB beta genes. Expression of the alpha and beta genes was detected by fluorescene-activated cell sorting (FACS) and two-dimensional gel electrophoresis using SB-specific monoclonal antibodies.

  6. Plasminogen activator inhibitor-I (PAI-I) polymorphisms in patients with obstructive sleep apnoea.

    PubMed

    Barceló, A; Llompart, E; Barbé, F; Morlá, M; Vila, M; Agustí, A G N

    2002-03-01

    Cardiovascular diseases are frequent among patients with the obstructive sleep apnoea syndrome (OSAS), The aetiopathogenesis of this association is unclear. Type 1 plasminogen activator inhibitor (PAI-1) is one of the primary regulators of the fibrinolytic system. A reported association between PAI-1 activity and an insertion/deletion polymorphism (4G/5G) in the promoter region of the PAI-1 gene suggests a critical role for this genomic region in the pathogenesis of several cardiovascular diseases. In this study, we determined the prevalence of this polymorphism in patients with OSAS and in healthy control subjects. The 4G/5G polymorphism in the promoter region of the PAI-1 gene was determined in 78 male patients with severe OSAS (56 +/- 2 apnoeas per hour) and in 70 healthy male, non-smoker volunteers of similar age, without personal or familial history of cardiovascular disease. The frequency ofthe 4G/4G, 4G/5G and 5G/5G genotypes in patients with OSAS (18%, 62%, 19%, respectively) was not significantly different from that seen in healthy subjects (16%, 60%, 24% P=NS). These results show that the distribution of the 4G/5G polymorphism in the promoter region ofthe PAI-1 gene in patients with OSAS is similar to that observed in healthy subjects. This observation suggests that the PAI-1 polymorphism has no relationship with the increased risk of cardiovascular diseases seen in patients with OSAS.

  7. Non-SMC condensin I complex, subunit D2 gene polymorphisms are associated with Parkinson's disease: a Han Chinese study.

    PubMed

    Zhang, Ping; Liu, Ling; Huang, Jinsha; Shao, Liang; Wang, Hongcai; Xiong, Nian; Wang, Tao

    2014-05-01

    Previous studies have indicated that non-SMC condensin I complex, subunit D2 (NCAPD2), an important protein in chromosome condensation, gene polymorphisms are associated with Alzheimer's disease. But no study has shown the relationship between NCAPD2 polymorphisms and Parkinson's disease. Here, we conducted a case-control study to investigate the relationship between NCAPD2 polymorphisms and the risk of Parkinson's disease in a Han Chinese population. Two single nuclear polymorphisms (SNPs) of NCAPD2 (rs7311174 and rs2072374) showed significant p values (p = 0.046 and p = 0.043, respectively) in 265 patients and 267 controls. Further analysis showed an effect of age and gender on the relationship between the two SNPs and the risk for Parkinson's disease. The A allele of rs7311174 and the T allele of rs2072374 were protective in the male patients (p = 0.016 and p = 0.019, respectively). The frequencies of the T allele of rs7311174 and the C allele of rs2072374 were significantly associated with late-onset Parkinson's disease (p = 0.048 and p = 0.044, respectively). This research demonstrates a positive relationship between the NCAPD2 gene and the risk for Parkinson's disease in a Han Chinese population and provides a potential genetic marker for sporadic Parkinson's disease.

  8. Complex patterns of cis-regulatory polymorphisms in ebony underlie standing pigmentation variation in Drosophila melanogaster.

    PubMed

    Miyagi, Ryutaro; Akiyama, Noriyoshi; Osada, Naoki; Takahashi, Aya

    2015-12-01

    Pigmentation traits in adult Drosophila melanogaster were used in this study to investigate how phenotypic variations in continuous ecological traits can be maintained in a natural population. First, pigmentation variation in the adult female was measured at seven different body positions in 20 strains from the Drosophila melanogaster Genetic Reference Panel (DGRP) originating from a natural population in North Carolina. Next, to assess the contributions of cis-regulatory polymorphisms of the genes involved in the melanin biosynthesis pathway, allele-specific expression levels of four genes were quantified by amplicon sequencing using a 454 GS Junior. Among those genes, ebony was significantly associated with pigmentation intensity of the thoracic segment. Detailed sequence analysis of the gene regulatory regions of this gene indicated that many different functional cis-regulatory alleles are segregating in the population and that variations outside the core enhancer element could potentially play important roles in the regulation of gene expression. In addition, a slight enrichment of distantly associated SNP pairs was observed in the ~10 kb cis-regulatory region of ebony, which suggested the presence of interacting elements scattered across the region. In contrast, sequence analysis in the core cis-regulatory region of tan indicated that SNPs within the region are significantly associated with allele-specific expression level of this gene. Collectively, the data suggest that the underlying genetic differences in the cis-regulatory regions that control intraspecific pigmentation variation can be more complex than those of interspecific pigmentation trait differences, where causal genetic changes are typically confined to modular enhancer elements.

  9. Plasminogen activator inhibitor-1 4G/5G polymorphism is associated with metabolic syndrome parameters in Malaysian subjects.

    PubMed

    Al-Hamodi, Zaid H; Saif-Ali, Riyadh; Ismail, Ikram S; Ahmed, Khaled A; Muniandy, Sekaran

    2012-05-01

    The plasminogen activator inhibitor-1 4G/5G and tissue plasminogen activator Alu-repeat insertion/deletion polymorphisms might be genetic determinations of increased or decreased of their plasma activities. The aim of this study was to investigate the association of plasminogen activator inhibitor-1 4G/5G and tissue plasminogen activator Alu-repeat I/D polymorphisms with metabolic syndrome parameters in normal Malaysian subjects and to assess the impact of these polymorphisms on their plasma activities and antigens. The genetic polymorphisms were genotyped in 130 normal subjects. In addition, the plasma activities and antigens of plasminogen activator inhibitor-1 and tissue plasminogen activator as well as levels of insulin, glucose, and lipid profile at fasting state were investigated. The subjects with homozygous 4G/4G showed association with an increased triglyceride (p = 0.007), body mass index (p = 0.01) and diastolic blood pressure (p = 0.03). In addition, the plasminogen activator inhibitor-1 4G/5G polymorphism modulates plasma plasminogen activator inhibitor-1 activity and antigen and tissue plasminogen activator activity (p = 0.002, 0.014, 0.003) respectively. These results showed that, the plasminogen activator inhibitor-1 4G/5G polymorphism is associated with metabolic syndrome parameters, plasminogen activator inhibitor-1 and tissue plasminogen activator activities in Malaysian subjects, and may serve to increase the risk of type 2 diabetes and cardiovascular disease in Malaysian subjects.

  10. Prion Protein M129V Polymorphism Affects Retrieval-Related Brain Activity

    ERIC Educational Resources Information Center

    Buchmann, Andreas; Mondadori, Christian R. A.; Hanggi, Jurgen; Aerni, Amanda; Vrticka, Pascal; Luechinger, Roger; Boesiger, Peter; Hock, Christoph; Nitsch, Roger M.; de Quervain, Dominique J.-F.; Papassotiropoulos, Andreas; Henke, Katharina

    2008-01-01

    The prion protein Met129Val polymorphism has recently been related to human long-term memory with carriers of either the 129[superscript MM] or the 129[superscript MV] genotype recalling 17% more words than 129[superscript VV] carriers at 24 h following learning. Here, we sampled genotype differences in retrieval-related brain activity at 30 min…

  11. Prion Protein M129V Polymorphism Affects Retrieval-Related Brain Activity

    ERIC Educational Resources Information Center

    Buchmann, Andreas; Mondadori, Christian R. A.; Hanggi, Jurgen; Aerni, Amanda; Vrticka, Pascal; Luechinger, Roger; Boesiger, Peter; Hock, Christoph; Nitsch, Roger M.; de Quervain, Dominique J.-F.; Papassotiropoulos, Andreas; Henke, Katharina

    2008-01-01

    The prion protein Met129Val polymorphism has recently been related to human long-term memory with carriers of either the 129[superscript MM] or the 129[superscript MV] genotype recalling 17% more words than 129[superscript VV] carriers at 24 h following learning. Here, we sampled genotype differences in retrieval-related brain activity at 30 min…

  12. [ACE gene polymorphisms associated with serum ACE activity in the Henan Hans of China].

    PubMed

    Kong, Xiang-Dong; Zhang, Si-Zhong

    2004-11-01

    In order to investigate the relationship between gene polymorphisms and serum activity of the angiotensin-1 converting enzyme(ACE) in Chinese population, eight loci in ACE gene were detected by polymerase chain reaction combined with restriction fragment length polymorphism or electrophoresis directly, and serum ACE activity was measured by spectrophometry. Using maximum likelihood estimation(MLE), the pattern of intragenic linkage disequilibrium and the haplotype structure were estimated. All the eight polymorphisms formed nine haplotypes,in which the two most frequent haplotypes were A (A-T-A-T-G-I-A-3) and B(C-C-T-C-A-D-G-2). Also haplotype A and haplotype B were completely different at all eight sites. Deduced from the maximum-parsimony tree,the haplotypes in Chinese population could be grouped into three clades. Clade III seemed to be generated by an ancestral recombination event between clade I and clade II. Every locus formed, the haplotype B was associated with high ACE activity. This findings suggested that serum ACE levels were partially determined by genetic predisposition (the polymorphism of ACE gene). Haplotype B may be related to the quantitative trait loci of high-level activity,whereas high-resolution genetic mapping linked with ACE was still necessary to characterize definitely the functional variants.

  13. Association of Pro12Ala polymorphism in peroxisome proliferator activated receptor gamma with proliferative diabetic retinopathy

    PubMed Central

    Tariq, Khadija; Malik, Saira Bano; Ali, Syeda Hafiza Benish; Maqsood, Sundas Ejaz; Azam, Aisha; Muslim, Irfan; Khan, Muhammad Shakil; Azam, Maleeha; Waheed, Nadia Khalida

    2013-01-01

    Purpose The association of non-synonymous substitution polymorphism rs1801282 (c.34C>G, p.Pro12Ala) in exon 4 of the peroxisome proliferator activated receptor gamma gene with diabetic retinopathy (DR) has been reported inconsistently. Therefore, the purpose of the present study was to understand the population-specific role of the Pro12Ala polymorphism in DR susceptibility in Pakistani subjects. Methods A total of 180 subjects with DR, 193 subjects with type 2 diabetes mellitus (T2DM) with no diabetic retinopathy, and 200 healthy normoglycemic non-retinopathic Pakistani individuals were genotyped for the rs1801282 (c.34C>G) polymorphism using polymerase chain reaction-restriction fragment length polymorphism. Results We found the individuals with T2DM carrying 12Ala were at a reduced risk of developing DR (odds ratio [OR]=0.53; 95% confidence interval [CI]=0.33–0.87). Upon stratified analysis regarding disease severity, we observed this protective effect was confined to proliferative DR (OR=0.4; 95% CI=0.2–0.8) with non-significant effects on the susceptibility of non-proliferative DR (OR=0.67; 95% CI=0.37–1.19). Conclusions We report a protective role of the 12Ala polymorphism against proliferative DR in individuals with T2DM in Pakistan. PMID:23559865

  14. Poly(ADP-ribose) polymerase-1 polymorphisms, expression and activity in selected human tumour cell lines

    PubMed Central

    Zaremba, T; Ketzer, P; Cole, M; Coulthard, S; Plummer, E R; Curtin, N J

    2009-01-01

    Background: Poly(ADP-ribose) polymerase-1 (PARP-1) is a DNA-binding enzyme activated by DNA breaks and involved in DNA repair and other cellular processes. Poly(ADP-ribose) polymerase activity can be higher in cancer than in adjacent normal tissue, but cancer predisposition is reported to be greater in individuals with a single-nucleotide polymorphism (SNP) V762A (T2444C) in the catalytic domain that reduces PARP-1 activity. Methods: To resolve these divergent observations, we determined PARP-1 polymorphisms, PARP-1 protein expression and activity in a panel of 19 solid and haematological, adult and paediatric human cancer cell lines. Results: There was a wide variation in PARP activity in the cell line panel (coefficient of variation, CV=103%), with the lowest and the highest activity being 2460 pmol PAR/106 (HS-5 cells) and 85 750 pmol PAR/106 (NGP cells). Lower variation (CV=32%) was observed in PARP-1 protein expression with the lowest expression being 2.0 ng μg−1 (HS-5 cells) and the highest being 7.1 ng μg−1 (ML-1 cells). The mean activity in the cancer cells was 45-fold higher than the mean activity in normal human lymphocytes and the PARP-1 protein levels were 23-fold higher. Conclusions: Surprisingly, there was no significant correlation between PARP activity and PARP-1 protein level or the investigated polymorphisms, T2444C and CA. PMID:19568233

  15. Collective dynamics of active filament complexes

    NASA Astrophysics Data System (ADS)

    Nogucci, Hironobu; Ishihara, Shuji

    2016-05-01

    Networks of biofilaments are essential for the formation of cellular structures that support various biological functions. For the most part, previous studies have investigated the collective dynamics of rodlike biofilaments; however, the shapes of the actual subcellular components are often more elaborate. In this study, we considered an active object composed of two active filaments, which represents the progression from rodlike biofilaments to complex-shaped biofilaments. Specifically, we numerically assessed the collective behaviors of these active objects in two dimensions and observed several types of dynamics, depending on the density and the angle of the two filaments as shape parameters of the object. Among the observed collective dynamics, a moving density band that we named a "moving smectic" is introduced here for the first time. By analyzing the trajectories of individual objects and the interactions among them, this study demonstrated how interactions among active biofilaments with complex shapes could produce collective dynamics in a nontrivial manner.

  16. Linking Complexity with Cultural Historical Activity Theory

    ERIC Educational Resources Information Center

    McMurtry, Angus

    2006-01-01

    This paper explores the similarities and differences between complexity science's and cultural-historical activity theory's understandings of human learning. Notable similarities include their emphasis on the importance of social systems or collectives in understanding human knowledge and practices, as well as their characterization of systems'…

  17. 14N NQR study of polymorphism and hydrogen bonding in molecular complex isonicotinamide-oxalic acid (2:1).

    PubMed

    Seliger, J; Žagar, V

    2010-11-18

    The complete (14)N nuclear quadrupole resonance (NQR) spectra have been measured in the two polymorphic crystalline phases of the molecular complex isonicotinamide-oxalic acid (2:1) by nuclear quadrupole double resonance. The observed NQR frequencies, quadrupole coupling constants, and asymmetry parameters (η) have been assigned to the two nitrogen positions (ring and amide) in a molecule on the basis of the intensity and multiplicity of the double resonance signals. The NQR data for the ring nitrogen in both polymorphic phases deviate from the correlation relations observed in substituted pyridines. This deviation is analyzed in a model, where it is assumed that an additional electric charge on the nitrogen atom changes the NQR parameters. The model suggests that this additional electric charge is negative so that the N···H-O hydrogen bond seem to be partially ionic, of the type N(-)···H-O.

  18. Associations of MC3R polymorphisms with physical activity in South African adolescents.

    PubMed

    Yako, Yandiswa Y; Hassan, Mogamat S; Erasmus, Rajiv T; van der Merwe, Lize; Janse van Rensburg, Susan; Matsha, Tandi Edith

    2013-08-01

    There is evidence demonstrating that the contribution of sedentary behavior and effect of physical activity on metabolic phenotypes is mediated by polymorphisms in genes. The type and frequency of physical activity was assessed by means of structured questionnaires in 1555 South African school learners. Anthropometric measurements, blood pressure, fasting blood glucose and lipids were measured using standard procedures. The effect of different types and frequency of physical activity on obesity-related traits was assessed in relation to MC3R T6K and V81I genotypes in 430 of the learners. Levels of total cholesterol were significantly lower in learners carrying the MC3R T6K and V81I minor alleles, after adjusting for age, race, gender, and each specific physical activity category. An activity-by-genotype interaction was also detected: learners heterozygous for the V81I polymorphism and performed house chores often had reduced total cholesterol. Though no association was observed between frequency of physical activity and BMI, television viewing was significantly associated with an increase in height, weight and marginally with waist circumference. Our findings suggest that physical activity even in the form of house chores has a positive effect on metabolic traits and this effect is further enhanced in the presence of MC3R polymorphisms.

  19. Polymorphisms of the equine major histocompatibility complex class II DRA locus.

    PubMed

    Brown, J J; Thomson, W; Clegg, P; Eyre, S; Kennedy, L J; Matthews, J; Carter, S; Ollier, W E R

    2004-08-01

    The full extent of the polymorphism of ELA-DRA in Equidae is not yet known. Given the apparent differences in DRA polymorphisms between Equidae and other species, the aims of this study were to more fully characterize ELA-DRA, determine the extent of gene polymorphism and establish the allele-frequency distribution. An allele reference panel for the second exon of ELA-DRA was established by sequence-based typing of 69 equine DNA samples consisting of various breeds of domestic horse (Equus caballus), together with donkeys (Equus asinus), Grant's zebras (Equus boehmi) and one onager (Equus hemionus). Five of the six previously reported alleles detected using single-strand conformation polymorphism were found: ELA-DRA*0101, ELA-DRA*0201, ELA-DRA*0301, ELA-DRA*0501 (Albright-Fraser DG et al. Polymorphism of DRA among equids. Immunogenetics 1996: 43: 315-7) and ELA-DRA*0601 (GenBank accession number AF5419361). In addition to the previously reported alleles, five novel ELA-DRA alleles were detected within the ELA-DRA allele reference panel. One of these was identified in E. caballus (ELA-DRA*JBH11), one in E. boehmi and E. hemionus (ELA-DRA*JBZ185) and three in E. asinus (ELA-DRA*JBD3, ELA-DRA*JBD17 and ELA-DRA*JBH45). A total of 565 equine DNA samples were screened using reference-strand-mediated conformation analysis, a double-stranded conformation-based mutation detection system that can be used to type existing ELA-DRA alleles and identify new variants. Based on our findings, at least 11 ELA-DRA alleles are now known to exist, and this level of polymorphism at the DRA locus appears to be unique to the genus Equus. Both the previously reported alleles and the new alleles displayed a species-specific distribution.

  20. Characterization, polymorphism and selection of major histocompatibility complex (MHC) DAB genes in vulnerable Chinese egret (Egretta eulophotes).

    PubMed

    Wang, Zeng; Zhou, Xiaoping; Lin, Qingxian; Fang, Wenzhen; Chen, Xiaolin

    2013-01-01

    The major histocompatibility complex (MHC) is an excellent molecular marker for the studies of evolutionary ecology and conservation genetics because it is a family of highly polymorphic genes that play a key role in vertebrate immune response. In this study, the functional genes of MHC Class II B (DAB) were isolated for the first time in a vulnerable species, the Chinese egret (Egrettaeulophotes). Using a full length DNA and cDNA produced by PCR and RACE methods, four potential MHC DAB loci were characterized in the genome of this egret and all four were expressed in liver and blood. At least four copies of the MHC gene complex were similar to two copies of the minimal essential MHC complex of chicken, but are less complex than the multiple copies expressed in passerine species. In MHC polymorphism, 19 alleles of exon 2 were isolated from 48 individuals using PCR. No stop codons or frameshift mutations were found in any of the coding regions. The signatures of positive selection detected in potential peptide-binding regions by Bayesian analysis, suggesting that all of these genes were functional. These data will provide the fundamental basis for further studies to elucidate the mechanisms and significance of MHC molecular adaptation in vulnerable Chinese egret and other ardeids.

  1. Analysis of myeloperoxidase promotor polymorphism and enzyme activity in Turkish patients with vitiligo.

    PubMed

    Aksoy, S Nur; Erbagci, Zulal; Saygili, E Ilker; Sever, Tugce; Erbagci, A Binnur; Pehlivan, Sacide

    2009-01-01

    Vitiligo is an acquired depigmentary disorder characterized by white areas of the skin due to loss of epidermal melanocytes. Oxidative stress and free radicals are suggested as important phenomena in the pathogenesis of vitiligo. Myeloperoxidase is a lysosomal enzyme of polymorphonuclear leukocytes and acts as a catalyst in the production of hypochlorous acid, a powerful oxidant. In this study we analysed enzyme activity and gene polymorphism of myeloperoxidase in patients with vitiligo. Fifty-four patients with vitiligo and 58 healthy controls were enrolled to this study. Patient groups were subdivided according to localization of the lesions; generalized, acrofacial and local. Plasma myeloperoxidase enzyme activity was determined with ELISA and G-463A gene (-463) polymorphism with the PCR-RFLP (AciI) method. The plasma MPO level was significantly lower in vitiligo patients than in the healthy controls (p = 0.005), however, it was not significantly different among subtypes of vitiligo (p = 0.8). A significant difference was not observed for G-463A genotype and allele distribution in patients with vitiligo. In conclusion, the present study is the first study investigating MPO G-463A polymorphism and enzyme levels, which warrants further studies with higher patient numbers and broader polymorphism panels.

  2. Cis-Acting Polymorphisms Affect Complex Traits through Modifications of MicroRNA Regulation Pathways

    PubMed Central

    Hartsperger, Mara L.; Pfeufer, Arne; Stümpflen, Volker

    2012-01-01

    Genome-wide association studies (GWAS) have become an effective tool to map genes and regions contributing to multifactorial human diseases and traits. A comparably small number of variants identified by GWAS are known to have a direct effect on protein structure whereas the majority of variants is thought to exert their moderate influences on the phenotype through regulatory changes in mRNA expression. MicroRNAs (miRNAs) have been identified as powerful posttranscriptional regulators of mRNAs. Binding to their target sites, which are mostly located within the 3′-untranslated region (3′-UTR) of mRNA transcripts, they modulate mRNA expression and stability. Until today almost all human mRNA transcripts are known to harbor at least one miRNA target site with an average of over 20 miRNA target sites per transcript. Among 5,101 GWAS-identified sentinel single nucleotide polymorphisms (SNPs) that correspond to 18,884 SNPs in linkage disequilibrium (LD) with the sentinels () we identified a significant overrepresentation of SNPs that affect the 3′-UTR of genes (OR = 2.33, 95% CI = 2.12–2.57, ). This effect was even stronger considering all SNPs in one LD bin a single signal (OR = 4.27, 95% CI = 3.84–4.74, ). Based on crosslinking immunoprecipitation data we identified four mechanisms affecting miRNA regulation by 3′-UTR mutations: (i) deletion or (ii) creation of miRNA recognition elements within validated RNA-induced silencing complex binding sites, (iii) alteration of 3′-UTR splicing leading to a loss of binding sites, and (iv) change of binding affinity due to modifications of 3′-UTR folding. We annotated 53 SNPs of a total of 288 trait-associated 3′-UTR SNPs as mediating at least one of these mechanisms. Using a qualitative systems biology approach, we demonstrate how our findings can be used to support biological interpretation of GWAS results as well as to provide new experimentally testable hypotheses. PMID:22606281

  3. The peroxisome proliferator-activated receptor-gamma2 Pro12Ala polymorphism.

    PubMed

    Stumvoll, Michael; Häring, Hans

    2002-08-01

    Peroxisome proliferator-activated receptor (PPAR)-gamma is a transcription factor with a key role in adipocyte differentiation. The Ala allele of the common Pro12Ala polymorphism in the isoform PPAR-gamma2 is associated with reduced risk for type 2 diabetes. The effect on the individual is weak, but because of a prevalence of >75% of the high-risk Pro allele, the population-attributable risk is enormous. The in vivo effects of the polymorphism are secondary to alterations in adipose tissue, where PPAR-gamma2 is predominantly expressed. Moderate reduction in transcriptional activity of PPAR-gamma as a result of the polymorphism modulates production and release of adipose-derived factors. Both decreased release of insulin-desensitizing free fatty acids, tumor necrosis factor-alpha, and resistin and increased release of the insulin-sensitizing hormone adiponectin result in secondary improvement of insulin sensitivity of glucose uptake and suppression of glucose production. The population effect of this polymorphism may be modulated by environmental or genetic factors such as obesity, ethnicity, ratio of unsaturated to saturated fatty acids, and genetic background. Once diabetes has developed, the protective effect of the Ala allele may be lost, since increased vascular complications and more pronounced beta-cell dysfunction have been reported. These observations, however, are currently unexplained. In conclusion, the Pro12Ala polymorphism in PPAR-gamma2 represents the first genetic variant with a broad impact on the risk of common type 2 diabetes. The precise understanding of its mechanism may lead to novel diagnostic, preventive, and therapeutic approaches for improving the management of type 2 diabetes.

  4. A Natural Polymorphism in rDNA Replication Origins Links Origin Activation with Calorie Restriction and Lifespan

    PubMed Central

    Kwan, Elizabeth X.; Foss, Eric J.; Tsuchiyama, Scott; Alvino, Gina M.; Kruglyak, Leonid; Kaeberlein, Matt; Raghuraman, M. K.; Brewer, Bonita J.; Kennedy, Brian K.; Bedalov, Antonio

    2013-01-01

    Aging and longevity are complex traits influenced by genetic and environmental factors. To identify quantitative trait loci (QTLs) that control replicative lifespan, we employed an outbred Saccharomyces cerevisiae model, generated by crossing a vineyard and a laboratory strain. The predominant QTL mapped to the rDNA, with the vineyard rDNA conferring a lifespan increase of 41%. The lifespan extension was independent of Sir2 and Fob1, but depended on a polymorphism in the rDNA origin of replication from the vineyard strain that reduced origin activation relative to the laboratory origin. Strains carrying vineyard rDNA origins have increased capacity for replication initiation at weak plasmid and genomic origins, suggesting that inability to complete genome replication presents a major impediment to replicative lifespan. Calorie restriction, a conserved mediator of lifespan extension that is also independent of Sir2 and Fob1, reduces rDNA origin firing in both laboratory and vineyard rDNA. Our results are consistent with the possibility that calorie restriction, similarly to the vineyard rDNA polymorphism, modulates replicative lifespan through control of rDNA origin activation, which in turn affects genome replication dynamics. PMID:23505383

  5. A single nucleotide polymorphism of porcine MX2 gene provides antiviral activity against vesicular stomatitis virus.

    PubMed

    Sasaki, Keisuke; Tungtrakoolsub, Pullop; Morozumi, Takeya; Uenishi, Hirohide; Kawahara, Manabu; Watanabe, Tomomasa

    2014-01-01

    The objective was to determine if single nucleotide polymorphisms (SNPs) in porcine MX2 gene affect its antiviral potential. MX proteins are known to suppress the multiplication of several viruses, including influenza virus and vesicular stomatitis virus (VSV). In domestic animals possessing highly polymorphic genome, our previous research indicated that a specific SNP in chicken Mx gene was responsible for its antiviral function. However, there still has been no information about SNPs in porcine MX2 gene. In this study, we first conducted polymorphism analysis in 17 pigs of MX2 gene derived from seven breeds. Consequently, a total of 30 SNPs, of which 11 were deduced to cause amino acid variations, were detected, suggesting that the porcine MX2 is very polymorphic. Next, we classified MX2 into eight alleles (A1-A8) and subsequently carried out infectious experiments with recombinant VSVΔG*-G to each allele. In A1-A5 and A8, position 514 amino acid (514 aa) of MX2 was glycine (Gly), which did not inhibit VSV multiplication, whereas in A6 and A7, 514 aa was arginine (Arg), which exhibited the antiviral ability against VSV. These results demonstrate that a SNP at 514 aa (Gly-Arg) of porcine MX2 plays a pivotal role in the antiviral activity as well as that at 631 aa of chicken Mx.

  6. Plasminogen activator inhibitor I 4G/5G polymorphism in neonatal respiratory distress syndrome.

    PubMed

    Armangil, Didem; Yurdakök, Murat; Okur, Hamza; Gürgey, Aytemiz

    2011-08-01

    Fibrin monomers inhibit surfactant function. 4G/5G insertion/deletion polymorphism plays an important role in the regulation of plasminogen activator inhibitor 1 (PAI-1) gene expression. To examine the genotype distribution of PAI-1 polymorphism in 60 infants with respiratory distress syndrome (RDS) and 53 controls, an allele-specific polymerase chain reaction (PCR) was used. The proportion of 4G/4G, 4G/5G, and 5G/5G genotypes did not differ statistically between the RDS and control groups (P > .05). Having PAI-1 4G/4G genotype polymorphism appears to increase the risk of RDS (odds ratio [OR] =1.5; 95% confidence interval [CI], 0.5-4.3), although it was not statistically significant. No relation was found between the PAI-1 4G/5G polymorphisms and RDS, but there was an increased risk associated with the 4G variant of the PAI-1 gene. We believe that our findings of increased 4G allele of the PAI-1 gene in infants with RDS would also help to clarify the pathogenesis of RDS.

  7. Haplotyping the human T-cell receptor. beta. -chain gene complex by use of restriction fragment length polymorphisms

    SciTech Connect

    Charmley, P.; Chao, A.; Gatti, R.A. ); Concannon, P. ); Hood, L. )

    1990-06-01

    The authors have studied the genetic segregation of human T-cell receptor {beta}-chain (TCR{beta}) genes on chromosome 7q in 40 CEPH (Centre d'Etude du Polymorphisme Humain) families by using restriction fragment length polymorphisms (RFLPs). They constructed haplotypes from eight RFLPs by using variable- and constant-region cDNA probes, which detect polymorphisms that span more than 600 kilobases of the TCR{beta} gene complex. Analysis of allele distributions between TCR{beta} genes revealed significant linkage disequilibrium between only 6 of the 28 different pairs of RFLPs. This linkage disequilibrium strongly influences the most efficient order to proceed for typing of these RFLPs in order to achieve maximum genetic informativeness, which in this study revealed a 97.3% level of heterozygosity within the TCR{beta} gene complex. The results should provide new insight into recent reports of disease associations with the TCR{beta} gene complex and should assist in designing future experiments to detect or confirm the existence of disease-susceptibility loci in this region of the human genome.

  8. Divergent population structure and climate associations of a chromosomal inversion polymorphism across the Mimulus guttatus species complex

    PubMed Central

    Oneal, Elen; Lowry, David B.; Wright, Kevin M.; Zhu, Zhirui; Willis, John H.

    2014-01-01

    Chromosomal rearrangement polymorphisms are common and increasingly found to be associated with adaptive ecological divergence and speciation. Rearrangements, such as inversions, reduce recombination in heterozygous individuals and thus can protect favourable allelic combinations at linked loci, facilitating their spread in the presence of gene flow. Recently, we identified a chromosomal inversion polymorphism that contributes to ecological adaptation and reproductive isolation between annual and perennial ecotypes of the yellow monkeyflower, Mimulus guttatus. Here we evaluate the population genetic structure of this inverted region in comparison with the collinear regions of the genome across the M. guttatus species complex. We tested whether annual and perennial M. guttatus exhibit different patterns of divergence for loci in the inverted and noninverted regions of the genome. We then evaluated whether there are contrasting climate associations with these genomic regions through redundancy analysis. We found that the inversion exhibits broadly different patterns of divergence among annual and perennial M. guttatus and is associated with environmental variation across population accessions. This study is the first widespread population genetic survey of the diversity of the M. guttatus species complex. Our findings contribute to a greater understanding of morphological, ecological, and genetic evolutionary divergence across this highly diverse group of closely related ecotypes and species. Finally, understanding species relationships among M. guttatus sp. has hitherto been stymied by accumulated evidence of substantial gene flow among populations as well as designated species. Nevertheless, our results shed light on these relationships and provide insight into adaptation in life history traits within the complex. PMID:24796267

  9. Characterization of Influenza Vaccine Hemagglutinin Complexes by Cryo-Electron Microscopy and Image Analyses Reveals Structural Polymorphisms

    PubMed Central

    McCraw, Dustin M.; Gallagher, John R.

    2016-01-01

    Influenza virus afflicts millions of people worldwide on an annual basis. There is an ever-present risk that animal viruses will cross the species barrier to cause epidemics and pandemics resulting in great morbidity and mortality. Zoonosis outbreaks, such as the H7N9 outbreak, underscore the need to better understand the molecular organization of viral immunogens, such as recombinant influenza virus hemagglutinin (HA) proteins, used in influenza virus subunit vaccines in order to optimize vaccine efficacy. Here, using cryo-electron microscopy and image analysis, we show that recombinant H7 HA in vaccines formed macromolecular complexes consisting of variable numbers of HA subunits (range, 6 to 8). In addition, HA complexes were distributed across at least four distinct structural classes (polymorphisms). Three-dimensional (3D) reconstruction and molecular modeling indicated that HA was in the prefusion state and suggested that the oligomerization and the structural polymorphisms observed were due to hydrophobic interactions involving the transmembrane regions. These experiments suggest that characterization of the molecular structures of influenza virus HA complexes used in subunit vaccines will lead to better understanding of the differences in vaccine efficacy and to the optimization of subunit vaccines to prevent influenza virus infection. PMID:27074939

  10. ITS polymorphisms shed light on hybrid evolution in apomictic plants: a case study on the Ranunculus auricomus complex.

    PubMed

    Hodač, Ladislav; Scheben, Armin Patrick; Hojsgaard, Diego; Paun, Ovidiu; Hörandl, Elvira

    2014-01-01

    The reconstruction of reticulate evolutionary histories in plants is still a major methodological challenge. Sequences of the ITS nrDNA are a popular marker to analyze hybrid relationships, but variation of this multicopy spacer region is affected by concerted evolution, high intraindividual polymorphism, and shifts in mode of reproduction. The relevance of changes in secondary structure is still under dispute. We aim to shed light on the extent of polymorphism within and between sexual species and their putative natural as well as synthetic hybrid derivatives in the Ranunculus auricomus complex to test morphology-based hypotheses of hybrid origin and parentage of taxa. We employed direct sequencing of ITS nrDNA from 68 individuals representing three sexuals, their synthetic hybrids and one sympatric natural apomict, as well as cloning of ITS copies in four representative individuals, RNA secondary structure analysis, and landmark geometric morphometric analysis on leaves. Phylogenetic network analyses indicate additivity of parental ITS variants in both synthetic and natural hybrids. The triploid synthetic hybrids are genetically much closer to their maternal progenitors, probably due to ploidy dosage effects, although exhibiting a paternal-like leaf morphology. The natural hybrids are genetically and morphologically closer to the putative paternal progenitor species. Secondary structures of ITS1-5.8S-ITS2 were rather conserved in all taxa. The observed similarities in ITS polymorphisms suggest that the natural apomict R. variabilis is an ancient hybrid of the diploid sexual species R. notabilis and the sexual species R. cassubicifolius. The additivity pattern shared by R. variabilis and the synthetic hybrids supports an evolutionary and biogeographical scenario that R. variabilis originated from ancient hybridization. Concerted evolution of ITS copies in R. variabilis is incomplete, probably due to a shift to asexual reproduction. Under the condition of

  11. ITS Polymorphisms Shed Light on Hybrid Evolution in Apomictic Plants: A Case Study on the Ranunculus auricomus Complex

    PubMed Central

    Hodač, Ladislav; Scheben, Armin Patrick; Hojsgaard, Diego; Paun, Ovidiu; Hörandl, Elvira

    2014-01-01

    The reconstruction of reticulate evolutionary histories in plants is still a major methodological challenge. Sequences of the ITS nrDNA are a popular marker to analyze hybrid relationships, but variation of this multicopy spacer region is affected by concerted evolution, high intraindividual polymorphism, and shifts in mode of reproduction. The relevance of changes in secondary structure is still under dispute. We aim to shed light on the extent of polymorphism within and between sexual species and their putative natural as well as synthetic hybrid derivatives in the Ranunculus auricomus complex to test morphology-based hypotheses of hybrid origin and parentage of taxa. We employed direct sequencing of ITS nrDNA from 68 individuals representing three sexuals, their synthetic hybrids and one sympatric natural apomict, as well as cloning of ITS copies in four representative individuals, RNA secondary structure analysis, and landmark geometric morphometric analysis on leaves. Phylogenetic network analyses indicate additivity of parental ITS variants in both synthetic and natural hybrids. The triploid synthetic hybrids are genetically much closer to their maternal progenitors, probably due to ploidy dosage effects, although exhibiting a paternal-like leaf morphology. The natural hybrids are genetically and morphologically closer to the putative paternal progenitor species. Secondary structures of ITS1-5.8S-ITS2 were rather conserved in all taxa. The observed similarities in ITS polymorphisms suggest that the natural apomict R. variabilis is an ancient hybrid of the diploid sexual species R. notabilis and the sexual species R. cassubicifolius. The additivity pattern shared by R. variabilis and the synthetic hybrids supports an evolutionary and biogeographical scenario that R. variabilis originated from ancient hybridization. Concerted evolution of ITS copies in R. variabilis is incomplete, probably due to a shift to asexual reproduction. Under the condition of

  12. Selection and trans-species polymorphism of major histocompatibility complex class II genes in the order Crocodylia.

    PubMed

    Jaratlerdsiri, Weerachai; Isberg, Sally R; Higgins, Damien P; Miles, Lee G; Gongora, Jaime

    2014-01-01

    Major Histocompatibility Complex (MHC) class II genes encode for molecules that aid in the presentation of antigens to helper T cells. MHC characterisation within and between major vertebrate taxa has shed light on the evolutionary mechanisms shaping the diversity within this genomic region, though little characterisation has been performed within the Order Crocodylia. Here we investigate the extent and effect of selective pressures and trans-species polymorphism on MHC class II α and β evolution among 20 extant species of Crocodylia. Selection detection analyses showed that diversifying selection influenced MHC class II β diversity, whilst diversity within MHC class II α is the result of strong purifying selection. Comparison of translated sequences between species revealed the presence of twelve trans-species polymorphisms, some of which appear to be specific to the genera Crocodylus and Caiman. Phylogenetic reconstruction clustered MHC class II α sequences into two major clades representing the families Crocodilidae and Alligatoridae. However, no further subdivision within these clades was evident and, based on the observation that most MHC class II α sequences shared the same trans-species polymorphisms, it is possible that they correspond to the same gene lineage across species. In contrast, phylogenetic analyses of MHC class II β sequences showed a mixture of subclades containing sequences from Crocodilidae and/or Alligatoridae, illustrating orthologous relationships among those genes. Interestingly, two of the subclades containing sequences from both Crocodilidae and Alligatoridae shared specific trans-species polymorphisms, suggesting that they may belong to ancient lineages pre-dating the divergence of these two families from the common ancestor 85-90 million years ago. The results presented herein provide an immunogenetic resource that may be used to further assess MHC diversity and functionality in Crocodylia.

  13. Selection and Trans-Species Polymorphism of Major Histocompatibility Complex Class II Genes in the Order Crocodylia

    PubMed Central

    Jaratlerdsiri, Weerachai; Isberg, Sally R.; Higgins, Damien P.; Miles, Lee G.; Gongora, Jaime

    2014-01-01

    Major Histocompatibility Complex (MHC) class II genes encode for molecules that aid in the presentation of antigens to helper T cells. MHC characterisation within and between major vertebrate taxa has shed light on the evolutionary mechanisms shaping the diversity within this genomic region, though little characterisation has been performed within the Order Crocodylia. Here we investigate the extent and effect of selective pressures and trans-species polymorphism on MHC class II α and β evolution among 20 extant species of Crocodylia. Selection detection analyses showed that diversifying selection influenced MHC class II β diversity, whilst diversity within MHC class II α is the result of strong purifying selection. Comparison of translated sequences between species revealed the presence of twelve trans-species polymorphisms, some of which appear to be specific to the genera Crocodylus and Caiman. Phylogenetic reconstruction clustered MHC class II α sequences into two major clades representing the families Crocodilidae and Alligatoridae. However, no further subdivision within these clades was evident and, based on the observation that most MHC class II α sequences shared the same trans-species polymorphisms, it is possible that they correspond to the same gene lineage across species. In contrast, phylogenetic analyses of MHC class II β sequences showed a mixture of subclades containing sequences from Crocodilidae and/or Alligatoridae, illustrating orthologous relationships among those genes. Interestingly, two of the subclades containing sequences from both Crocodilidae and Alligatoridae shared specific trans-species polymorphisms, suggesting that they may belong to ancient lineages pre-dating the divergence of these two families from the common ancestor 85–90 million years ago. The results presented herein provide an immunogenetic resource that may be used to further assess MHC diversity and functionality in Crocodylia. PMID:24503938

  14. Gender differences in association between serotonin transporter gene polymorphism and resting-state EEG activity.

    PubMed

    Volf, N V; Belousova, L V; Knyazev, G G; Kulikov, A V

    2015-01-22

    Human brain oscillations represent important features of information processing and are highly heritable. Gender has been observed to affect association between the 5-HTTLPR (serotonin-transporter-linked polymorphic region) polymorphism and various endophenotypes. This study aimed to investigate the effects of 5-HTTLPR on the spontaneous electroencephalography (EEG) activity in healthy male and female subjects. DNA samples extracted from buccal swabs and resting EEG recorded at 60 standard leads were collected from 210 (101 men and 109 women) volunteers. Spectral EEG power estimates and cortical sources of EEG activity were investigated. It was shown that effects of 5-HTTLPR polymorphism on electrical activity of the brain vary as a function of gender. Women with the S/L genotype had greater global EEG power compared to men with the same genotype. In men, current source density was markedly different among genotype groups in only alpha 2 and alpha 3 frequency ranges: S/S allele carriers had higher current source density estimates in the left inferior parietal lobule in comparison with the L/L group. In women, genotype difference in global power asymmetry was found in the central-temporal region. Contrasting L/L and S/L genotype carriers also yielded significant effects in the right hemisphere inferior parietal lobule and the right postcentral gyrus with L/L genotype carriers showing lower current source density estimates than S/L genotype carriers in all but gamma bands. So, in women, the effects of 5-HTTLPR polymorphism were associated with modulation of the EEG activity in a wide range of EEG frequencies. The significance of the results lies in the demonstration of gene by sex interaction with resting EEG that has implications for understanding sex-related differences in affective states, emotion and cognition.

  15. Association of FKBP5 polymorphisms and resting-state activity in a frontotemporal–parietal network

    PubMed Central

    Bryant, R A; Felmingham, K L; Liddell, B; Das, P; Malhi, G S

    2016-01-01

    The FKBP5 polymorphism is a key regulator of the glucocorticoid system underpinning stress responsivity, and risk alleles can increase vulnerability for developing posttraumatic stress disorder. To delineate the specific role of FKBP5 risk alleles unencumbered by the confounds of psychopathology, this study investigated whether high-risk alleles of the FKBP5 polymorphism are characterized by distinctive neural activity during resting state. Thirty-seven healthy participants were selected on the basis of four SNPs in the FKBP5 gene region (rs3800373, rs9296158, rs1360780 and rs9470080) to determine participants who were carriers of the FKBP5 high- and low-risk alleles. Spatial maps, power spectra and connectivity in neural networks active during resting state were assessed with functional magnetic resonance imaging (fMRI). During resting-state fMRI, FKBP5 low-risk allele group displayed more power in the low frequency range (<0.1 Hz) than the high-risk allele group, who had significantly more power in higher frequency bins (>0.15 Hz). This difference was apparent only in a frontotemporoparietal network underpinning salience detection and emotion processing. This study provides initial evidence that the risk alleles of the FKBP5 polymorphism are associated with different resting-state activity in a frontotemporal–parietal network, and may point to mechanisms underpinning high-risk carriers' vulnerability to severe stress reactions. PMID:27754486

  16. IL23R(Arg381Gln) Functional Polymorphism Is Associated with Active Pulmonary Tuberculosis Severity

    PubMed Central

    Boukadida, Jalel

    2012-01-01

    The purpose of our study was to investigate the association between a functional single nucleotide polymorphism (SNP) in the interleukin-23 receptor gene (IL23R; rs11209026, 1142 Gwild type → Areduced function, Arg381Gln) and disease severity outcome in pulmonary tuberculosis (TB) in the Tunisian population. SNP was investigated in a population of 168 patients with active pulmonary TB (cases were stratified into patients with minimal/moderate lung involvement, i.e., patients with minimal/moderate disease [Pmd], and patients with extensive lung involvement, i.e., patients with active disease [Pad]) and 150 healthy subjects. Genotype analyses were carried out using the PCR-restriction fragment length polymorphism method. We have found that the IL23R reduced-function allele 1142A and genotypes AA and AG were overrepresented, especially in the Pad subgroup compared with the control group (51% versus 18% [P = 10−8], 33% versus 5% [P = 10−8], and 36% versus 26% [P = 5 × 10−3], respectively). Additionally, comparison of the Pad and the Pmd groups showed that the A allele and AA genotype seemed to be associated with 2.79-fold (P = 4 × 10−5) and 7.74-fold (P = 10−5) increased risks of TB with minimal/moderate lung involvement, respectively. Our results demonstrate that the reduced-function polymorphism 1142G → A encoded by IL23R influences the outcome of disease severity of active pulmonary TB in Tunisian patients. PMID:22695161

  17. Cancer Activation and Polymorphisms of Human Cytochrome P450 1B1.

    PubMed

    Chun, Young-Jin; Kim, Donghak

    2016-04-01

    Human cytochrome P450 enzymes (P450s, CYPs) are major oxidative catalysts that metabolize various xenobiotic and endogenous compounds. Many carcinogens induce cancer only after metabolic activation and P450 enzymes play an important role in this phenomenon. P450 1B1 mediates bioactivation of many procarcinogenic chemicals and carcinogenic estrogen. It catalyzes the oxidation reaction of polycyclic aromatic carbons, heterocyclic and aromatic amines, and the 4-hydroxylation reaction of 17β-estradiol. Enhanced expression of P450 1B1 promotes cancer cell proliferation and metastasis. There are at least 25 polymorphic variants of P450 1B1 and some of these have been reported to be associated with eye diseases. In addition, P450 1B1 polymorphisms can greatly affect the metabolic activation of many procarcinogenic compounds. It is necessary to understand the relationship between metabolic activation of such substances and P450 1B1 polymorphisms in order to develop rational strategies for the prevention of its toxic effect on human health.

  18. Cancer Activation and Polymorphisms of Human Cytochrome P450 1B1

    PubMed Central

    Chun, Young-Jin; Kim, Donghak

    2016-01-01

    Human cytochrome P450 enzymes (P450s, CYPs) are major oxidative catalysts that metabolize various xenobiotic and endogenous compounds. Many carcinogens induce cancer only after metabolic activation and P450 enzymes play an important role in this phenomenon. P450 1B1 mediates bioactivation of many procarcinogenic chemicals and carcinogenic estrogen. It catalyzes the oxidation reaction of polycyclic aromatic carbons, heterocyclic and aromatic amines, and the 4-hydroxylation reaction of 17β-estradiol. Enhanced expression of P450 1B1 promotes cancer cell proliferation and metastasis. There are at least 25 polymorphic variants of P450 1B1 and some of these have been reported to be associated with eye diseases. In addition, P450 1B1 polymorphisms can greatly affect the metabolic activation of many procarcinogenic compounds. It is necessary to understand the relationship between metabolic activation of such substances and P450 1B1 polymorphisms in order to develop rational strategies for the prevention of its toxic effect on human health. PMID:27123158

  19. Restriction fragment length polymorphism within the class I gene loci of the equine major histocompatibility complex

    SciTech Connect

    Alexander, A.J.; Bailey, E.; Woodward, J.G.

    1986-03-05

    Fourteen standard bred horses were serotyped as homozygous for 1 of 6 Equine Leukocyte Antigen (ELA) specificities. DNA was purified from peripheral leukocytes and digested with Hind III or Pvu II. Southern blot hybridization analysis was carried out using a /sup 32/P-labeled mouse cDNA probe (PH2IIa) specific for class I MHC genes. Both enzymes generated blots that contained a large number of bands (23 to 30) per horse. Significant polymorphism existed among most fragment sizes, while a dozen highly conserved band sizes suggested the presence of Qa/tla - like genes. Only 2 animals (both W6's) showed identical band patterns. Polymorphism was greatest between horses of different serotypes and was significantly decreased within serotypes. Unique bands were present on both blots for both W1's and W6's and may account for the serologic specificity seen in ELA W1 and W6 horses. This study is consistent with the findings in other higher vertebrates and implies that the MHC of the horse includes a highly polymorphic class I multigene family.

  20. Glass Durability Modeling, Activated Complex Theory (ACT)

    SciTech Connect

    CAROL, JANTZEN

    2005-02-04

    The most important requirement for high-level waste glass acceptance for disposal in a geological repository is the chemical durability, expressed as a glass dissolution rate. During the early stages of glass dissolution in near static conditions that represent a repository disposal environment, a gel layer resembling a membrane forms on the glass surface through which ions exchange between the glass and the leachant. The hydrated gel layer exhibits acid/base properties which are manifested as the pH dependence of the thickness and nature of the gel layer. The gel layer has been found to age into either clay mineral assemblages or zeolite mineral assemblages. The formation of one phase preferentially over the other has been experimentally related to changes in the pH of the leachant and related to the relative amounts of Al{sup +3} and Fe{sup +3} in a glass. The formation of clay mineral assemblages on the leached glass surface layers ,lower pH and Fe{sup +3} rich glasses, causes the dissolution rate to slow to a long-term steady state rate. The formation of zeolite mineral assemblages ,higher pH and Al{sup +3} rich glasses, on leached glass surface layers causes the dissolution rate to increase and return to the initial high forward rate. The return to the forward dissolution rate is undesirable for long-term performance of glass in a disposal environment. An investigation into the role of glass stoichiometry, in terms of the quasi-crystalline mineral species in a glass, has shown that the chemistry and structure in the parent glass appear to control the activated surface complexes that form in the leached layers, and these mineral complexes ,some Fe{sup +3} rich and some Al{sup +3} rich, play a role in whether or not clays or zeolites are the dominant species formed on the leached glass surface. The chemistry and structure, in terms of Q distributions of the parent glass, are well represented by the atomic ratios of the glass forming components. Thus, glass

  1. Polymorphic phase behavior of platelet-activating factor.

    PubMed Central

    Huang, C; Mason, J T; Stephenson, F A; Levin, I W

    1986-01-01

    Vibrational Raman and 31P NMR spectroscopic experiments have been performed as a function of temperature on aqueous dispersions of 1-0-octadecyl-2-acetoyl-sn-glycero-3-phosphocholine, a chemically synthesized platelet-activating factor. In the temperature range of -7 to 30 degrees C, the C(18)/PAF-H2O system is shown, upon heating, to undergo two thermal phase transitions centered at 9.2 degrees and 18.4 degrees C. The low temperature transition, attributed to the interdigitated lamellar gel (II)----gel (I) phase transition, is characterized by the breakdown of large lamellar organizations into small, but aggregated, bilayer vesicles. The high-temperature transition corresponds to the interdigitated lamellar gel (I)----micellar transition. The molecular ordering and packing structure of C(18)/PAF in the two lamellar phases and phase transition regions are described. It appears that the interdigitated lamellar gel (I) phase is unique for C(18)/PAF dispersions when compared with the behavior of other chemically closely related phospholipids in excess water. PMID:3697472

  2. Genetic polymorphisms in peroxisome proliferator-activated receptor delta associated with obesity.

    PubMed

    Shin, Hyoung Doo; Park, Byung Lae; Kim, Lyoung Hyo; Jung, Hye Seung; Cho, Young Min; Moon, Min Kyong; Park, Young Joo; Lee, Hong Kyu; Park, Kyong Soo

    2004-03-01

    Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors regulating the expression of genes involved in lipid and glucose metabolism. Three different PPARs, PPAR-alpha, -gamma, and -delta, have been characterized, and they are distinguished from each other by tissue distribution and cell activation. All PPARs are, to different extents, activated by fatty acids and derivatives. Recently, it has been shown that PPAR-delta serves as a widespread regulator of fat burning, suggesting that it might be a potential target in the treatment of obesity and type 2 diabetes. In an effort to identify polymorphic markers in potential candidate genes for type 2 diabetes, we have sequenced PPAR-delta, including -1,500 bp of the 5' flanking region. Nine polymorphisms were identified in PPAR-delta: four in the intron, one in the 5' untranslated region (UTR), and four in the 3' UTR. Among identified polymorphisms, five common sites, including c.-13454G>T, c.-87T>C, c.2022+12G>A, c.2629T>C, and c.2806C>G, were genotyped in subjects with type 2 diabetes and normal control subjects (n = 702). The genetic associations with the risk of type 2 diabetes and metabolic phenotype were analyzed. No significant associations with the risk of type 2 diabetes were detected. However, several positive associations of PPAR-delta polymorphisms with fasting plasma glucose and BMI were detected in nondiabetic control subjects. The genetic information about PPAR-delta from this study would be useful for further genetic study of obesity, diabetes, and other metabolic diseases.

  3. Additional Common Polymorphisms in the PON Gene Cluster Predict PON1 Activity but Not Vascular Disease

    PubMed Central

    Kim, Daniel S.; Burt, Amber A.; Ranchalis, Jane E.; Richter, Rebecca J.; Marshall, Julieann K.; Eintracht, Jason F.; Rosenthal, Elisabeth A.; Furlong, Clement E.; Jarvik, Gail P.

    2012-01-01

    Background. Paraoxonase 1 (PON1) enzymatic activity has been consistently predictive of cardiovascular disease, while the genotypes at the four functional polymorphisms at PON1 have not. The goal of this study was to identify additional variation at the PON gene cluster that improved prediction of PON1 activity and determine if these variants predict carotid artery disease (CAAD). Methods. We considered 1,328 males in a CAAD cohort. 51 tagging single-nucleotide polymorphisms (tag SNPs) across the PON cluster were evaluated to determine their effects on PON1 activity and CAAD status. Results. Six SNPs (four in PON1 and one each in PON2/3) predicted PON1 arylesterase (AREase) activity, in addition to the four previously known functional SNPs. In total, the 10 SNPs explained 30.1% of AREase activity, 5% of which was attributable to the six identified predictive SNPs. We replicate rs854567 prediction of 2.3% of AREase variance, the effects of rs3917510, and a PON3 haplotype that includes rs2375005. While AREase activity strongly predicted CAAD, none of the 10 SNPs predicting AREase predicted CAAD. Conclusions. This study identifies new genetic variants that predict additional PON1 AREase activity. Identification of SNPs associated with PON1 activity is required when evaluating the many phenotypes associated with genetic variation near PON1. PMID:22685667

  4. Polymorphism in the major histocompatibility complex (MHC class II B) genes of the Rufous-backed Bunting (Emberiza jankowskii)

    PubMed Central

    Li, Dan; Zhao, Yunjiao; Lin, Aiqing; Li, Shi; Feng, Jiang

    2017-01-01

    Genetic diversity is one of the pillars of conservation biology research. High genetic diversity and abundant genetic variation in an organism may be suggestive of capacity to adapt to various environmental changes. The major histocompatibility complex (MHC) is known to be highly polymorphic and plays an important role in immune function. It is also considered an ideal model system to investigate genetic diversity in wildlife populations. The Rufous-backed Bunting (Emberiza jankowskii) is an endangered species that has experienced a sharp decline in both population and habitat size. Many historically significant populations are no longer present in previously populated regions, with only three breeding populations present in Inner Mongolia (i.e., the Aolunhua, Gahaitu and Lubei557 populations). Efforts focused on facilitating the conservation of the Rufous-backed Bunting (Emberiza jankowskii) are becoming increasingly important. However, the genetic diversity of E. jankowskii has not been investigated. In the present study, polymorphism in exon 2 of the MHCIIB of E. jankowskii was investigated. This polymorphism was subsequently compared with a related species, the Meadow Bunting (Emberiza cioides). A total of 1.59 alleles/individual were detected in E. jankowskii and 1.73 alleles/individual were identified in E. cioides. The maximum number of alleles per individual from the three E. jankowskii populations suggest the existence of at least three functional loci, while the maximum number of alleles per individual from the three E. cioides populations suggest the presence of at least four functional loci. Two of the alleles were shared between the E. jankowskii and E. cioides. Among the 12 unique alleles identified in E. jankowskii, 10.17 segregating sites per allele were detected, and the nucleotide diversity was 0.1865. Among the 17 unique alleles identified in E. cioides, eight segregating sites per allele were detected, and the nucleotide diversity was 0

  5. Active Monitoring Complex-Envelope Processing

    NASA Astrophysics Data System (ADS)

    Unger, R.

    2011-12-01

    Pseudo-random 3-D signal transmission followed by quadrature signal processing significantly enhances seismic Active Monitoring (AM). The algorithm produces complex-envelope seismograms consisting of the dual time series of instantaneous amplitude and phase. Minimum-standard-deviation signal arrival detection and timing from coherent instantaneous-phase seismogram ensembles yields signal time errors inversely proportional to frequency and signal-to-noise ratio. In particular, application to piezo-electric acoustic cross well monitoring as in SAFOD experiments should result in nano-second multiple-signal detection and timing precision. The method is applicable to all types (seismic, EM, acoustic) of AM.

  6. Association of the macrophage activating factor (MAF) precursor activity with polymorphism in vitamin D-binding protein.

    PubMed

    Nagasawa, Hideko; Sasaki, Hideyuki; Uto, Yoshihiro; Kubo, Shinichi; Hori, Hitoshi

    2004-01-01

    Serum vitamin D-binding protein (Gc protein or DBP) is a highly expressed polymorphic protein, which is a precursor of the inflammation-primed macrophage activating factor, GcMAF, by a cascade of carbohydrate processing reactions. In order to elucidate the relationship between Gc polymorphism and GcMAF precursor activity, we estimated the phagocytic ability of three homotypes of Gc protein, Gc1F-1F, Gc1S-1S and Gc2-2, through processing of their carbohydrate moiety. We performed Gc typing of human serum samples by isoelectric focusing (IEF). Gc protein from human serum was purified by affinity chromatography with 25-hydroxyvitamin D3-sepharose. A phagocytosis assay of Gc proteins, modified using beta-glycosidase and sialidase, was carried out. The Gc1F-1F phenotype was revealed to possess Galbeta1-4GalNAc linkage by the analysis of GcMAF precursor activity using beta1-4 linkage-specific galactosidase from jack bean. The GcMAF precursor activity of the Gc1F-1F phenotype was highest among three Gc homotypes. The Gc polymorphism and carbohydrate diversity of Gc protein are significant for its pleiotropic effects.

  7. Globoid cell leukodystrophy (Krabbe disease): normal umbilical cord blood galactocerebrosidase activity and polymorphic mutations.

    PubMed

    Raghavan, S; Zeng, B; Torres, P A; Pastores, G M; Kolodny, E H; Kurtzberg, J; Krivit, W

    2005-01-01

    Globoid cell leukodystrophy is an inherited metabolic disorder of the central nervous system caused by deficiency of the lysosomal enzyme galactocerebrosidase. Haematopoietic stem cell transplantation is the only available effective treatment. The engraftment from normal donors provides competent cells able to correct the metabolic defect. Umbilical cord blood cells have proved to significantly decrease complications and improve engraftment rate compared to adult marrow cells in haematopoietic stem cell transplantation. Umbilical cord blood cells must be of sufficient activity to provide central nervous system recovery after engraftment is obtained. Galactocerebrosidase activity is known to be affected by two polymorphic alleles found at nucleotides 502 and 1637 of the cDNA for this gene. This enzyme activity and the polymorphic alleles noted above were analysed in 83 random samples of umbilical cord blood. The activity, assayed with the fluorogenic substrate 6-hexadecanoylamino-4-methylumbelliferyl-beta-galactopyranoside, in those with neither polymorphic allele was 4.6 +/- 1.7 units (nmol/h per mg protein). This optimal choice of cord blood was found in only 24% of specimens. Homozygotes for 1637T > C with activity of only 1.5 +/- 0.4 units represented 16% of the samples. Those heterozygous for 1637T > C with slightly better activity (2.3 +/- 0.7 units) represented 52% of the samples. Choice of umbilical cord blood for haematopoietic stem cell transplantation, therefore, requires consideration not only of cell quantity and HLA compatibility but also selection for normal alleles to obtain maximal enzymatic activity for central nervous system correction.

  8. Cloning, expression and investigation for polymorphisms of canine peroxisome proliferator-activated receptors.

    PubMed

    Nishii, Naohito; Takasu, Masaki; Soe, Ok Kar; Maeda, Sadatoshi; Ohba, Yasunori; Inoue-Murayama, Miho; Kitagawa, Hitoshi

    2007-08-01

    Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors implicated in lipid metabolism. In this study, the full-length cDNA of canine PPARbeta and gamma were sequenced, and expression of PPARs was evaluated in normal tissues and primary cultures of adipocytes in dogs, followed by investigations for polymorphisms of canine PPARgamma. Comparison of the deduced amino acid sequences of canine PPARbeta and gamma cDNA with that of human PPARbeta and gamma cDNA revealed 95.9% and 98.2% identity, respectively. PPARbeta expression was ubiquitous and high PPARgamma expression was detected in the subcutaneous and omental adipose tissues, spleen and large intestine. Canine PPARgamma mRNA expression in cultured adipocytes began to increase from 4 days after induction of differentiation, and increased nearly ninefold within 10 days after induction of differentiation. Although expression level of PPARalpha was low in the cultured adipocytes, it slightly increased within 10 days. In contrast, expression of PPARbeta showed only small variations during adipocyte differentiation, though expression levels were relatively high. These results suggest that PPARgamma may play an important role in adipocyte differentiation in dogs. Investigations for polymorphisms of PPARgamma revealed a silent polymorphism, C1362T, in 3 of 92 dogs.

  9. Biologic Activity of Porphyromonas endodontalis complex lipids

    PubMed Central

    Mirucki, Christopher S.; Abedi, Mehran; Jiang, Jin; Zhu, Qiang; Wang, Yu-Hsiung; Safavi, Kamran E.; Clark, Robert B.; Nichols, Frank C.

    2014-01-01

    Introduction Periapical infections secondary to pulpal necrosis are associated with bacterial contamination of the pulp. Porphyromonas endodontalis, a Gram-negative organism, is considered to be a pulpal pathogen. P. gingivalis is phylogenetically related to P. endodontalis and synthesizes several classes of novel complex lipids that possess biological activity, including the capacity to promote osteoclastogenesis and osteoclast activation. The purpose of this study was to extract and characterize constituent lipids of P. endodontalis, and evaluate their capacity to promote pro-inflammatory secretory responses in the macrophage cell line, RAW 264.7, as well as their capacity to promote osteoclastogenesis and inhibit osteoblast activity. Methods Constituent lipids of both organisms were fractionated by HPLC and were structurally characterized using electrospray-mass spectrometry (ESI-MS) or ESI-MS/MS. The virulence potential of P. endodontalis lipids was then compared with known biologically active lipids isolated from P. gingivalis. Results P. endodontalis total lipids were shown to promote TNF-α secretion from RAW 264.7 cells and the serine lipid fraction appeared to account for the majority of this effect. P. endodontalis lipid preparations also increased osteoclast formation from RAW 264.7 cells but osteoblast differentiation in culture was inhibited and appeared to be dependent on TLR2 expression. Conclusions These effects underscore the importance of P. endodontalis lipids in promoting inflammatory and bone cell activation processes that could lead to periapical pathology. PMID:25146013

  10. An Association Between Functional Polymorphisms of the Interleukin 1 Gene Complex and Schizophrenia Using Transmission Disequilibrium Test.

    PubMed

    Kapelski, Pawel; Skibinska, Maria; Maciukiewicz, Malgorzata; Pawlak, Joanna; Dmitrzak-Weglarz, Monika; Szczepankiewicz, Aleksandra; Zaremba, Dorota; Twarowska-Hauser, Joanna

    2016-12-01

    IL1 gene complex has been implicated in the etiology of schizophrenia. To assess whether IL1 gene complex is associated with susceptibility to schizophrenia in Polish population we conducted family-based study. Functional polymorphisms from IL1A (rs1800587, rs17561, rs11677416), IL1B (rs1143634, rs1143643, rs16944, rs4848306, rs1143623, rs1143633, rs1143627) and IL1RN (rs419598, rs315952, rs9005, rs4251961) genes were genotyped in 143 trio with schizophrenia. Statistical analysis was performed using transmission disequilibrium test. We have found a trend toward an association of rs1143627, rs16944, rs1143623 in IL1B gene with the risk of schizophrenia. Our results show a protective effect of allele T of rs4251961 in IL1RN against schizophrenia. We also performed haplotype analysis of IL1 gene complex and found a trend toward an association with schizophrenia of GAGG haplotype (rs1143627, rs16944, rs1143623, rs4848306) in IL1B gene, haplotypes: TG (rs315952, rs9005) and TT (rs4251961, rs419598) in IL1RN. Haplotype CT (rs4251961, rs419598) in IL1RN was found to be associated with schizophrenia. After correction for multiple testing associations did not reach significance level. Our results might support theory that polymorphisms of interleukin 1 complex genes (rs1143627, rs16944, rs1143623, rs4848306 in IL1B gene and rs4251961, rs419598, rs315952, rs9005 in IL1RN gene) are involved in the pathogenesis of schizophrenia, however, none of the results reach significance level after correction for multiple testing.

  11. Complex-disease networks of trait-associated single-nucleotide polymorphisms (SNPs) unveiled by information theory

    PubMed Central

    Li, Haiquan; Lee, Younghee; Chen, James L; Rebman, Ellen; Li, Jianrong

    2012-01-01

    Objective Thousands of complex-disease single-nucleotide polymorphisms (SNPs) have been discovered in genome-wide association studies (GWAS). However, these intragenic SNPs have not been collectively mined to unveil the genetic architecture between complex clinical traits. The authors hypothesize that biological annotations of host genes of trait-associated SNPs may reveal the biomolecular modularity across complex-disease traits and offer insights for drug repositioning. Methods Trait-to-polymorphism (SNPs) associations confirmed in GWAS were used. A novel method to quantify trait–trait similarity anchored in Gene Ontology annotations of human proteins and information theory was developed. The results were then validated with the shortest paths of physical protein interactions between biologically similar traits. Results A network was constructed consisting of 280 significant intertrait similarities among 177 disease traits, which covered 1438 well-validated disease-associated SNPs. Thirty-nine percent of intertrait connections were confirmed by curators, and the following additional studies demonstrated the validity of a proportion of the remainder. On a phenotypic trait level, higher Gene Ontology similarity between proteins correlated with smaller ‘shortest distance’ in protein interaction networks of complexly inherited diseases (Spearman p<2.2×10−16). Further, ‘cancer traits’ were similar to one another, as were ‘metabolic syndrome traits’ (Fisher's exact test p=0.001 and 3.5×10−7, respectively). Conclusion An imputed disease network by information-anchored functional similarity from GWAS trait-associated SNPs is reported. It is also demonstrated that small shortest paths of protein interactions correlate with complex-disease function. Taken together, these findings provide the framework for investigating drug targets with unbiased functional biomolecular networks rather than worn-out single-gene and subjective canonical pathway approaches

  12. Plasminogen activator inhibitor-1 4G/5G polymorphism is associated with metabolic syndrome parameters in Malaysian subjects

    PubMed Central

    Al-Hamodi, Zaid H.; Saif-Ali, Riyadh; Ismail, Ikram S.; Ahmed, Khaled A.; Muniandy, Sekaran

    2012-01-01

    The plasminogen activator inhibitor-1 4G/5G and tissue plasminogen activator Alu-repeat insertion/deletion polymorphisms might be genetic determinations of increased or decreased of their plasma activities. The aim of this study was to investigate the association of plasminogen activator inhibitor-1 4G/5G and tissue plasminogen activator Alu-repeat I/D polymorphisms with metabolic syndrome parameters in normal Malaysian subjects and to assess the impact of these polymorphisms on their plasma activities and antigens. The genetic polymorphisms were genotyped in 130 normal subjects. In addition, the plasma activities and antigens of plasminogen activator inhibitor-1 and tissue plasminogen activator as well as levels of insulin, glucose, and lipid profile at fasting state were investigated. The subjects with homozygous 4G/4G showed association with an increased triglyceride (p = 0.007), body mass index (p = 0.01) and diastolic blood pressure (p = 0.03). In addition, the plasminogen activator inhibitor-1 4G/5G polymorphism modulates plasma plasminogen activator inhibitor-1 activity and antigen and tissue plasminogen activator activity (p = 0.002, 0.014, 0.003) respectively. These results showed that, the plasminogen activator inhibitor-1 4G/5G polymorphism is associated with metabolic syndrome parameters, plasminogen activator inhibitor-1 and tissue plasminogen activator activities in Malaysian subjects, and may serve to increase the risk of type 2 diabetes and cardiovascular disease in Malaysian subjects. PMID:22573918

  13. Analysis of the associations between polymorphisms in GNAS complex locus and growth, carcass and meat quality traits in pigs.

    PubMed

    Oczkowicz, Maria; Ropka-Molik, Katarzyna; Tyra, Mirosław

    2013-11-01

    Imprinted genes are interesting candidates for marker assisted selection in farm animals. One of them-GNAS complex locus is engaged in obesity pathogenesis in humans and mice. In our study, we identified new polymorphism in porcine GNAS gene (variable number of CT repeats, accession number: rs196952953) and found that this polymorphism is in linkage disequilibrum with GNAS AM490165:g.324C>T. Statistical analysis (GLM procedure), performed on 552 animals (Large White n = 258 and Landrace n = 269), revealed that deduced haplotypes and GNAS AM490165:g.324C>T are associated with growth performance and a few carcass traits, but not with feed intake. We observed significant additive effects of GNAS AM490165:g.324C>T genotype and haplotype 2 (C/278 bp) on test daily gain (TDG), average daily gain (ADG), number of days on test, age of the slaughter (P < 0.01) and FCR ratio (P < 0.05). Animals with two copies of C/278 haplotype had significantly higher: TDG, ADG, lower feed:gain ratio and faster reached the weight of 100 kg. When carcass traits were considered, significant associations between GNAS AM490165:g.324C>T polymorphism, haplotype 2 (C/278) and weight of ham with and without backfat and skin (WH) (WH2), length of the carcass, height and the width of the loin, meat percentage, weight of the main cuts were identified. The significant dominance effects of GNAS AM490165:g.324C>T polymorphism and haplotype 2 on WH and WH2 were observed (P < 0.05). When the two breeds were analyzed separately significant associations were observed for most of the traits in Landrace while in Large White the same trends were present but the differences were mostly not significant. Among meat quality traits we found significant association between haplotype and IMF content in Landrace (P < 0.03). Our results show for the first time that GNAS complex locus may modulate economically important traits in pigs.

  14. The BDNF Val66Met Polymorphism Influences Reading Ability and Patterns of Neural Activation in Children

    PubMed Central

    Jasińska, Kaja K.; Molfese, Peter J.; Kornilov, Sergey A.; Mencl, W. Einar; Frost, Stephen J.; Lee, Maria; Pugh, Kenneth R.; Grigorenko, Elena L.; Landi, Nicole

    2016-01-01

    Understanding how genes impact the brain’s functional activation for learning and cognition during development remains limited. We asked whether a common genetic variant in the BDNF gene (the Val66Met polymorphism) modulates neural activation in the young brain during a critical period for the emergence and maturation of the neural circuitry for reading. In animal models, the bdnf variation has been shown to be associated with the structure and function of the developing brain and in humans it has been associated with multiple aspects of cognition, particularly memory, which are relevant for the development of skilled reading. Yet, little is known about the impact of the Val66Met polymorphism on functional brain activation in development, either in animal models or in humans. Here, we examined whether the BDNF Val66Met polymorphism (dbSNP rs6265) is associated with children’s (age 6–10) neural activation patterns during a reading task (n = 81) using functional magnetic resonance imaging (fMRI), genotyping, and standardized behavioral assessments of cognitive and reading development. Children homozygous for the Val allele at the SNP rs6265 of the BDNF gene outperformed Met allele carriers on reading comprehension and phonological memory, tasks that have a strong memory component. Consistent with these behavioral findings, Met allele carriers showed greater activation in reading–related brain regions including the fusiform gyrus, the left inferior frontal gyrus and left superior temporal gyrus as well as greater activation in the hippocampus during a word and pseudoword reading task. Increased engagement of memory and spoken language regions for Met allele carriers relative to Val/Val homozygotes during reading suggests that Met carriers have to exert greater effort required to retrieve phonological codes. PMID:27551971

  15. The BDNF Val66Met Polymorphism Influences Reading Ability and Patterns of Neural Activation in Children.

    PubMed

    Jasińska, Kaja K; Molfese, Peter J; Kornilov, Sergey A; Mencl, W Einar; Frost, Stephen J; Lee, Maria; Pugh, Kenneth R; Grigorenko, Elena L; Landi, Nicole

    2016-01-01

    Understanding how genes impact the brain's functional activation for learning and cognition during development remains limited. We asked whether a common genetic variant in the BDNF gene (the Val66Met polymorphism) modulates neural activation in the young brain during a critical period for the emergence and maturation of the neural circuitry for reading. In animal models, the bdnf variation has been shown to be associated with the structure and function of the developing brain and in humans it has been associated with multiple aspects of cognition, particularly memory, which are relevant for the development of skilled reading. Yet, little is known about the impact of the Val66Met polymorphism on functional brain activation in development, either in animal models or in humans. Here, we examined whether the BDNF Val66Met polymorphism (dbSNP rs6265) is associated with children's (age 6-10) neural activation patterns during a reading task (n = 81) using functional magnetic resonance imaging (fMRI), genotyping, and standardized behavioral assessments of cognitive and reading development. Children homozygous for the Val allele at the SNP rs6265 of the BDNF gene outperformed Met allele carriers on reading comprehension and phonological memory, tasks that have a strong memory component. Consistent with these behavioral findings, Met allele carriers showed greater activation in reading-related brain regions including the fusiform gyrus, the left inferior frontal gyrus and left superior temporal gyrus as well as greater activation in the hippocampus during a word and pseudoword reading task. Increased engagement of memory and spoken language regions for Met allele carriers relative to Val/Val homozygotes during reading suggests that Met carriers have to exert greater effort required to retrieve phonological codes.

  16. Age-related macular degeneration associated polymorphism rs10490924 in ARMS2 results in deficiency of a complement activator.

    PubMed

    Micklisch, Sven; Lin, Yuchen; Jacob, Saskia; Karlstetter, Marcus; Dannhausen, Katharina; Dasari, Prasad; von der Heide, Monika; Dahse, Hans-Martin; Schmölz, Lisa; Grassmann, Felix; Alene, Medhanie; Fauser, Sascha; Neumann, Harald; Lorkowski, Stefan; Pauly, Diana; Weber, Bernhard H; Joussen, Antonia M; Langmann, Thomas; Zipfel, Peter F; Skerka, Christine

    2017-01-05

    Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. The polymorphism rs10490924 in the ARMS2 gene is highly associated with AMD and linked to an indel mutation (del443ins54), the latter inducing mRNA instability. At present, the function of the ARMS2 protein, the exact cellular sources in the retina and the biological consequences of the rs10490924 polymorphism are unclear. Recombinant ARMS2 was expressed in Pichia pastoris, and protein functions were studied regarding cell surface binding and complement activation in human serum using fluoresence-activated cell sorting (FACS) as well as laser scanning microscopy (LSM). Biolayer interferometry defined protein interactions. Furthermore, endogenous ARMS2 gene expression was studied in human blood derived monocytes and in human induced pluripotent stem cell-derived microglia (iPSdM) by PCR and LSM. The ARMS2 protein was localized in human genotyped retinal sections and in purified monocytes derived from AMD patients without the ARMS2 risk variant by LSM. ARMS2 expression in monocytes under oxidative stress was determined by Western blot analysis. Here, we demonstrate for the first time that ARMS2 functions as surface complement regulator. Recombinant ARMS2 binds to human apoptotic and necrotic cells and initiates complement activation by recruiting the complement activator properdin. ARMS2-properdin complexes augment C3b surface opsonization for phagocytosis. We also demonstrate for the first time expression of ARMS2 in human monocytes especially under oxidative stress and in microglia cells of the human retina. The ARMS2 protein is absent in monocytes and also in microglia cells, derived from patients homozygous for the ARMS2 AMD risk variant (rs10490924). ARMS2 is likely involved in complement-mediated clearance of cellular debris. As AMD patients present with accumulated proteins and lipids on Bruch's membrane, ARMS2 protein deficiency due to the genetic risk variant

  17. MDR-1 and MRP2 Gene Polymorphisms in Mexican Epileptic Pediatric Patients with Complex Partial Seizures

    PubMed Central

    Escalante-Santiago, David; Feria-Romero, Iris Angélica; Ribas-Aparicio, Rosa María; Rayo-Mares, Dario; Fagiolino, Pietro; Vázquez, Marta; Escamilla-Núñez, Consuelo; Grijalva-Otero, Israel; López-García, Miguel Angel; Orozco-Suárez, Sandra

    2014-01-01

    Although the Pgp efflux transport protein is overexpressed in resected tissue of patients with epilepsy, the presence of polymorphisms in MDR1/ABCB1 and MRP2/ABCC2 in patients with antiepileptic-drugs resistant epilepsy (ADR) is controversial. The aim of this study was to perform an exploratory study to identify nucleotide changes and search new and reported mutations in patients with ADR and patients with good response (CTR) to antiepileptic drugs (AEDs) in a rigorously selected population. We analyzed 22 samples In Material and Methods, from drug-resistant patients with epilepsy and 7 samples from patients with good response to AEDs. Genomic DNA was obtained from leukocytes. Eleven exons in both genes were genotyped. The concentration of drugs in saliva and plasma was determined. The concentration of valproic acid in saliva was lower in ADR than in CRT. In ABCB1, five reported SNPs and five unreported nucleotide changes were identified; rs2229109 (GA) and rs2032582 (AT and AG) were found only in the ADR. Of six SNPs associated with the ABCC2 that were found in the study population, rs3740066 (TT) and 66744T > A (TG) were found only in the ADR. The strongest risk factor in the ABCB1 gene was identified as the TA genotype of rs2032582, whereas for the ABCC2 gene the strongest risk factor was the T allele of rs3740066. The screening of SNPs in ACBC1 and ABCC2 indicates that the Mexican patients with epilepsy in this study display frequently reported ABCC1 polymorphisms; however, in the study subjects with a higher risk factor for drug resistance, new nucleotide changes were found in the ABCC2 gene. Thus, the population of Mexican patients with AED-resistant epilepsy (ADR) used in this study exhibits genetic variability with respect to those reported in other study populations; however, it is necessary to explore this polymorphism in a larger population of patients with ADR. PMID:25346718

  18. MDR-1 and MRP2 Gene Polymorphisms in Mexican Epileptic Pediatric Patients with Complex Partial Seizures.

    PubMed

    Escalante-Santiago, David; Feria-Romero, Iris Angélica; Ribas-Aparicio, Rosa María; Rayo-Mares, Dario; Fagiolino, Pietro; Vázquez, Marta; Escamilla-Núñez, Consuelo; Grijalva-Otero, Israel; López-García, Miguel Angel; Orozco-Suárez, Sandra

    2014-01-01

    Although the Pgp efflux transport protein is overexpressed in resected tissue of patients with epilepsy, the presence of polymorphisms in MDR1/ABCB1 and MRP2/ABCC2 in patients with antiepileptic-drugs resistant epilepsy (ADR) is controversial. The aim of this study was to perform an exploratory study to identify nucleotide changes and search new and reported mutations in patients with ADR and patients with good response (CTR) to antiepileptic drugs (AEDs) in a rigorously selected population. We analyzed 22 samples In Material and Methods, from drug-resistant patients with epilepsy and 7 samples from patients with good response to AEDs. Genomic DNA was obtained from leukocytes. Eleven exons in both genes were genotyped. The concentration of drugs in saliva and plasma was determined. The concentration of valproic acid in saliva was lower in ADR than in CRT. In ABCB1, five reported SNPs and five unreported nucleotide changes were identified; rs2229109 (GA) and rs2032582 (AT and AG) were found only in the ADR. Of six SNPs associated with the ABCC2 that were found in the study population, rs3740066 (TT) and 66744T > A (TG) were found only in the ADR. The strongest risk factor in the ABCB1 gene was identified as the TA genotype of rs2032582, whereas for the ABCC2 gene the strongest risk factor was the T allele of rs3740066. The screening of SNPs in ACBC1 and ABCC2 indicates that the Mexican patients with epilepsy in this study display frequently reported ABCC1 polymorphisms; however, in the study subjects with a higher risk factor for drug resistance, new nucleotide changes were found in the ABCC2 gene. Thus, the population of Mexican patients with AED-resistant epilepsy (ADR) used in this study exhibits genetic variability with respect to those reported in other study populations; however, it is necessary to explore this polymorphism in a larger population of patients with ADR.

  19. Association of G22A and A4223C ADA1 gene polymorphisms and ADA activity with PCOS.

    PubMed

    Salehabadi, Mahshid; Farimani, Marzieh; Tavilani, Heidar; Ghorbani, Marzieh; Poormonsefi, Faranak; Poorolajal, Jalal; Shafiei, Gholamreza; Ghasemkhani, Neda; Khodadadi, Iraj

    2016-06-01

    Adenosine deaminase-1 (ADA1) regulates the concentration of adenosine as the main modulator of oocyte maturation. There is compelling evidence for the association of ADA1 gene polymorphisms with many diseases but the importance of ADA1 polymorphisms in polycystic ovary syndrome (PCOS) has not been studied before. This study investigates serum total ADA activity (tADA), ADA1 and ADA2 isoenzyme activities, and genotype and allele frequencies of G22A and A4223C polymorphisms in healthy and PCOS women. In this case-control study 200 PCOS patients and 200 healthy women were enrolled. Genomic DNA was extracted from whole blood and the PCR-RFLP technique was used to determine the G22A and A4223C variants. The genotype frequencies were calculated and the association between polymorphic genotypes and enzyme activities were determined. tADA activity was significantly lower in the PCOS group compared with the control group (27.76±6.0 vs. 39.63±7.48, respectively). PCOS patients also showed reduced activity of ADA1 and ADA2. PCOS was not associated with G22A polymorphism whereas AA, AC, and CC genotypes of A4223C polymorphism were found distributed differently between the control and the PCOS women where the C allele showed a strong protective role for PCOS (odds ratio=1.876, p=0.033). The present study for the first time showed that lower ADA activity may be involved in pathogenesis of PCOS by maintaining a higher concentration of adenosine affecting follicular growth. As a novel finding, we also showed great differences in genotype distribution and allele frequencies of A4223C polymorphism between groups indicating a protective role for C allele against PCOS. AbbreviationsADA: adenosine deaminase PCOS: polycystic ovary syndrome PCR-RFLP: polymerase chain reaction-restriction fragment length polymorphism tADA: total adenosine deaminase.

  20. Paraoxonase (PON1) polymorphism and activity as the determinants of sensitivity to organophosphates in human subjects.

    PubMed

    Sirivarasai, Jintana; Kaojarern, Sming; Yoovathaworn, Krongtong; Sura, Thanyachai

    2007-07-20

    Paraoxonase (PON1) plays an important role in mechanism of organophosphorus compound (OP) toxicity, as seen both in vitro and in vivo studies. Polymorphisms of PON1 gene at coding and promoter regions have also been to affect on the hydrolytic activity and PON1 level. The objectives of this study were to determine PON1 polymorphism and activity in an OP-exposed population and the effects on inhibition of cholinesterase activity. The studied population consisted of control (n=30) and exposed groups (n=90). All enzyme activities (AChE, BuChE, paraoxonase, arylesterase and diazonase) were measured once for control group and two periods of exposure for exposed group. Three polymorphisms of PON1 (Q192R, L55M and T-108C) were identified only in the exposed subjects. The results demonstrated that AChE activity in both high (345.5 microkat/gHb) and low exposure periods (496.9 microkat/gHb) of the exposed group were significantly different from control group (649.7 microkat/gHb, p<0.01). For BuChE activity, the exposed group also showed the statistically lower level in both periods (high exposure period: 62.17 microkat/L and low exposure period: 81.84 microkat/L) than those in the control group (93.35 microkat/L). Serum paraoxonase activity was significantly different among individual genotypes, RR>QR>RR, LL>LM and -108CC>-108CT>-108TT, but this was not found for those of arylesterase and diazonase activities. Q192R and L55M as well as Q192R and T-108C also presented substantial linkage disequilibrium. Further analysis was performed with haplotypes and various enzyme activities. AChE activity was not affected by haplotypes. Individuals with "211" haplotype showed significantly higher paraoxonase activity and BuChE activity than other haplotypes but not in diazonase activity. In conclusion, PON1 gene exhibited a wide variation in enzyme activities both within and between genotypes which implied insights of a potentially difference in sensitivity to OP toxicity.

  1. Plasminogen activator inhibitor-1 4G/5G polymorphism is associated with type 2 diabetes risk

    PubMed Central

    Zhao, Luqian; Huang, Ping

    2013-01-01

    A number of studies were performed to assess the association between plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism and susceptibility to type 2 diabetes (T2DM). However, the results were inconsistent and inconclusive. In the present study, the possible association was investigated by a meta-analysis. Eligible articles were identified for the period up to June 2013. Pooled odds ratios (OR) with 95% confidence intervals (CI) were appropriately derived from random-effects models or fixed-effects models. Fourteen case-control studies with a total of 2487 cases and 3538 controls were eligible. In recessive model, PAI-1 4G/5G polymorphism was associated with T2DM risk (OR = 1.23; 95% CI 1.07-1.41; P = 0.004). In the subgroup analysis by ethnicity, a significant association was found among Asians (OR = 1.27; 95% CI 1.08-1.51; P = 0.005). This meta-analysis suggested that PAI-1 4G/5G polymorphism may be associated with T2DM development. PMID:24040470

  2. Divergent population structure and climate associations of a chromosomal inversion polymorphism across the Mimulus guttatus species complex.

    PubMed

    Oneal, Elen; Lowry, David B; Wright, Kevin M; Zhu, Zhirui; Willis, John H

    2014-06-01

    Chromosomal rearrangement polymorphisms are common and increasingly found to be associated with adaptive ecological divergence and speciation. Rearrangements, such as inversions, reduce recombination in heterozygous individuals and thus can protect favourable allelic combinations at linked loci, facilitating their spread in the presence of gene flow. Recently, we identified a chromosomal inversion polymorphism that contributes to ecological adaptation and reproductive isolation between annual and perennial ecotypes of the yellow monkeyflower, Mimulus guttatus. Here we evaluate the population genetic structure of this inverted region in comparison with the collinear regions of the genome across the M. guttatus species complex. We tested whether annual and perennial M. guttatus exhibit different patterns of divergence for loci in the inverted and noninverted regions of the genome. We then evaluated whether there are contrasting climate associations with these genomic regions through redundancy analysis. We found that the inversion exhibits broadly different patterns of divergence among annual and perennial M. guttatus and is associated with environmental variation across population accessions. This study is the first widespread population genetic survey of the diversity of the M. guttatus species complex. Our findings contribute to a greater understanding of morphological, ecological, and genetic evolutionary divergence across this highly diverse group of closely related ecotypes and species. Finally, understanding species relationships among M. guttatus sp. has hitherto been stymied by accumulated evidence of substantial gene flow among populations as well as designated species. Nevertheless, our results shed light on these relationships and provide insight into adaptation in life history traits within the complex.

  3. Plasminogen activator inhibitor-1 C/G polymorphism in relation to plasma levels in rheumatoid arthritis.

    PubMed

    Torres-Carrillo, Norma; Torres-Carrillo, Nora Magdalena; Martínez-Bonilla, Gloria Esther; Vázquez-Del Mercado, Mónica; Palafox-Sánchez, Claudia Azucena; Oregón-Romero, Edith; Bernard-Medina, Ana Guilaisne; Rangel-Villalobos, Héctor; Muñoz-Valle, José Francisco

    2009-09-01

    Plasminogen activator inhibitor type 1 (PAI-1) is an inhibitor of plasmin production. Plasmin can directly or indirectly to degrade cartilage and bone matrix. The PAI-1 HindIII polymorphism has been associated with high PAI-1 plasma levels in myocardial infarction patients and control populations. Furthermore, it has been associated with the angiographic extent of coronary artery disease, but their involvement in other diseases is still uncertain. Here, we assessed the relationship between PAI-1 HindIII polymorphism and PAI-1 plasma levels in rheumatoid arthritis (RA). One hundred and twenty-five RA patients and 132 control subjects (CS) were included. Genotypes were identified by the polymerase chain reaction-restriction fragment length polymorphism technique and PAI-1 plasma levels were quantified using an ELISA kit. Not significant differences in genotype and allele frequencies between both studied groups were observed (P > 0.05). RA patients showed lower PAI-1 plasma levels (18.92 +/- 12.94 ng/ml) than CS (23.68 +/- 23.38 ng/ml), without significant difference (P = 0.299). However, in RA patients the C/G genotype carriers showed higher PAI-1 plasma levels (23.00 +/- 13.81 ng/ml) with respect to C/C (16.77 +/- 11.97 ng/ml) and G/G (10.47 +/- 7.07 ng/ml) genotype carriers (P = 0.036). The PAI-1 HindIII polymorphism was not associated with RA susceptibility. However, the C/G genotype is associated with high PAI-1 plasma levels in RA patients.

  4. Overdominant Effect of a CHRNA4 Polymorphism on Cingulo-Opercular Network Activity and Cognitive Control.

    PubMed

    Sadaghiani, Sepideh; Ng, Bernard; Altmann, Andre; Poline, Jean-Baptiste; Banaschewski, Tobias; Bokde, Arun L W; Bromberg, Uli; Büchel, Christian; Burke Quinlan, Erin; Conrod, Patricia; Desrivières, Sylvane; Flor, Herta; Frouin, Vincent; Garavan, Hugh; Gowland, Penny; Gallinat, Jürgen; Heinz, Andreas; Ittermann, Bernd; Martinot, Jean-Luc; Paillère Martinot, Marie-Laure; Lemaitre, Hervé; Nees, Frauke; Papadopoulos Orfanos, Dimitri; Paus, Tomáš; Poustka, Luise; Millenet, Sabina; Fröhner, Juliane H; Smolka, Michael N; Walter, Henrik; Whelan, Robert; Schumann, Gunter; Napolioni, Valerio; Greicius, Michael

    2017-10-04

    The nicotinic system plays an important role in cognitive control and is implicated in several neuropsychiatric conditions. However, the contributions of genetic variability in this system to individuals' cognitive control abilities are poorly understood and the brain processes that mediate such genetic contributions remain largely unidentified. In this first large-scale neuroimaging genetics study of the human nicotinic receptor system (two cohorts, males and females, fMRI total N = 1586, behavioral total N = 3650), we investigated a common polymorphism of the high-affinity nicotinic receptor α4β2 (rs1044396 on the CHRNA4 gene) previously implicated in behavioral and nicotine-related studies (albeit with inconsistent major/minor allele impacts). Based on our prior neuroimaging findings, we expected this polymorphism to affect neural activity in the cingulo-opercular (CO) network involved in core cognitive control processes including maintenance of alertness. Consistent across the cohorts, all cortical areas of the CO network showed higher activity in heterozygotes compared with both types of homozygotes during cognitive engagement. This inverted U-shaped relation reflects an overdominant effect; that is, allelic interaction (cumulative evidence p = 1.33 * 10(-5)). Furthermore, heterozygotes performed more accurately in behavioral tasks that primarily depend on sustained alertness. No effects were observed for haplotypes of the surrounding CHRNA4 region, supporting a true overdominant effect at rs1044396. As a possible mechanism, we observed that this polymorphism is an expression quantitative trait locus modulating CHRNA4 expression levels. This is the first report of overdominance in the nicotinic system. These findings connect CHRNA4 genotype, CO network activation, and sustained alertness, providing insights into how genetics shapes individuals' cognitive control abilities.SIGNIFICANCE STATEMENT The nicotinic acetylcholine system plays a central role in

  5. Polymorphisms in oxidative stress genes, physical activity, and breast cancer risk

    PubMed Central

    Santella, Regina M.; Cleveland, Rebecca J.; Bradshaw, Patrick T.; Millikan, Robert C.; North, Kari E.; Olshan, Andrew F.; Eng, Sybil M.; Ambrosone, Christine B.; Ahn, Jiyoung; Steck, Susan E.; Teitelbaum, Susan L.; Neugut, Alfred I.; Gammon, Marilie D.

    2013-01-01

    Purpose The mechanisms driving the physical activity–breast cancer association are unclear. Exercise both increases reactive oxygen species production, which may transform normal epithelium to a malignant phenotype, and enhances antioxidant capacity, which could protect against subsequent oxidative insult. Given the paradoxical effects of physical activity, the oxidative stress pathway is of interest. Genetic variation in CAT or antioxidant-related polymorphisms may mediate the physical activity–breast cancer association. Methods We investigated the main and joint effects of three previously unreported polymorphisms in CAT on breast cancer risk. We also estimated interactions between recreational physical activity (RPA) and 13 polymorphisms in oxidative stress-related genes. Data were from the Long Island Breast Cancer Study Project, with interview and biomarker data available on 1,053 cases and 1,102 controls. Results Women with ≥1 variant allele in CAT rs4756146 had a 23 % reduced risk of postmenopausal breast cancer compared with women with the common TT genotype (OR = 0.77; 95 % CI = 0.59–0.99). We observed two statistical interactions between RPA and genes in the anti-oxidant pathway (p = 0.043 and 0.006 for CAT and GSTP1, respectively). Highly active women harboring variant alleles in CAT rs1001179 were at increased risk of breast cancer compared with women with the common CC genotype (OR = 1.61; 95 % CI, 1.06–2.45). Risk reductions were observed among moderately active women carrying variant alleles in GSTP1 compared with women homozygous for the major allele (OR = 0.56; 95 % CI, 0.38–0.84). Conclusions Breast cancer risk may be jointly influenced by RPA and genes involved in the antioxidant pathway, but our findings require confirmation. PMID:23053794

  6. Effect of interleukin-1beta gene functional polymorphism on dorsolateral prefrontal cortex activity in schizophrenic patients.

    PubMed

    Papiol, Sergi; Molina, Vicente; Rosa, Araceli; Sanz, Javier; Palomo, Tomás; Fañanás, Lourdes

    2007-12-05

    Hypoactivity of the dorsolateral prefrontal cortex (DLPFC) during cognitive tasks is among the most consistent findings in schizophrenia. The biological factors contributing to this hypofrontality are only partially known. Previous reports have shown the influence of genes mapped to IL-1 cluster (i) in the risk to develop schizophrenia and (ii) on brain morphological abnormalities in these patients. Moreover, Interleukin-1beta (IL-1beta), encoded by IL-1B gene (IL-1 cluster, chromosome 2q13) has a key role in dopaminergic differentiation and dendrite growth in developing cortical neurons. The authors explored the role of a genetic functional polymorphism at IL-1B gene in relation to DLPFC activity. DLPFC (left and right) metabolic activity was measured in a sample of 19 DSM-IV diagnosed schizophrenic patients of Spanish origin using a procedure based on MRI/PET image fusion. During PET studies, subjects performed a contingent Continuous Performance Test aiming to activate DLPFC. Functional promoter polymorphism -511 C/T (rs16944) of IL-1B gene was genotyped in these patients. Those patients who were allele 2 (-511 T) carriers showed a lower metabolic activity in the left DLPFC with respect to patients homozygous for allele 1 (-511 C) (U = 16, z = -2.32, P = 0.02). Our results suggest that hypofrontality reported in some schizophrenic patients might be explained, at least in part, by this functional polymorphism at IL-1B gene. Genetic variants with influence on brain functionality may account for the neurocognitive heterogeneity observed in schizophrenic patients.

  7. Rifabutin Is Active Against Mycobacterium abscessus Complex.

    PubMed

    Aziz, Dinah Binte; Low, Jian Liang; Wu, Mu-Lu; Gengenbacher, Martin; Teo, Jeanette W P; Dartois, Véronique; Dick, Thomas

    2017-04-10

    Lung infections with Mycobacterium abscessus are emerging as a global threat to individuals with cystic fibrosis and other patient groups. Recent evidence for human-to-human transmission worsens the situation. M. abscessus is an intrinsically multidrug resistant pathogen showing resistance even against standard anti tuberculosis drugs such as rifampicin. Here, our objective was to identify existing drugs that may be employed for the treatment of M. abscessus lung disease. A collection of more than 2700 approved drugs was screened at a single point concentration against an M. abscessus clinical isolate. Hits were confirmed with fresh solids in dose response experiments. For the most attractive hit, growth inhibition and bactericidal activities against reference strains of the three M. abscessus subspecies and a collection of clinical isolates were determined. Surprisingly, the rifampicin derivative rifabutin had an MIC of 3 ± 2 μM (3 μg/mL) against the screening strain, the reference strains M. abscessus subsp. abscessus ATCC 19977, M. abscessus subsp. bolletii CCUG 50184-T and M. abscesuss subsp. massiliense CCUG 48898-T, as well as a collection of clinical isolates. Furthermore, rifabutin was active against clarithromycin resistant strains. In conclusion, rifabutin - in contrast to rifampicin - is active against the Mycobacterium abscessus complex bacteria in vitro and may be considered for treatment of M. abscessus lung disease.

  8. Activation Pattern of the Polymorphic Ventricular Tachycardia and Ventricular Fibrillation on Body Surface Mapping in Patients With Brugada Syndrome.

    PubMed

    Ueoka, Akira; Morita, Hiroshi; Watanabe, Atsuyuki; Nakagawa, Koji; Nishii, Nobuhiro; Nagase, Satoshi; Ohe, Tohru; Ito, Hiroshi

    2016-07-25

    Clinical and experimental studies have shown the existence of an arrhythmogenic substrate in the right ventricular outflow tract (RVOT) in patients with Brugada syndrome (BrS). To evaluate the importance of the RVOT, we evaluated the activation pattern of induced ventricular tachyarrhythmias using body surface mapping (BSM) in patients with BrS. We examined 14 patients with BrS in whom ventricular tachyarrhythmias were induced by programmed electrical stimulation. The 87-lead BSM was recorded during induced ventricular tachyarrhythmias, and an activation map and an isopotential map of QRS complexes every 5 ms were constructed to evaluate the activation pattern of ventricular tachyarrhythmias. BSM during 20 episodes of ventricular tachyarrhythmias induced at the RVOT showed that repetitive excitation was generated at the RVOT and propagated to the inferior RV and left ventricle, and then returned to the RVOT. Polymorphic QRS change during ventricular tachyarrhythmias was associated with migration of the earliest activation site and rotor. BSM during 4 episodes of ventricular fibrillation (VF) showed that the excitation front moved randomly with formation of multiple wavefronts. Programmed stimulation initiated repetitive firing from the RVOT. Migration and competition of the earliest activation site and rotor and local conduction delay changed the QRS morphology. Degeneration of the reentrant circuit into multiple wavefronts resulted in VF. (Circ J 2016; 80: 1734-1743).

  9. Association of serotonin transporter promoter regulatory region polymorphism and cerebral activity to visual presentation of food.

    PubMed

    Kaurijoki, Salla; Kuikka, Jyrki T; Niskanen, Eini; Carlson, Synnöve; Pietiläinen, Kirsi H; Pesonen, Ullamari; Kaprio, Jaakko M; Rissanen, Aila; Tiihonen, Jari; Karhunen, Leila

    2008-07-01

    Recent functional magnetic resonance imaging (fMRI) studies have revealed links between genetic polymorphisms and cognitive and behavioural processes. Serotonin is a classical neurotransmitter of central nervous system, and it is connected to the control of appetite and satiety. In this study, the relationship between the functional variation in the serotonin transporter gene and the activity in the left posterior cingulate cortex (PCC), a brain area activated by visual food stimuli was explored. Thirty subjects underwent serial fMRI studies and provided DNA for genetic analyses. Subjects homozygous for the long allele exhibited greater left PCC activity in the comparison food > non-food compared with individuals heterozygous or homozygous for the short allele. The association between genotype and activation was linear, the subjects with two copies of the long allele variant having the strongest activation. These results demonstrate the possible genetically driven variation in the response of the left PCC to visual presentation of food in humans.

  10. Major histocompatibility complex class II polymorphisms in forest musk deer (Moschus berezovskii) and their probable association with purulent disease.

    PubMed

    Li, L; Wang, B B; Ge, Y F; Wan, Q H

    2014-10-01

    Genes of the major histocompatibility complex (MHC) family are crucial in immune responses because they present pathogenic peptides to T cells. In this study, we analysed the genetic variation in forest musk deer (Moschus berezovskii) MHC II genes and its potential association with musk deer purulent disease. In total, 53 purulent disease-susceptible and 46 purulent disease-resistant individuals were selected for MHC II exon 2 fragment analysis. Among them, 16 DQ alleles and four additional DR alleles were identified, with DQ exon 2 fragments displaying a low level of polymorphism. The nonsynonymous substitutions exceeded the synonymous substitutions in the peptide-binding sites of DQA2, DQB1 and DQB2. Then, 28 MHC II alleles were used to analyse the distribution patterns of purulent disease between the susceptible and resistant groups. Among them, three alleles (DQA1*01, DQA1*02 and DQA2*04) were found to be resistant, and five alleles (DRB3*07, DQA1*03, DQA1*04, DQA2*05 and DQA2*06) were found to increase susceptibility. Additionally, three haplotypes were found to be putatively associated with musk deer purulent disease. However, these three haplotypes were only found in the resistant or susceptible group, and their frequencies were low. The results from our study support a contributory role of MHC II polymorphisms in the development of purulent disease in forest musk deer.

  11. Chitotriosidase Activity and Gene Polymorphism in Iranian Patients with Gaucher Disease and Sibling Carriers

    PubMed Central

    MOZAFARI, Hadi; TAGHIKHANI, Mohammad; KHATAMI, Shohreh; ALAEI, Mohammad Reza; VAISI-RAYGANI, Asad; RAHIMI, Zohreh

    2016-01-01

    Objective Chitotriosidase (CT) activity is a useful biomarker for diagnosis and monitoring of Gaucher disease (GD). Its application is limited by some variants in the CT gene. Two main polymorphisms are 24 bp duplication and G102S led to reduce CT activity. The aim of this study was to determine these variants influencing on plasma CT activity. Materials & Methods Blood samples were collected from 33 patients with GD, 15 sibling carriers and 105 healthy individuals serving as controls. CT activity was measured using 4-methylumbelliferyl-β-D-N,N′,N″triacetylchitotrioside substrate in plasma samples. The CT genotypes of 24 bp duplication and G102S variants were determined using PCR and PCR-RFLP. Results Untreated GD patients had a significantly higher CT activity compared to treated patients (P = 0.021). In addition, chitotriosidase activity in carriers was higher rather than controls. Allele frequencies of 24 bp duplication in GD patients, sibling carriers and controls were 0.21, 0.266 and 0.29 and for G102S were 0.318, 0.366 and 0.219, respectively. Different G102S genotypes had not significant effect on CT activity. Chitotriosidase activity has a positive correlation with age in normal group, carriers, and negative correlation with hemoglobin in GD patients. Using cut-off level of 80.75 nmol/ml/h, sensitivity and specificity of CT activity were 93.9% and 100%, respectively. Conclusion Chitotriosidase activity is a suitable biomarker for diagnosis and monitoring of GD. Determination of 24 bp duplication is helpful for more accurate monitoring the GD patient’s therapy. However, it seems that, specifying of the G102S polymorphism is not required for Iranian GD patients. PMID:27843468

  12. FAS rs2234767 and rs1800682 polymorphisms jointly contributed to risk of colorectal cancer by affecting SP1/STAT1 complex recruitment to chromatin

    PubMed Central

    Wang, Shizhi; Wu, Shenshen; Meng, Qingtao; Li, Xiaobo; Zhang, Jinchun; Chen, Rui; Wang, Meilin

    2016-01-01

    FAS rs2234767 (−1377 G>A), rs1800682 (−670 A>G) and FASLG rs763110 (−844 C>T) promoter polymorphisms can influence transcriptional activities of the genes and thus multiple tumors susceptibility. To investigate their association with risk of colorectal cancer (CRC), the three SNPs were genotyped in 878 cases and 884 controls and the results showed that the FAS rs2234767 and rs1800682 were in a high linkage disequilibrium (LD) with each other (D’ = 0.994) and jointly contributed to an increased risk of CRC (without vs. with rs2234767 GG/rs1800682 AA genotypes, adjusted OR = 1.30, 95% CI = 1.05 − 1.61). In vivo ChIP assays evaluated the effect of rs2234767 and rs1800682 on recruitment of SP1 and STAT1, respectively, to chromatin. The results showed SP1 interacting specifically with STAT1 recruited to their respective motifs for transcriptional activation. The mutant alleles rs2234767 A and rs1800682 G jointly affected coupled SP1 and STAT1 recruitment to chromatin. The interplay between SP1 and STAT1 was critical for the functional outcome of rs2234767 and rs1800682 in view of their high LD. In conclusion, the FAS rs2234767 and rs1800682 polymorphisms were in high LD with each other, and they jointly contributed to an increased risk of CRC by altering recruitment of SP1/STAT1 complex to the FAS promoter for transcriptional activation. PMID:26759270

  13. Transcriptionally active LTR retrotransposons in Eucalyptus genus are differentially expressed and insertionally polymorphic.

    PubMed

    Marcon, Helena Sanches; Domingues, Douglas Silva; Silva, Juliana Costa; Borges, Rafael Junqueira; Matioli, Fábio Filippi; Fontes, Marcos Roberto de Mattos; Marino, Celso Luis

    2015-08-14

    In Eucalyptus genus, studies on genome composition and transposable elements (TEs) are particularly scarce. Nearly half of the recently released Eucalyptus grandis genome is composed by retrotransposons and this data provides an important opportunity to understand TE dynamics in Eucalyptus genome and transcriptome. We characterized nine families of transcriptionally active LTR retrotransposons from Copia and Gypsy superfamilies in Eucalyptus grandis genome and we depicted genomic distribution and copy number in two Eucalyptus species. We also evaluated genomic polymorphism and transcriptional profile in three organs of five Eucalyptus species. We observed contrasting genomic and transcriptional behavior in the same family among different species. RLC_egMax_1 was the most prevalent family and RLC_egAngela_1 was the family with the lowest copy number. Most families of both superfamilies have their insertions occurring <3 million years, except one Copia family, RLC_egBianca_1. Protein theoretical models suggest different properties between Copia and Gypsy domains. IRAP and REMAP markers suggested genomic polymorphisms among Eucalyptus species. Using EST analysis and qRT-PCRs, we observed transcriptional activity in several tissues and in all evaluated species. In some families, osmotic stress increases transcript values. Our strategy was successful in isolating transcriptionally active retrotransposons in Eucalyptus, and each family has a particular genomic and transcriptional pattern. Overall, our results show that retrotransposon activity have differentially affected genome and transcriptome among Eucalyptus species.

  14. Paraoxonase1 192 (PON1 192) gene polymorphism and serum paraoxonase activity in panic disorder patients.

    PubMed

    Atasoy, Hande; Güleç-Yilmaz, Seda; Ergen, Arzu; Görmüş, Uzay; Küçükhüseyin, Özlem; Dalan, Burak; Ol, Kevser Kusat; Ögüt, Dicle Bilge; Güleç, Hüseyin; Çetin, Buğra; Timirci-Kahraman, Özlem; Örmeci, Burcu; Uçunoğlu, Nazli; Gultekin, Guldal Inal; İsbir, Turgay

    2015-01-01

    Reactive oxygen species (ROS) are involved in the development of certain neuropsychiatric disorders. Paraoxonase 1 (PON1) activity has been suggested to be adversely related to oxidative stress in plasma. The purpose of the present study was to demonstrate the relationship between serum PON1 activity and PON1 192 polymorphism in panic disorder (PD). Fourty-two patients with PD and 46 healthy controls were included in this study. PON1 192 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. PON1 activity was measured by spectrophotometric assay of p-nitrophenol production following the addition of paraoxon. PON1 192 AA genotype and A allele in PD were significantly higher than in the control group, whereas the B allele was found to be significantly higher in the control group. Patients with panic disorder have lower PON1 activity than the control group. The PON1 192 AA genotype may increase the risk of PD depending on lipid peroxidation. Copyright © 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  15. Molecular approaches to identify cryptic species and polymorphic species within a complex community of fig wasps.

    PubMed

    Xiao, Jin-Hua; Wang, Ning-Xin; Li, Yan-Wei; Murphy, Robert W; Wan, Dong-Guang; Niu, Li-Ming; Hu, Hao-Yuan; Fu, Yue-Guan; Huang, Da-Wei

    2010-11-29

    Cryptic and polymorphic species can complicate traditional taxonomic research and both of these concerns are common in fig wasp communities. Species identification is very difficult, despite great effort and the ecological importance of fig wasps. Herein, we try to identify all chalcidoid wasp species hosted by one species of fig, using both morphological and molecular methods. We compare the efficiency of four different DNA regions and find that ITS2 is highly effective for species identification, while mitochondrial COI and Cytb regions appear less reliable, possibly due to the interference signals from either nuclear copies of mtDNA, i.e. NUMTs, or the effects of Wolbachia infections. The analyses suggest that combining multiple markers is the best choice for inferring species identifications as any one marker may be unsuitable in a given case.

  16. Association analysis of peroxisome proliferator-activated receptors gamma gene polymorphisms with asprin hypersensitivity in asthmatics

    PubMed Central

    Oh, Sun-Hee; Park, Se-Min; Park, Jong-Sook; Jang, An-Soo; Lee, Yong-Mok; Uh, Soo-Taek; Kim, Young Hoon; Choi, In-Seon; Kim, Mi-Kyeong; Park, Byeong Lae

    2009-01-01

    Purpose Peroxisome proliferator-activated receptors (PPARs) are transcriptional factors activated by ligands of the nuclear hormone receptor superfamily. The activation of PPARγ regulates inflammation by downregulating the production of Th2 type cytokines and eosinophil function. In addition, a range of natural substances, including arachidonate pathway metabolites such as 15-hydroxyeicosatetranoic acid (15-HETE), strongly promote PPARG expression. Therefore, genetic variants of the PPARG gene may be associated with the development of aspirin-intolerant asthma (AIA). We investigated the relationship between single nucleotide polymorphism (SNP) of the PPARG gene and AIA. Methods Based on the results of an oral aspirin challenge, asthmatics (n=403) were categorized into two groups: those with a decrease in FEV1 of 15% or greater (AIA) or less than 15% (aspirin-tolerant asthma, ATA). We genotyped two single nucleotide polymorphisms in the PPARG gene from Korean asthmatics and normal controls (n=449): +34C>G (Pro12Ala) and +82466C>T (His449His). Results Logistic regression analysis showed that +82466C>T and haplotype 1 (CC) were associated with the development of aspirin hypersensitivity in asthmatics (P=0.04). The frequency of the rare allele of +82466C>T was significantly higher in AIA patients than in ATA patients in the recessive model [P=0.04, OR=3.97 (1.08-14.53)]. In addition, the frequency of PPARG haplotype 1 was significantly lower in AIA patients than in ATA patients in the dominant model (OR=0.25, P=0.04). Conclusions The +82466C>T polymorphism and haplotype 1 of the PPARG gene may be linked to increased risk for aspirin hypersensitivity in asthma. PMID:20224667

  17. IL23R(Arg381Gln) functional polymorphism is associated with active pulmonary tuberculosis severity.

    PubMed

    Ben-Selma, Walid; Boukadida, Jalel

    2012-08-01

    The purpose of our study was to investigate the association between a functional single nucleotide polymorphism (SNP) in the interleukin-23 receptor gene (IL23R; rs11209026, 1142 G(wild type) → A(reduced function), Arg381Gln) and disease severity outcome in pulmonary tuberculosis (TB) in the Tunisian population. SNP was investigated in a population of 168 patients with active pulmonary TB (cases were stratified into patients with minimal/moderate lung involvement, i.e., patients with minimal/moderate disease [Pmd], and patients with extensive lung involvement, i.e., patients with active disease [Pad]) and 150 healthy subjects. Genotype analyses were carried out using the PCR-restriction fragment length polymorphism method. We have found that the IL23R reduced-function allele 1142A and genotypes AA and AG were overrepresented, especially in the Pad subgroup compared with the control group (51% versus 18% [P = 10(-8)], 33% versus 5% [P = 10(-8)], and 36% versus 26% [P = 5 × 10(-3)], respectively). Additionally, comparison of the Pad and the Pmd groups showed that the A allele and AA genotype seemed to be associated with 2.79-fold (P = 4 × 10(-5)) and 7.74-fold (P = 10(-5)) increased risks of TB with minimal/moderate lung involvement, respectively. Our results demonstrate that the reduced-function polymorphism 1142G → A encoded by IL23R influences the outcome of disease severity of active pulmonary TB in Tunisian patients.

  18. Emotional Fronto-Cingulate Cortex Activation and Brain Derived Neurotrophic Factor Polymorphism in Premenstrual Dysphoric Disorder

    PubMed Central

    Erika, Comasco; Andreas, Hahn; Sebastian, Ganger; Malin, Gingnell; Elin, Bannbers; Lars, Oreland; Johan, Wikström; Neill, Epperson C.; Rupert, Lanzenberger; Inger, Sundström-Poromaa

    2014-01-01

    Premenstrual dysphoric disorder (PMDD) is the prototypical sex-specific disorder in which symptom onset and offset require a particular hormonal milieu and for which there is moderate heritability. The present study investigated brain emotion processing in PMDD and healthy controls, as well as functional polymorphisms in two candidate genes for PMDD, the serotonin transporter (5-HTT) and brain derived neurotrophic factor (BDNF). The 5-HTT linked polymorphic region (5-HTTLPR) and BDNF Val66Met polymorphisms were genotyped in 31 patients with PMDD and 31 healthy controls. A subset of 16 patients and 15 controls participated in two functional magnetic resonance imaging-sessions performing an emotion processing task; once in the mid-follicular, and once in the late luteal phase which corresponds with maximum severity of mood symptoms. Genotypes were not directly associated with PMDD. A main effect of group was found in the whole brain analysis, with patients having lower activation of the pre-genual anterior cingulate and ventro-medial prefrontal cortex, independent of menstrual cycle phase. Post-hoc functional ROI analyses in the fronto-cingulate cluster showed no effect of 5-HTTLPR genotype but a genotype-by-group-by-phase interaction effect of BDNF Val66Met. Women with PMDD who were carriers of the Met-allele had lower fronto-cingulate cortex activation in the luteal phase compared to Met-allele carrying controls. The results provide suggestive evidence of impaired emotion-induced fronto-cingulate cortex activation in PMDD patients. Although limited by a small sample, the potential influence of BDNF Val66Met in PMDD is in line with preclinical research. PMID:24615932

  19. Alzheimer’s Disease Associated Polymorphisms in Human OGG1 Alter Catalytic Activity and Sensitize Cells to DNA Damage

    PubMed Central

    Jacob, Kimberly D.; Hooten, Nicole Noren; Tadokoro, Takashi; Lohani, Althaf; Barnes, Janice; Evans, Michele K.

    2013-01-01

    Brain tissues from Alzheimer’s Disease (AD) patients show increased levels of oxidative DNA damage and 7,8-dihydro-8-oxoguanine (8-oxoG) accumulation. In humans, the base excision repair protein 8-oxoguanine-DNA glycosylase (OGG1) is the major enzyme that recognizes and excises the mutagenic DNA base lesion 8-oxoG. Recently, two polymorphisms of OGG1, A53T and A288V, have been identified in brain tissues of AD patients, but little is known about how these polymorphisms may contribute to AD. We characterized the A53T and A288V polymorphic variants and detected a significant reduction in the catalytic activity for both proteins in vitro and in cells. Additionally, the A53T polymorphism has decreased substrate binding, while the A288V polymorphism has reduced AP lyase activity. Both variants have decreased binding to known OGG1 binding partners PARP-1 and XRCC1. We found that OGG1−/− cells expressing A53T and A288V OGG1 were significantly more sensitive to DNA damage and had significantly decreased survival. Our results provide both biochemical and cellular evidence that A53T and A288V polymorphic proteins have deficiencies in catalytic and protein binding activities that could be related to the increase in oxidative damage to DNA found in AD brains. PMID:23684897

  20. Vitamin D receptor gene polymorphisms are associated with obesity and inflammosome activity.

    PubMed

    Al-Daghri, Nasser M; Guerini, Franca R; Al-Attas, Omar S; Alokail, Majed S; Alkharfy, Khalid M; Draz, Hossam M; Agliardi, Cristina; Costa, Andrea S; Saulle, Irma; Mohammed, Abdul Khader; Biasin, Mara; Clerici, Mario

    2014-01-01

    To explore the mechanisms underlying the suggested role of the vitamin D/vitamin D receptor (VDR) complex in the pathogenesis of obesity we performed genetic and immunologic analyses in obese and non-obese Saudi individuals without other concomitant chronic diseases. Genomic DNA was genotyped for gene single nucleotide polymorphisms (SNPs) of VDR by allelic discrimination in 402 obese (body mass index -BMI≥30 kg/m2) and 489 non-obese (BMI<30 kg/m2) Saudis. Q-PCR analyses were performed using an ABI Prism 7000 Sequence Detection System. The inflammosome pathway was analysed by PCR, cytokines and plasma lipopolysaccaride (LPS) concentrations with ELISA assays. Results showed that the VDR SNPs rs731236 (G) (TaqI) and rs1544410 (T) (Bsm-I) minor allele polymorphisms are significantly more frequent in obese individuals (p = 0.009, β = 0.086 and p = 0.028, β = 0.072, respectively). VDR haplotypes identified are positively (GTA) (p = 0.008, β = 1.560); or negatively (ACC) (p = 0.044, β = 0.766) associated with obesity and higher BMI scores. The GTA "risk" haplotype was characterized by an up-regulation of inflammosome components, a higher production of proinflammatory cytokines (p<0.05) and a lower VDR expression. Plasma LPS concentration was also increased in GTA obese individuals (p<0.05), suggesting an alteration of gut permeability leading to microbial translocation. Data herein indicate that polymorphisms affecting the vitamin D/VDR axis play a role in obesity that is associated with an ongoing degree of inflammation, possibly resulting from alterations of gut permeability and microbial translocation. These results could help the definition of VDR fingerprints that predict an increased risk of developing obesity and might contribute to the identification of novel therapeutic strategies for this metabolic condition.

  1. PON1 gene polymorphisms and plasma PON1 activities in Takayasu's arteritis disease.

    PubMed

    Huesca-Gómez, Claudia; Soto, María Elena; Castrejón-Téllez, Vicente; Pérez-Méndez, Oscar; Gamboa, Ricardo

    2013-04-01

    Takayasu's arteritis (TA) is a chronic inflammation that affects the large vessels; however, its etiology is still unknown. Human serum paraoxonase hydrolyzes oxidized lipids into low-density lipoproteins and could therefore be associated with the prevalence of inflammation processes. Therefore, the purpose of study was to elucidate the influence of PON1 gene polymorphisms and plasma PON1 activities in Takayasu's arteritis disease. Fifty-four patients with TA and 173 clinically healthy Mexicans were studied. The PON1 polymorphism was determined by the TaqMan PCR method. PON1 activity was assessed spectrophotometrically by paraoxon (p-nitrophenylphosphate) hydrolysis. In TA patients, the frequency of PON1(192R) allele (51% vs. 39%, P=0.043, OR=1.60, 95% CI=1.03-2.47), PON1(55M) allele (21% vs. 6.6%, P=0.0001, OR=3.80, 95% CI=2.03-7.10), and PON1(-108T) (60.1% vs. 46%, P=0.011, OR 1.79 (95% CI=1.15-2.79) were significantly higher than in healthy controls. PON1 activity was significantly lower for PON in TA vs. controls (136.14 vs. 322.79 μmol min(-1) ml(-1), P=0.001, showing a decreasing activity in all genotypes in TA patients with respect to the control subjects. These results show significantly lower PON1 activity associated with HDL-C in TA patients, this activity could be depending on PON1 genotypes; showing that QR/LM/CT has the lowest hydrolytic activity toward paraoxon meanwhile, PON1(192,55,-108) genetic variations are related with reduced PON1 activities, these could be factors contributing to the development of TA disease. Copyright © 2013 Elsevier B.V. All rights reserved.

  2. Relationship between the LHPP Gene Polymorphism and Resting-State Brain Activity in Major Depressive Disorder

    PubMed Central

    Cui, Lingling; Gong, Xiaohong; Tang, Yanqing; Kong, Lingtao; Chang, Miao; Geng, Haiyang

    2016-01-01

    A single-nucleotide polymorphism at the LHPP gene (rs35936514) has been reported in genome-wide association studies to be associated with major depressive disorder (MDD). However, the neural system effects of rs35936514 that mediate the association are unknown. The present work explores whether the LHPP rs35936514 polymorphism moderates brain regional activity in MDD. A total of 160 subjects were studied: a CC group homozygous for the C allele (23 individuals with MDD and 57 controls) and a T-carrier group carrying the high risk T allele (CT/TT genotypes; 22 MDD and 58 controls). All participants underwent resting-state functional magnetic resonance imaging (rs-fMRI) scanning. Brain activity was assessed using the amplitudes of low-frequency fluctuations (ALFF). MDD patients showed a significant increased ALFF in the left middle temporal gyrus and occipital cortex. The T-carrier group showed increased ALFF in the left superior temporal gyrus. Significant diagnosis × genotype interaction was noted in the bilateral lingual gyri, bilateral dorsal lateral prefrontal cortex (dlPFC), and left medial prefrontal cortex (mPFC) (P < 0.05, corrected). Results demonstrated that MDD patients with LHPP rs35936514 CT/TT genotype may influence the regional brain activity. These findings implicate the effects of the rs35936514 variation on the neural system in MDD. PMID:27843651

  3. Molecular differentiation of three closely related members of the mosquito species complex, Anopheles moucheti, by mitochondrial and ribosomal DNA polymorphism.

    PubMed

    Kengne, P; Antonio-Nkondjio, C; Awono-Ambene, H P; Simard, F; Awolola, T S; Fontenille, D

    2007-06-01

    Distinction between members of the equatorial Africa malaria vector Anopheles moucheti (Evans) s.l. (Diptera: Culicidae) has been based mainly on doubtful morphological features. To determine the level of genetic differentiation between the three morphological forms of this complex, we investigated molecular polymorphism in the gene encoding for mitochondrial cytochrome oxidase b (CytB) and in the ribosomal internal transcribed spacers (ITS1 and ITS2). The three genomic regions revealed sequence differences between the three morphological forms similar in degree to the differences shown previously for members of other anopheline species groups or complexes (genetic distance d = 0.047-0.05 for CytB, 0.084-0.166 for ITS1 and 0.03-0.05 for ITS2). Using sequence variation in the ITS1 region, we set up a diagnostic polymerase chain reaction (PCR) for rapid and reliable identification of each subspecies within the An. moucheti complex. Specimens of An. moucheti s.l. collected in Cameroon, the Democratic Republic of Congo (DRC), Uganda and Nigeria were successfully identified, demonstrating the general applicability of this technique.

  4. Polymorphisms in the VEGFA promoter are associated with susceptibility to hepatocellular carcinoma by altering promoter activity.

    PubMed

    Wu, Xiaopan; Xin, Zhenhui; Zhang, Wei; Wu, Jia; Chen, Kangmei; Wang, Huifen; Zhu, Xilin; Pan, Liping; Li, Zhuo; Li, Hui; Liu, Ying

    2013-09-01

    Accumulated evidences indicate that single nucleotide polymorphisms (SNP) in angiogenesis and tumorigenesis related genes are associated with risk of hepatocellular carcinoma (HCC). Vascular endothelial growth factor A (VEGFA), one of the most significant mediators of angiogenesis, plays an important role in carcinogenesis and development via promoting tumor growth. We carried out a two-stage association study in 1,838 chronic hepatitis B (CHB) patients and 1,207 hepatitis B virus (HBV) related HCC patients in Han Chinese populations from Beijing, Guangxi and Jiangsu. We systematically screened polymorphisms in the VEGFA gene and examined the association between the SNPs and susceptibility to HCC. Functional analyses were conducted to verify biological significances of associated SNPs. We identified two promoter SNPs (rs833061 and rs1570360) were associated with susceptibility to HCC (rs833061: ptrend  = 0.008 in Youan_Beijing samples, ptrend  = 0.01 in Guangxi samples, ptrend  = 0.01 in Jiangsu samples. rs1570360: ptrend  = 0.00003 in Youan_Beijing samples, ptrend  = 0.006 in Guangxi samples, ptrend  = 0.02 in Jiangsu samples). These two SNPs were further validated in four independent groups of major HBV outcomes, indicating rs833061 and rs1570360 may associate exclusively to HCC. Functional analyses show that CA haplotype constructed by rs833061 and rs1570360 had higher luciferase activity compared with TG haplotype (p < 0.05). A 18 bp insert/del polymorphism was in absolute linkage disequilibrium (LD) with rs833061. The 18 bp insert allele created a Sp1 binding site. We observed higher VEGFA transcription in peripheral blood of HCC patients compared with CHB patients and healthy individuals (p < 0.05). These findings indicate that VEGFA promoter SNPs may contribute to susceptibility of HCC by altering promoter activity. Copyright © 2013 UICC.

  5. Paraoxonase activity and genetic polymorphisms in greenhouse workers with long term pesticide exposure.

    PubMed

    Hernández, Antonio F; Mackness, Bharti; Rodrigo, Lourdes; López, Olga; Pla, Antonio; Gil, Fernando; Durrington, Paul N; Pena, Gloria; Parrón, Tesifón; Serrano, José L; Mackness, Michael I

    2003-11-01

    Serum paraoxonase (PON1) is a high-density lipoprotein (HDL) associated protein, which plays a critical role in the pathogenesis of atherosclerosis, although it was primarily associated with the hydrolysis of organophosphorus compounds. PON1 was initially thought to be independent from physiological or pathological states, although recently some environmental factors have been reported to modulate its activity. In this study, we have investigated the promoter (PON1 -108C/T and -909 C/G) and coding region (PON1 192Q/R and 55L/M) polymorphisms, as well as PON1 activity towards different substrates (paraoxon, phenylacetate and diazoxon) in 102 individuals with long term low dose exposure to pesticides in a plastic greenhouse setting (sprayers), who are probably the group of agricultural workers with the highest exposure to pesticides. PON1 activity towards paraoxon was nonsignificantly decreased (up to 53.5%) in the sprayers subgroup exposed to organophosphates (n = 41) compared with nonsprayers acting as controls (n = 39). None of the genotypes studied was associated significantly with the subgroup of individuals exposed to organophosphates, although differences between sprayers and nonsprayers were observed in the PON1 -909 G/C polymorphism. Among the environmental factors that significantly predicted lower rates of PON1 activity towards paraoxon are, interestingly, the exposure to organophosphates and current smoking. By contrast, the utilization of protective clothing while spraying pesticides inside the greenhouses was positively associated with PON1 activity, very likely by preventing the pesticides from being absorbed. This study suggests that chronic exposure to pesticides might decrease PON1 activity and pinpoints the potential usefulness of monitoring PON1 activity in occupational settings where exposure to organophosphates occurs.

  6. Molecular phylogeny and systematics of the highly polymorphic Rumex bucephalophorus complex (Polygonaceae).

    PubMed

    Talavera, M; Balao, F; Casimiro-Soriguer, R; Ortiz, M Á; Terrab, A; Arista, M; Ortiz, P L; Stuessy, T F; Talavera, S

    2011-12-01

    Rumex bucephalophorus is a very polymorphic species that has been subjected to various taxonomic studies in which diverse infraspecific taxa have been recognised on the basis of diaspore traits. In this study we used molecular markers (ITS and AFLP) to explore this remarkable diversity, to test previous hypotheses of classification, and attempt to explain biogeographic patterns. Results show that R. bucephalophorus forms a monophyletic group in which diversification began around 4.2 Mya, at the end of Messinian Salinity Crisis. The two molecular markers clearly show a deep divergence separating subsp. bucephalophorus from all other subspecific taxa, among which subsp. canariensis also constitutes a separate and well distinguishable unit. In contrast, subspecies hispanicus and subsp. gallicus constitute a monophyletic group in which three subgroups can be recognised: subsp. hispanicus, subsp. gallicus var. gallicus and subsp. gallicus var. subaegeus. However, these three subgroups are not clearly distinguished genetically or morphologically, so that in formal classification it would be preferable to treat them at the varietal level. Copyright © 2011 Elsevier Inc. All rights reserved.

  7. Association between peroxisome proliferator-activated receptor-alpha, delta, and gamma polymorphisms and risk of coronary heart disease

    PubMed Central

    Qian, Yufeng; Li, Peiwei; Zhang, Jinjie; Shi, Yu; Chen, Kun; Yang, Jun; Wu, Yihua; Ye, Xianhua

    2016-01-01

    Abstract Objectives: Risk of coronary heart disease (CHD) has been suggested to be associated with polymorphisms of peroxisome proliferator-activated receptors (PPARs), while the results were controversial. We aimed to systematically assess the association between PPAR polymorphisms and CHD risk. Methods: A case–control study with 446 subjects was conducted to evaluate the association between CHD risk and C161T polymorphism, which was of our special interest as this polymorphism showed different effects on risks of CHD and acute coronary syndrome (ACS). Meta-analyses were conducted to assess all PPAR polymorphisms. Either a fixed- or a random-effects model was adopted to estimate overall odds ratios (ORs). Results: In the case–control study, T allele carriers of C161T polymorphism were not significantly associated with CHD risk (Odds ratio (OR) = 0.74, 95% confidence interval (CI) 0.47–1.15, P = 0.19), while T allele carriers showed higher risk of ACS (OR = 1.63, 95% CI 1.00–2.65, P = 0.048). The meta-analysis indicated that compared with CC homozygous, T allele carriers had lower CHD risk (OR = 0.69, 95% CI 0.59–0.82, P < 0.001) but higher ACS risk (OR = 1.43, 95% CI 1.09–1.87, P = 0.010). Three other polymorphisms were also found to be significantly associated with CHD risk under dominant model: PPAR-alpha intron 7G/C polymorphism (CC+GC vs GG, OR 1.42, 95% CI 1.13–1.78, P = 0.003), L162V polymorphism (VV+LV vs LL, OR 0.74, 95% CI 0.56–0.97, P = 0.031), and PPAR-delta +294T/C polymorphism (CC+TC vs TT, OR 1.51, 95% CI 1.12–2.05, P = 0.007). Conclusions: The results suggested that PPAR-alpha intron 7G/C and L162V, PPAR-delta +294T/C and PPAR-gamma C161T polymorphisms could affect CHD susceptibility, and C161T polymorphism might have different effects on CHD and ACS. PMID:27512842

  8. Use of amplified-fragment length polymorphism to study the ecology of Campylobacter jejuni in environmental water and to predict multilocus sequence typing clonal complexes.

    PubMed

    Lévesque, Simon; St-Pierre, Karen; Frost, Eric; Arbeit, Robert D; Michaud, Sophie

    2012-04-01

    We determined the genetic variability among water isolates of Campylobacter jejuni by using amplified-fragment length polymorphism (AFLP) and multilocus sequence typing (MLST). Across a highly diverse collection of isolates, AFLP clusters did not correlate with MLST clonal complexes, suggesting that AFLP is not reliable for deciphering population genetic relationships and may be problematic for larger epidemiologic analyses.

  9. DRD2/ANKK1 Polymorphism Modulates the Effect of Ventral Striatal Activation on Working Memory Performance

    PubMed Central

    Nymberg, Charlotte; Banaschewski, Tobias; Bokde, Arun LW; Büchel, Christian; Conrod, Patricia; Flor, Herta; Frouin, Vincent; Garavan, Hugh; Gowland, P; Heinz, Andreas; Ittermann, Bernd; Mann, Karl; Martinot, Jean-Luc; Nees, Frauke; Paus, Tomas; Pausova, Zdenka; Rietschel, Marcella; Robbins, Trevor W; Smolka, Michael N; Ströhle, Andreas; Schumann, Gunter; Klingberg, Torkel; Reed, L; Williams, S; Lourdusamy, A; Costafreda, S; Cattrell, A; Nymberg, C; Topper, L; Smith, L; Havatzias, S; Stueber, K; Mallik, C; Clarke, T-K; Stacey, D; Wong, C Peng; Werts, H; Williams, S; Andrew, C; Desrivieres, S; Zewdie, S; Heinz, A; Häke, I; Ivanov, N; Klär, A; Reuter, J; Palafox, C; Hohmann, C; Schilling, C; Lüdemann, K; Romanowski, A; Ströhle, A; Wolff, E; Rapp, M; Ittermann, B; Brühl, R; Ihlenfeld, A; Walaszek, B; Schubert, F; Connolly, C; Jones, J; Lalor, E; McCabe, E; Ní, A; Spanagel, R; Leonardi-Essmann, F; Sommer, W; Vollstaedt-Klein, S; Poustka, L; Steiner, S; Buehler, M; Vollstedt-Klein, S; Stolzenburg, E; Schmal, C; Schirmbeck, F; Gowland, P; Heym, N; Lawrence, C; Newman, C; Huebner, T; Ripke, S; Mennigen, E; Muller, K U; Ziesch, V; Bromberg, U; Fadai, T; Lueken, L; Yacubian, J; Finsterbusch, J; Martinot, J-L; Artiges, E; Bordas, N; de Bournonville, S; Bricaud, Z; Gollier Briand, F; Lemaitre, H; Massicotte, J; Miranda, R; Penttilä, J; Barbot, A; Schwartz, Y; Lalanne, C; Frouin, V; Thyreau, B; Dalley, J; Mar, A; Subramaniam, N; Theobald, D; Richmond, N; de Rover, M; Molander, A; Jordan, E; Robinson, E; Hipolata, L; Moreno, M; Stephens, D; Ripley, T; Crombag, H; Pena, Y; Zelenika, D; Heath, S; Lanzerath, D; Heinrichs, B; Spranger, T; Fuchs, B; Speiser, C; Resch, F; Haffner, J; Parzer, P; Brunner, R; Klaassen, A; Klaassen, I; Constant, P; Mignon, X; Thomsen, T; Zysset, S; Vestboe, A; Ireland, J; Rogers, J

    2014-01-01

    Motivation is important for learning and cognition. Although dopaminergic (D2) transmission in the ventral striatum (VS) is associated with motivation, learning, and cognition are more strongly associated with function of the dorsal striatum, including activation in the caudate nucleus. A recent study found an interaction between intrinsic motivation and the DRD2/ANKK1 polymorphism (rs1800497), suggesting that A-carriers of rs1800497 are significantly more sensitive to motivation in order to improve during working memory (WM) training. Using data from the two large-scale imaging genetic data sets, IMAGEN (n=1080, age 13–15 years) and BrainChild (n∼300, age 6–27), we investigated whether rs1800497 is associated with WM. In the IMAGEN data set, we tested whether VS/caudate activation during reward anticipation was associated with WM performance and whether rs1800497 and VS/caudate activation interact to affect WM performance. We found that rs1800497 was associated with WM performance in IMAGEN and BrainChild. Higher VS and caudate activation during reward processing were significantly associated with higher WM performance (p<0.0001). An interaction was found between the DRD2/ANKK1 polymorphism rs1800497 and VS activation during reward anticipation on WM (p<0.01), such that carriers of the minor allele (A) showed a significant correlation between VS activation and WM, whereas the GG-homozygotes did not, suggesting that the effect of VS BOLD on WM is modified by inter-individual genetic differences related to D2 dopaminergic transmission. PMID:24713612

  10. DRD2/ANKK1 polymorphism modulates the effect of ventral striatal activation on working memory performance.

    PubMed

    Nymberg, Charlotte; Banaschewski, Tobias; Bokde, Arun L W; Büchel, Christian; Conrod, Patricia; Flor, Herta; Frouin, Vincent; Garavan, Hugh; Gowland, P; Heinz, Andreas; Ittermann, Bernd; Mann, Karl; Martinot, Jean-Luc; Nees, Frauke; Paus, Tomas; Pausova, Zdenka; Rietschel, Marcella; Robbins, Trevor W; Smolka, Michael N; Ströhle, Andreas; Schumann, Gunter; Klingberg, Torkel

    2014-09-01

    Motivation is important for learning and cognition. Although dopaminergic (D2) transmission in the ventral striatum (VS) is associated with motivation, learning, and cognition are more strongly associated with function of the dorsal striatum, including activation in the caudate nucleus. A recent study found an interaction between intrinsic motivation and the DRD2/ANKK1 polymorphism (rs1800497), suggesting that A-carriers of rs1800497 are significantly more sensitive to motivation in order to improve during working memory (WM) training. Using data from the two large-scale imaging genetic data sets, IMAGEN (n=1080, age 13-15 years) and BrainChild (n∼300, age 6-27), we investigated whether rs1800497 is associated with WM. In the IMAGEN data set, we tested whether VS/caudate activation during reward anticipation was associated with WM performance and whether rs1800497 and VS/caudate activation interact to affect WM performance. We found that rs1800497 was associated with WM performance in IMAGEN and BrainChild. Higher VS and caudate activation during reward processing were significantly associated with higher WM performance (p<0.0001). An interaction was found between the DRD2/ANKK1 polymorphism rs1800497 and VS activation during reward anticipation on WM (p<0.01), such that carriers of the minor allele (A) showed a significant correlation between VS activation and WM, whereas the GG-homozygotes did not, suggesting that the effect of VS BOLD on WM is modified by inter-individual genetic differences related to D2 dopaminergic transmission.

  11. Complex Network for Solar Active Regions

    NASA Astrophysics Data System (ADS)

    Daei, Farhad; Safari, Hossein; Dadashi, Neda

    2017-08-01

    In this paper we developed a complex network of solar active regions (ARs) to study various local and global properties of the network. The values of the Hurst exponent (0.8-0.9) were evaluated by both the detrended fluctuation analysis and the rescaled range analysis applied on the time series of the AR numbers. The findings suggest that ARs can be considered as a system of self-organized criticality (SOC). We constructed a growing network based on locations, occurrence times, and the lifetimes of 4227 ARs recorded from 1999 January 1 to 2017 April 14. The behavior of the clustering coefficient shows that the AR network is not a random network. The logarithmic behavior of the length scale has the characteristics of a so-called small-world network. It is found that the probability distribution of the node degrees for undirected networks follows the power law with exponents of about 3.7-4.2. This indicates the scale-free nature of the AR network. The scale-free and small-world properties of the AR network confirm that the system of ARs forms a system of SOC. Our results show that the occurrence probability of flares (classified by GOES class C> 5, M, and X flares) in the position of the AR network hubs takes values greater than that obtained for other nodes.

  12. Active Particles in Complex and Crowded Environments

    NASA Astrophysics Data System (ADS)

    Bechinger, Clemens; Di Leonardo, Roberto; Löwen, Hartmut; Reichhardt, Charles; Volpe, Giorgio; Volpe, Giovanni

    2016-10-01

    Differently from passive Brownian particles, active particles, also known as self-propelled Brownian particles or microswimmers and nanoswimmers, are capable of taking up energy from their environment and converting it into directed motion. Because of this constant flow of energy, their behavior can be explained and understood only within the framework of nonequilibrium physics. In the biological realm, many cells perform directed motion, for example, as a way to browse for nutrients or to avoid toxins. Inspired by these motile microorganisms, researchers have been developing artificial particles that feature similar swimming behaviors based on different mechanisms. These man-made micromachines and nanomachines hold a great potential as autonomous agents for health care, sustainability, and security applications. With a focus on the basic physical features of the interactions of self-propelled Brownian particles with a crowded and complex environment, this comprehensive review will provide a guided tour through its basic principles, the development of artificial self-propelling microparticles and nanoparticles, and their application to the study of nonequilibrium phenomena, as well as the open challenges that the field is currently facing.

  13. An Artemis polymorphic variant reduces Artemis activity and confers cellular radiosensitivity.

    PubMed

    Woodbine, Lisa; Grigoriadou, Sofia; Goodarzi, Aaron A; Riballo, Enriqueta; Tape, Christopher; Oliver, Antony W; van Zelm, Menno C; Buckland, Matthew S; Davies, E Graham; Pearl, Laurence H; Jeggo, Penny A

    2010-09-04

    Artemis is required for V(D)J recombination and the repair of a subset of radiation-induced DNA double strand breaks (DSBs). Artemis-null patients display radiosensitivity (RS) and severe combined immunodeficiency (SCID), classified as RS-SCID. Strongly impacting hypomorphic Artemis mutations confer marked infant immunodeficiency and a predisposition for EBV-associated lymphomas. Here, we provide evidence that a polymorphic Artemis variant (c.512C > G: p.171P > R), which has a world-wide prevalence of 15%, is functionally impacting. The c.512C > G mutation causes an approximately 3-fold decrease in Artemis endonuclease activity in vitro. Cells derived from a patient who expressed a single Artemis allele with the polymorphic mutational change, showed radiosensitivity and a DSB repair defect in G2 phase, with Artemis cDNA expression rescuing both phenotypes. The c.512C > G change has an additive impact on Artemis function when combined with a novel C-terminal truncating mutation (p.436C > X), which also partially inactivates Artemis activity. Collectively, our findings provide strong evidence that monoallelic expression of the c.512C > G variant impairs Artemis function causing significant radiosensitivity and a G2 phase DSB repair defect. The patient exhibiting monoallelic c.512C > G-Artemis expression showed immunodeficiency only in adulthood, developed bilateral carcinoma of the nipple and myelodysplasia raising the possibility that modestly decreased Artemis function can impact clinically. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  14. Polymorphism of DNA-anionic liposome complexes reveals hierarchy of ion-mediated interactions.

    PubMed

    Liang, Hongjun; Harries, Daniel; Wong, Gerard C L

    2005-08-09

    Self-assembled DNA delivery systems based on anionic lipids (ALs) complexed with DNA mediated by divalent cations have been recently introduced as an alternative to cationic lipid-DNA complexes because of their low cytotoxicity. We investigate AL-DNA complexes induced by different cations by using synchrotron small angle x-ray scattering and confocal microscopy to show how different ion-mediated interactions are expressed in the self-assembled structures and phase behavior of AL-DNA complexes. The governing interactions in AL-DNA systems are complex: divalent ions can mediate strong attractions between different combinations of the components (such as DNA-DNA and membrane-membrane). Moreover, divalent cations can coordinate non-electrostatically with lipids and modify the resultant membrane structure. We find that at low membrane charge densities AL-DNA complexes organize into a lamellar structure of alternating DNA and membrane layers crosslinked by ions. At high membrane charge densities, a new phase with no analog in cationic lipid-DNA systems is observed: DNA is expelled from the complex, and a lamellar stack of membranes and intercalated ions is formed. For a subset of the ionic species, high ion concentrations generate an inverted hexagonal phase comprised of DNA strands wrapped by ion-coated lipid tubes. A simple theoretical model that takes into account the electrostatic and membrane elastic contributions to the free energy shows that this transition is consistent with an ion-induced change in the membrane spontaneous curvature, c0. Moreover, the crossover between the lamellar and inverted hexagonal phases occurs at a critical c0 that agrees well with experimental values.

  15. Different non-synonymous polymorphisms modulate the interaction of the WRN protein to its protein partners and its enzymatic activities

    PubMed Central

    Gagné, Jean-Philippe; Lachapelle, Sophie; Garand, Chantal; Tsofack, Serges P.; Coulombe, Yan; Caron, Marie-Christine; Poirier, Guy G.; Masson, Jean-Yves; Lebel, Michel

    2016-01-01

    Werner syndrome (WS) is characterized by the premature onset of several age-associated pathologies including cancer. The protein defective in WS patients (WRN) is a helicase/exonuclease involved in DNA replication and repair. Here, we present the results of a large-scale proteome analysis that has been undertaken to determine protein partners of different polymorphic WRN proteins found with relatively high prevalence in the human population. We expressed different fluorescently tagged-WRN (eYFP-WRN) variants in human 293 embryonic kidney cells (HEK293) and used a combination of affinity-purification and mass spectrometry to identify different compositions of WRN-associated protein complexes. We found that a WRN variant containing a phenylalanine residue at position 1074 and an arginine at position 1367 (eYFP-WRN(F-R)) possesses more affinity for DNA-PKc, KU86, KU70, and PARP1 than a variant containing a leucine at position 1074 and a cysteine at position 1367 (eYFP-WRN(L-C)). Such results were confirmed in a WRN-deficient background using WS fibroblasts. Interestingly, the exonuclase activity of WRN recovered from immunoprecipitated eYFP-WRN(L-C) variant was lower than the eYFP-WRN(F-R) in WS cells. Finally, HEK293 cells and WS fibroblasts overexpressing the eYFP-WRN(F-R) variant were more resistant to the benzene metabolite hydroquinone than cells expressing the eYFP-WRN(L-C) variant. These results indicate that the protein-protein interaction landscape of WRN is subject to modulation by polymorphic amino acids, a characteristic associated with distinctive cell survival outcome. PMID:27863399

  16. Polymorphism and division of labour in a socially complex ant: neuromodulation of aggression in the Australian weaver ant, Oecophylla smaragdina

    PubMed Central

    Kamhi, J. Frances; Nunn, Kelley; Robson, Simon K. A.; Traniello, James F. A.

    2015-01-01

    Complex social structure in eusocial insects can involve worker morphological and behavioural differentiation. Neuroanatomical variation may underscore worker division of labour, but the regulatory mechanisms of size-based task specialization in polymorphic species are unknown. The Australian weaver ant, Oecophylla smaragdina, exhibits worker polyphenism: larger major workers aggressively defend arboreal territories, whereas smaller minors nurse brood. Here, we demonstrate that octopamine (OA) modulates worker size-related aggression in O. smaragdina. We found that the brains of majors had significantly higher titres of OA than those of minors and that OA was positively and specifically correlated with the frequency of aggressive responses to non-nestmates, a key component of territorial defence. Pharmacological manipulations that effectively switched OA action in major and minor worker brains reversed levels of aggression characteristic of each worker size class. Results suggest that altering OA action is sufficient to produce differences in aggression characteristic of size-related social roles. Neuromodulators therefore may generate variation in responsiveness to task-related stimuli associated with worker size differentiation and collateral behavioural specializations, a significant component of division of labour in complex social systems. PMID:26136448

  17. Effects of Intronic and Exonic Polymorphisms of Paraoxonase 1 (PON1) Gene on Serum PON1 Activity in a Korean Population

    PubMed Central

    Eom, Sang-Yong; Kim, Yun-Sik; Lee, Chung-Jong; Lee, Chul-Ho; Kim, Yong-Dae

    2011-01-01

    Paraoxonase 1 (PON1) hydrolyzes a number of toxic organophosphorous compounds and reduces lipid peroxide accumulation, and PON1 genetic polymorphisms in the coding region modulate serum PON1 activity. In this study, we investigated the association between 3 polymorphisms of PON1 located in intron 5 (17899insdelTT and 17974CT) and exon 6 (192QR) and serum PON1 activity. The genetic polymorphisms and serum activity of PON1 were analyzed in 153 healthy Koreans by using a direct sequencing assay and spectrophotometric method, respectively. A significant linkage disequilibrium (LD) was observed between all tested single nucleotide polymorphisms, with the strongest LD observed between 17899insdelTT and 192QR (D' = 0.984). The 17899insdelTT, 17974CT and 192QR genetic polymorphisms were associated with significant differences in serum paraoxonase activity. In multiple regression analyses, smoking, triglyceride level, high-density lipoprotein (HDL) level, and the 17899insdelTT and 192QR genetic polymorphisms were significant determinants of serum paraoxonase activity, while age, smoking, triglyceride level, HDL level, and the 192QR genetic polymorphism were significant determinants of serum arylesterase activity. These results suggest that although the 192QR genetic polymorphism in the coding region of PON1 is primarily associated with serum PON1 activity, the intronic polymorphisms are also involved in serum PON1 activity, and this association may be mediated by LD. PMID:21655055

  18. Association of Plasminogen Activator Inhibitor-1 (PAI-1) Gene Polymorphisms with Osteoporotic Vertebral Compression Fractures (OVCFs) in Postmenopausal Women

    PubMed Central

    Kim, Jung Oh; Han, Soo Hong; Lee, Yeon Ho; Ahn, Tae Keun; Lim, Jae Joon; Chung, Young Sun; Shin, Dong Eun; Lee, Woo Sik; Han, In Bo; Kim, Nam Keun

    2016-01-01

    Osteoporosis and osteoporotic fractures are strongly associated with mortality and morbidity, both in developing and developed countries. Menopause accelerates bone loss due to estrogen deficiency and age-related linear bone loss. We investigated plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms in postmenopausal women with osteoporotic vertebral compression fractures (OVCFs). In this case-control study, 355 postmenopausal women were genotyped for the presence of PAI-1 gene polymorphisms −844A > G, −675 4G > 5G, 43G > A, 9785A > G, and 11053T > G. Genetic polymorphisms of PAI-1 were analyzed by the polymerization chain reaction restriction fragment length polymorphism assay, and their association with disease status and folate and homocysteine levels was determined in 158 OVCF patients and 197 control subjects. The PAI-1 −675 5G5G (adjusted odds ratio (AOR), 3.302; p = 0.017) and 43GA + AA (AOR, 2.087; p = 0.042) genotype frequencies showed significant association with the increased prevalence of OVCFs in postmenopausal women. In addition, we performed gene–environment interaction studies and demonstrated an association between PAI-1 gene polymorphisms and OVCF prevalence. Our novel finding is the identification of several PAI-1 genetic variants that increase susceptibility to OVCF. Our findings suggest that polymorphisms in PAI-1 may contribute to OVCF, and that they can be developed as biomarkers for evaluating OVCF risk. PMID:27941685

  19. Influence of hydroxyl contents on photocatalytic activities of polymorphic titania nanoparticles

    SciTech Connect

    kaewguna, Sujaree; Nolpha, Christopher A.; Lee, Burtrand I.; Wang, Li Q.

    2009-03-15

    Polymorphic titania nanoparticles, prepared by a Water-based Ambient Condition Sol (WACS) process, were post-treated by a Solvent-based Ambient Condition Sol (SACS) process in sec-butanol. All samples were characterized for phase composition, surface area, lattice hydroxyl contamination, and particle morphology by X-ray diffraction, N2 physisorption, FT-IR, solid state Magic Angle Spinning (MAS) 1H NMR and scanning electron microscopy. The resultswerecompared to acommercial titania, Degussa P25. Evaluation of methyl orange degradation under UV irradiation results showed that the lower lattice hydroxyl content in SACS titania nanoparticles enhances photocatalytic activity. As-prepared titania and post-treated SACS samples, which have similar surface areas and crystallinity, were compared in order to prove that the superior photocatalytic activity came from a reduction in lattice hydroxyl content.

  20. Tissue plasminogen activator and plasminogen activator inhibitor type 1 gene polymorphism in patients with gastric ulcer complicated with bleeding.

    PubMed Central

    Kim, Hong-Soo; Hwang, Kyu-Yoon; Chung, Il-Kwon; Park, Sang-Heum; Lee, Moon-Ho; Kim, Sun-Joo; Hong, Sae-Yong

    2003-01-01

    Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) may be involved in the pathogenesis of peptic ulcers through suppression of fibrinolysis. This study was designed to investigate associations of t-PA and PAI-1 genes with clinical features of the patients with bleeding gastric ulcers. Eighty-four patients with peptic ulcers and 100 controls were studied between January 1998 and April 2000. We used polymerase chain reaction and endonuclease digestion to genotype for 4G/5G polymorphism in the promoter region of the PAI-1 gene and the Alurepeat insertion/deletion (I/D) polymorphism in intron h of the t-PA gene. Various clinical features, including lesion site, bleeding event, recurrence of ulcer, and rebleeding, were assessed using a multiple logistic regression model. The genotype distributions of both the t-PA and PAI-1 genes did not differ between the patient and control groups. The occurrence of the I/D or D/D genotype of t-PA was significantly higher in cases of duodenal ulcer (adjusted OR=4.39, 95% CI=1.12-17.21). When a dominant effect (i.e., 4G/4G or 4G/5G versus 5G/5G) of the 4G allele was assumed, the PAI-1 4G/4G genotype was independently associated with rebleeding after hemostasis (adjusted OR=5.07, 95% CI=1.03-24.87). Our data suggest that t-PA gene polymorphism is associated with duodenal ulcers, and that the PAI-1 gene may be a risk factor leading to recurrent bleeding after initial hemostasis. PMID:12589088

  1. Exploiting Complexity Information for Brain Activation Detection

    PubMed Central

    Zhang, Yan; Liang, Jiali; Lin, Qiang; Hu, Zhenghui

    2016-01-01

    We present a complexity-based approach for the analysis of fMRI time series, in which sample entropy (SampEn) is introduced as a quantification of the voxel complexity. Under this hypothesis the voxel complexity could be modulated in pertinent cognitive tasks, and it changes through experimental paradigms. We calculate the complexity of sequential fMRI data for each voxel in two distinct experimental paradigms and use a nonparametric statistical strategy, the Wilcoxon signed rank test, to evaluate the difference in complexity between them. The results are compared with the well known general linear model based Statistical Parametric Mapping package (SPM12), where a decided difference has been observed. This is because SampEn method detects brain complexity changes in two experiments of different conditions and the data-driven method SampEn evaluates just the complexity of specific sequential fMRI data. Also, the larger and smaller SampEn values correspond to different meanings, and the neutral-blank design produces higher predictability than threat-neutral. Complexity information can be considered as a complementary method to the existing fMRI analysis strategies, and it may help improving the understanding of human brain functions from a different perspective. PMID:27045838

  2. Exploiting Complexity Information for Brain Activation Detection.

    PubMed

    Zhang, Yan; Liang, Jiali; Lin, Qiang; Hu, Zhenghui

    2016-01-01

    We present a complexity-based approach for the analysis of fMRI time series, in which sample entropy (SampEn) is introduced as a quantification of the voxel complexity. Under this hypothesis the voxel complexity could be modulated in pertinent cognitive tasks, and it changes through experimental paradigms. We calculate the complexity of sequential fMRI data for each voxel in two distinct experimental paradigms and use a nonparametric statistical strategy, the Wilcoxon signed rank test, to evaluate the difference in complexity between them. The results are compared with the well known general linear model based Statistical Parametric Mapping package (SPM12), where a decided difference has been observed. This is because SampEn method detects brain complexity changes in two experiments of different conditions and the data-driven method SampEn evaluates just the complexity of specific sequential fMRI data. Also, the larger and smaller SampEn values correspond to different meanings, and the neutral-blank design produces higher predictability than threat-neutral. Complexity information can be considered as a complementary method to the existing fMRI analysis strategies, and it may help improving the understanding of human brain functions from a different perspective.

  3. Differential activation of polymorphisms of the formyl peptide receptor by formyl peptides

    PubMed Central

    Mills, John S.

    2007-01-01

    We have investigated the role of two polymorphic sites (R190W and N192K) on the binding and activation of the formyl peptide receptor (FPR) by viral and formyl peptides. WEDWVGWI, a peptide with antiviral activity derived from the membrane proximal region of feline immunodeficiency virus, binds with high affinity to FPR. The three tryptophans in the peptide are all essential for FPR binding, just as they were essential for antiviral activity (Giannecchini, S. et al., J. Virol. 77 (2003) 3724). Formyl-NleWEDWVGWI behaved as a weak partial agonist with FPR W190/N192 but a stronger partial agonist with FPR R190/K192 and FPR R190/N192. Formyl-NleNleWEDWVGWI behaved as a full agonist toward all three FPRs but exhibited a much higher EC50 with W190/N192 FPR (300±45 nM) than for R190/K192 FPR (40±3 nM) or R190/N192 (60±8 nM). Formyl-MYKWPWYVWL preferentially activated R190/K192 and R190/N192 FPRs by >5 fold compared to W190/N192 FPR. Formyl-MFEDAVAWF, a peptide derived from a protein in Mycobacterium avium subsp. paratuberculosis and formyl-MFTFEPFPTN, a peptide derived from the N-terminus of chemotaxis inhibitory protein of Staphylococcus aureus with an added N-terminal methionine exhibited the greatest selectivity for R190/K192 and R190/N192 FPRs with ~10 fold lower EC50S than that observed with FPR W190/N192. Thus, individuals with the W190 polymorphism may display a reduced ability to detect certain formyl peptides. PMID:17644322

  4. The effect of pH on polymorph formation of the pharmaceutically active compound tianeptine.

    PubMed

    Orola, Liana; Veidis, Mikelis V; Sarcevica, Inese; Actins, Andris; Belyakov, Sergey; Platonenko, Aleksandrs

    2012-08-01

    The anti-depressant pharmaceutical tianeptine has been investigated to determine the dynamics of polymorph formation under various pH conditions. By varying the pH two crystalline polymorphs were isolated. The molecular and crystal structures have been determined to identify the two polymorphs. One polymorph is an amino carboxylic acid and the other polymorph is a zwitterion. In the solid state the tianeptine moieties are bonded through hydrogen bonds. The zwitterion was found to be less stable and transformed to the acid form. During this investigation an amorphous form was identified.

  5. A functional polymorphism in the prodynorphin gene affects cognitive flexibility and brain activation during reversal learning

    PubMed Central

    Votinov, Mikhail; Pripfl, Juergen; Windischberger, Christian; Moser, Ewald; Sailer, Uta; Lamm, Claus

    2015-01-01

    Whether the opioid system plays a role in the ability to flexibly adapt behavior is still unclear. We used fMRI to investigate the effect of a nucleotide tandem repeat (68-bp VNTR) functional polymorphism of the prodynorphin (PDYN) gene on cerebral activation during a reversal learning task in which participants had to flexibly adapt stimulus-response associations. Past studies suggested that alleles with 3 or 4 repeats (HH genotype) of this polymorphism are associated with higher levels of dynorphin peptides than alleles with 1 or 2 repeats (LL genotype). On the behavioral level, the HH group made more perseverative errors than the LL group. On the neural level, the HH group demonstrated less engagement of left orbitofrontal cortex (lOFC) and cortico-striatal circuitry, and lower effective connectivity of lOFC with anterior midcingulate cortex and anterior insula/ventrolateral prefrontal cortex during reversal learning and processing negative feedback. This points to a lower ability of the HH genotype to monitor or adapt to changes in reward contingencies. These findings provide first evidence that dynorphins may contribute to individual differences in reversal learning, and that considering the opioid system may shed new light on the neurochemical correlates of decision-making and behavioral regulation. PMID:26190983

  6. Analysis of the Relationship between Antioxidant Enzyme Gene Polymorphisms and Their Activity in Post-Traumatic Gonarthrosis.

    PubMed

    Vnukov, V V; Panina, S B; Milyutina, N P; Krolevets, I V; Zabrodin, M A

    2016-05-01

    Analysis of polymorphisms of genes encoding antioxidant enzymes SOD1 (G7958A), SOD2 (T58C), CAT (C-262T), and GSTP1 (Ile105Val) in 93 patients with post-traumatic gonarthrosis showed that GSTP1 Ile105Val polymorphism is often associated with heterozygous mutation in catalase gene CAT C-262T. In gonarthrosis, catalase activity in peripheral blood mononuclear cells in patients with CT genotype of the C-262T locus of CAT gene more than 2-fold surpassed that in CC genotype and more than 50% surpassed the normal. Changes in the balance of activity of antioxidant enzymes can affect viability of mononuclear cells.

  7. sE-Selectin expression and A561C polymorphism in relation to rheumatoid arthritis clinical activity.

    PubMed

    Navarro-Hernández, Rosa Elena; Oregón-Romero, Edith; Rangel-Villalobos, Héctor; Vázquez-Del Mercado, Mónica; Ruiz-Quezada, Sandra Luz; Maldonado-González, Monserrat; Torres-Vitela, Refugio; Muñoz-Valle, José Francisco

    2006-10-01

    To investigate the relationship of A561C polymorphism and sE-selectin levels with rheumatoid arthritis (RA) clinical activity. In a case-control study, we compared 60 patients with RA and 60 healthy subjects. Patients fulfilled the 1987 American College of Rheumatology criteria. Soluble E-selectin levels were measured from serum samples using the ELISA kit. We investigated E-selectin A561C polymorphism by the restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) technique. The disease activity was recorded with Spanish Health Assessment Questionnaire Disability Index (HAQ-DI), Spanish Arthritis Impact Measurement Scales (AIMS), and Disease Activity Score (DAS28) scores. A p value < 0.05 was considered significant. Patients with RA showed higher sE-selectin levels than controls (mean 91.7 vs 39 ng/ml; p = 0.002). A positive correlation between sE-selectin and rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), Spanish HAQ-DI, and DAS28 scores was found. The E-selectin polymorphism analysis showed diminished frequency in RA of heterozygous A/C genotype and increased frequency of homozygous wild-type A/A genotype (p = 0.043, OR 1.45; 95% CI 1.125-16.167) versus A/C and A/A genotype in healthy subjects. No significant association between A561C polymorphism and clinical activity was present. The sE-selectin, RF, and ESR, in addition to clinical indices, were associated with clinical activity in RA. We highlighted the presence of A/A genotype A561C polymorphism in our patients with RA.

  8. Polymorphism in the organic charge-transfer complex dibenzotetrathiafulvalene-7,7,8,8-tetracyanoquinodimethane (DBTTF-TCNQ) and its effect on optical and electrical properties (Presentation Recording)

    NASA Astrophysics Data System (ADS)

    Goetz, Katelyn P.; Tsutsumi, Jun ya; Pookpanratana, Sujitra; Chen, Jihua; Hasegawa, Tatsuo; Jurchescu, Oana D.

    2015-10-01

    We present the structural, optical, and electronic properties of two polymorphs of the charge-transfer complex dibenzotetrathiafulvalene-7,7,8,8-tetracyanoquinodimethane (DBTTF-TCNQ). The structures were resolved using electron diffraction. One is a rectangular-shaped platelet and exhibits ambipolar transport with gold contacts in organic field-effect transistors (OFETs). The second polymorph grows as a thin, circular platelet and shows p-type transport within the same OFET structure. The difference in electrical characteristics originates from two factors. First, the position of the HOMO level of the rectangular polymorph lies 0.07 eV below that of the circular polymorph, as determined by ultraviolet photoelectron spectroscopy (UPS). Second, using X-Ray photoelectron and Raman spectroscopies we find that the degree of charge transfer between the donor DBTTF and acceptor TCNQ varies from 0.4e +/- 0.1e for the rectangular crystals to 0.1e +/- 0.1e for the circular crystals. Additional differences between the two polymorphs arise when measuring the absorbance of the crystals. First, the peak corresponding to intermolecular charge transfer is offset by 0.05 eV between the two polymorphs, in agreement with UPS measurements. Additionally, the polarization angle dependence of the intermolecular CT band for the rectangular crystal is shifted by 60deg with respect to the angle dependence of the intramolecular transition. In contrast, this shift was only 20deg for the circular polymorph. These angle dependences allowed us to couple the anisotropy of the electrical characteristics to the optical measurements. Our results demonstrate how slight modifications in crystal structure yield drastic differences in optical and electrical properties in organic semiconducting materials.

  9. Association between Single Nucleotide Polymorphisms of the Major Histocompatibility Complex Class II Gene and Newcastle Disease Virus Titre and Body Weight in Leung Hang Khao Chickens

    PubMed Central

    Molee, A.; Kongroi, K.; Kuadsantia, P.; Poompramun, C.; Likitdecharote, B.

    2016-01-01

    The aim of the present study was to investigate the effect of single nucleotide polymorphisms in the major histocompatibility complex (MHC) class II gene on resistance to Newcastle disease virus and body weight of the Thai indigenous chicken, Leung Hang Khao (Gallus gallus domesticus). Blood samples were collected for single nucleotide polymorphism analysis from 485 chickens. Polymerase chain reaction sequencing was used to classify single nucleotide polymorphisms of class II MHC. Body weights were measured at the ages of 3, 4, 5, and 7 months. Titres of Newcastle disease virus at 2 weeks to 7 months were determined and the correlation between body weight and titre was analysed. The association between single nucleotide polymorphisms and body weight and titre were analysed by a generalized linear model. Seven single nucleotide polymorphisms were identified: C125T, A126T, C209G, C242T, A243T, C244T, and A254T. Significant correlations between log titre and body weight were found at 2 and 4 weeks. Associations between single nucleotide polymorphisms and titre were found for C209G and A254T, and between all single nucleotide polymorphisms (except A243T) and body weight. The results showed that class II MHC is associated with both titre of Newcastle disease virus and body weight in Leung Hang Khao chickens. This is of concern because improved growth traits are the main goal of breeding selection. Moreover, the results suggested that MHC has a pleiotropic effect on the titre and growth performance. This mechanism should be investigated in a future study. PMID:26732325

  10. Cdx2 Polymorphism Affects the Activities of Vitamin D Receptor in Human Breast Cancer Cell Lines and Human Breast Carcinomas

    PubMed Central

    Di Benedetto, Anna; Korita, Etleva; Goeman, Frauke; Sacconi, Andrea; Biagioni, Francesca; Blandino, Giovanni; Strano, Sabrina; Muti, Paola; Mottolese, Marcella; Falvo, Elisabetta

    2015-01-01

    Vitamin D plays a role in cancer development and acts through the vitamin D receptor (VDR). It regulates the action of hormone responsive genes and is involved in cell cycle regulation, differentiation and apoptosis. VDR is a critical component of the vitamin D pathway and different common single nucleotide polymorphisms have been identified. Cdx2 VDR polymorphism can play an important role in breast cancer, modulating the activity of VDR. The objective of this study is to assess the relationship between the Cdx2 VDR polymorphism and the activities of VDR in human breast cancer cell lines and carcinomas breast patients. Cdx2 VDR polymorphism and antiproliferative effects of vitamin D treatment were investigated in a panel of estrogen receptor-positive (MCF7 and T-47D) and estrogen receptor-negative (MDA-MB-231, SUM 159PT, SK-BR-3, BT549, MDA-MB-468, HCC1143, BT20 and HCC1954) human breast cancer cell lines. Furthermore, the potential relationship among Cdx2 VDR polymorphism and a number of biomarkers used in clinical management of breast cancer was assessed in an ad hoc set of breast cancer cases. Vitamin D treatment efficacy was found to be strongly dependent on the Cdx2 VDR status in ER-negative breast cancer cell lines tested. In our series of breast cancer cases, the results indicated that patients with variant homozygote AA were associated with bio-pathological characteristics typical of more aggressive tumours, such as ER negative, HER2 positive and G3. Our results may suggest a potential effect of Cdx2 VDR polymorphism on the efficacy of vitamin D treatment in aggressive breast cancer cells (estrogen receptor negative). These results suggest that Cdx2 polymorphism may be a potential biomarker for vitamin D treatment in breast cancer, independently of the VDR receptor expression. PMID:25849303

  11. Cdx2 polymorphism affects the activities of vitamin D receptor in human breast cancer cell lines and human breast carcinomas.

    PubMed

    Pulito, Claudio; Terrenato, Irene; Di Benedetto, Anna; Korita, Etleva; Goeman, Frauke; Sacconi, Andrea; Biagioni, Francesca; Blandino, Giovanni; Strano, Sabrina; Muti, Paola; Mottolese, Marcella; Falvo, Elisabetta

    2015-01-01

    Vitamin D plays a role in cancer development and acts through the vitamin D receptor (VDR). It regulates the action of hormone responsive genes and is involved in cell cycle regulation, differentiation and apoptosis. VDR is a critical component of the vitamin D pathway and different common single nucleotide polymorphisms have been identified. Cdx2 VDR polymorphism can play an important role in breast cancer, modulating the activity of VDR. The objective of this study is to assess the relationship between the Cdx2 VDR polymorphism and the activities of VDR in human breast cancer cell lines and carcinomas breast patients. Cdx2 VDR polymorphism and antiproliferative effects of vitamin D treatment were investigated in a panel of estrogen receptor-positive (MCF7 and T-47D) and estrogen receptor-negative (MDA-MB-231, SUM 159PT, SK-BR-3, BT549, MDA-MB-468, HCC1143, BT20 and HCC1954) human breast cancer cell lines. Furthermore, the potential relationship among Cdx2 VDR polymorphism and a number of biomarkers used in clinical management of breast cancer was assessed in an ad hoc set of breast cancer cases. Vitamin D treatment efficacy was found to be strongly dependent on the Cdx2 VDR status in ER-negative breast cancer cell lines tested. In our series of breast cancer cases, the results indicated that patients with variant homozygote AA were associated with bio-pathological characteristics typical of more aggressive tumours, such as ER negative, HER2 positive and G3. Our results may suggest a potential effect of Cdx2 VDR polymorphism on the efficacy of vitamin D treatment in aggressive breast cancer cells (estrogen receptor negative). These results suggest that Cdx2 polymorphism may be a potential biomarker for vitamin D treatment in breast cancer, independently of the VDR receptor expression.

  12. Recognition of a Nocardia transvalensis complex by resistance to aminoglycosides, including amikacin, and PCR-restriction fragment length polymorphism analysis.

    PubMed

    Wilson, R W; Steingrube, V A; Brown, B A; Blacklock, Z; Jost, K C; McNabb, A; Colby, W D; Biehle, J R; Gibson, J L; Wallace, R J

    1997-09-01

    Amikacin resistance, rare among nocardiae, was observed in 58 clinical isolates of nocardiae. All of these isolates hydrolyzed hypoxanthine, and 75 to 100% utilized citrate, D-galactose, and D-trehalose as sole carbon sources. Based on utilization of I-erythritol, D-glucitol, i-myo-inositol, D-mannitol, and ribitol and susceptibility to amoxicillin-clavulanic acid, the 58 isolates were separable into four groups. One group was negative for I-erythritol and ribitol and included all the isolates belonging to Nocardia asteroides complex antibiogram type IV. The remaining three groups were positive for I-erythritol and ribitol and were grouped within Nocardia transvalensis. The group that included the type strain was designated N. transvalensis sensu stricto, and the other two groups were designated new taxons 1 and 2. PCR-restriction fragment length polymorphism (RFLP) analysis of a 439-bp segment of the 65-kDa heat shock protein gene with XhoI and HinfI produced identical patterns for 53 (91%) and 58 (100%) isolates, respectively, and differentiated them from all other Nocardia taxa. NarI- and HaeIII-derived RFLP patterns clearly differentiated each of the four biochemically defined taxa. These four groups were also distinguishable by using the chromogenic substrates in Dade MicroScan test panels. By high-performance liquid chromatography, these isolates exhibited the same unique mycolic acid-ester elution patterns that differed from those of all other clinically significant nocardiae. Gas-liquid chromatographic analysis of fatty acids also produced similar patterns for all isolates that distinguished them from all other Nocardia taxa, but did not differentiate the four taxa within the complex. We propose the designation N. transvalensis complex for these four groups of nocardiae, pending further genetic evaluation.

  13. Association of peroxisome proliferator-activated receptor-gamma gene polymorphisms with the development of asthma.

    PubMed

    Oh, Sun-Hee; Park, Se-Min; Lee, Yoo Hoon; Cha, Ji Yeon; Lee, Ji-Yeon; Shin, Eun Kyong; Park, Jong-Sook; Park, Byeong-Lae; Shin, Hyoung Doo; Park, Choon-Sik

    2009-07-01

    The peroxisome proliferator-activated receptors (PPAR) are the nuclear hormone receptor superfamily of ligand-activated transcriptional factors. PPAR-gamma (PPARG) activation downregulates production of Th2 type cytokines and eosinophil function. Additionally, treatment with a synthetic PPARG ligand can reduce lung inflammation and IFN-gamma, IL-4, and IL-2 production in experimental allergic asthma. In patients with asthma, PPARG gene expression is known to be associated with the airway inflammatory and remodeling responses. Thus, genetic variants of PPARG may be associated with the development of asthma. We genotyped two single nucleotide polymorphisms on the PPARG gene, +34C>G (Pro12Ala) and +82466C>T (His449His), in Korean subjects (839 subjects with asthma and 449 normal controls). Association analysis using logistic regression analysis showed that +82466C>T and haplotypes 1(CC) and 2(CT) were associated with the development of asthma (p=0.01-0.04). The frequency of PPARG-ht2 was significantly lower in the patients with asthma compared to the normal controls in codominant and dominant models (p=0.01, p(corr)=0.03 and p=0.02, p(corr)=0.03, respectively). Conversely, the frequency of PPARG-ht1 was significantly higher in the patients with asthma compared to the normal controls in the codominant model [p=0.04, OR: 1.27 (1.01-1.6)]. In addition, the rare allele frequency of +82466C>T was significantly lower in patients with asthma in comparison to normal controls in the codominant model (OR: 0.78, p=0.04). Thus, polymorphism of the PPARG gene may be linked to an increased risk of asthma development.

  14. Contribution of oxytocin receptor polymorphisms to amygdala activation in schizophrenia spectrum disorders

    PubMed Central

    Bettella, Francesco; Brandt, Christine Lycke; Quintana, Daniel S.; Nerhus, Mari; Bjella, Thomas; Djurovic, Srdjan; Westlye, Lars T.; Andreassen, Ole A.; Melle, Ingrid; Tesli, Martin

    2016-01-01

    Background Oxytocin has been proposed to mediate amygdala dysfunction associated with altered emotion processing in schizophrenia, but the contribution of oxytocin pathway genes is yet to be investigated. Aims To identify potential different contributions of three oxytocin receptor polymorphisms (rs53576, rs237902 and rs2254298) between patients with schizophrenia spectrum disorders (SCZ), affective spectrum disorders (AD) and healthy controls (HC). Method In a total of 346 participants (104 with SCZ, 100 with AD, and 142 HC) underwent genotyping and functional magnetic resonance imaging (fMRI) during an emotional faces matching paradigm. Genetic association analyses were performed to test the possible effects on task-induced BOLD amygdala response to fearful/angry faces. Results In participants with SCZ, the rs237902 G allele was associated with low amygdala activation (left hemisphere: b=−4.99, Bonferroni corrected P=0.04) and interaction analyses showed that this association was disorder specific (left hemisphere: Bonferroni corrected P=0.003; right hemisphere: Bonferroni corrected P=0.03). There were no associations between oxytocin polymorphisms and amygdala activation in the total sample, among AD patients or HC. Conclusions Rs237902 was associated with amygdala activation in response to fearful/angry faces only in patients with SCZ. Our findings indicate that the endogenous oxytocin system could serve as a contributing factor in biological underpinnings of emotion processing and that this contribution is disorder specific. Declaration of interest O.A.A. received speaker’s honoraria from GSK, Otsuka, Lundbeck. Copyright and usage © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence. PMID:27847593

  15. Association of CAT polymorphisms with catalase activity and exposure to environmental oxidative stimuli

    PubMed Central

    Nadif, Rachel; Mintz, Margaret; Jedlicka, Anne; Bertrand, Jean-Pierre; Kleeberger, Steven R.; Kauffmann, Francine

    2005-01-01

    We tested the hypotheses that catalase activity is modified by CAT single nucleotide polymorphisms (SNPs) (–262;–844), and by their interactions with oxidant exposures (coal dusts, smoking), lymphotoxin alpha (LTA, NcoI) and tumor necrosis factor (TNF, -308) in 196 miners. Erythrocyte catalase, superoxide dismutase, and glutathione peroxidase activities were measured. The CAT –262 SNP was related to lower catalase activity (104, 87 and 72 k/g hemoglobin for CC, CT and TT respectively, p<0.0001). Regardless of CAT SNPs, the LTA NcoI but not the TNF –308 SNP was associated with catalase activity (p=0.04 and p=0.8). CAT –262 T carriers were less frequent in highly exposed miners (OR=0.39 [0.20 – 0.78], p=0.007). In CAT –262 T carriers only, catalase activity decreased with high dust exposure (p=0.01). Haplotype analyses (combined CAT SNPs) confirm these results. Results show that CAT –262 and LTA NcoI SNPs, and interaction with coal dust exposure, influenced catalase activity. PMID:16298864

  16. Polymorphisms in the RANTES gene increase susceptibility to active tuberculosis in Tunisia.

    PubMed

    Ben-Selma, Walid; Harizi, Hedi; Bougmiza, Iheb; Ben Kahla, Imen; Letaief, Mahmoud; Boukadida, Jalel

    2011-10-01

    RANTES plays a pivotal role in attracting and activating various leukocyte populations that control Mycobacterium tuberculosis infection. The present study investigated the relationship between the RANTES polymorphisms (-28C/G; rs2280788, and -403G/A; rs2107538) and susceptibility to active tuberculosis (TB) in Tunisian populations. A total of 168 patients with pulmonary TB (pTB), 55 with extrapulmonary TB (epTB), and 150 control subjects were studied. Genotype analyses were carried out using polymerase chain reaction-restriction fragment length polymorphism method. We found that the -28 GG genotype was significantly associated with susceptibility to pTB (odds ratio [OR]=11.19; 95% confidence intervals [CI], 5.14-25; P corrected for the number of genotypes [Pc]=10(-8)) and epTB (OR=11.67; 95% CI, 4.74-29.33; Pc=10(-8)). However, the -28 CC genotype was found to be significantly associated with resistance to pTB (OR=0.08; 95% CI, 0.04-0.16; Pc=10(-8)) and epTB development (OR=0.11; 95% CI, 0.05-0.27; Pc=10(-8)). -403A allele was associated with increased risk development of epTB (OR=2.21; 95% CI, 1.18-4.14; p=0.007). G-G and A-C haplotypes and the AG/GC diplotype were associated with increase susceptibility to pTB (OR=7.88, 95% CI, 5.38-11.55; Pc=3.10(-8); OR=2.32, 95% CI, 1.32-4.11; Pc=3.10(-3); OR=13.26, 95% CI, 6.06-29.89; Pc=3.10(-8); respectively) and epTB (OR=6.64, 95% CI, 4-11.05; Pc=3.10(-8); OR=2.6, 95% CI, 1.26-5.35; Pc=12.10(-3); OR=11.26, 95% CI, 4.44-29.28; Pc=3.10(-8); respectively). Collectively, our findings suggested an association of the RANTES -28C/G and -403G/A functional polymorphisms with susceptibility to Mycobacterium tuberculosis infection in Tunisian populations.

  17. Enzyme-like activities of algal polysaccharide - cerium complexes

    NASA Astrophysics Data System (ADS)

    Wang, Dongfeng; Sun, Jipeng; Du, Dehong; Ye, Shen; Wang, Changhong; Zhou, Xiaoling; Xue, Changhu

    2005-01-01

    Water-soluble algal polysaccharides (APS) (alginic acid, fucoidan and laminaran) possess many pharmacological activities. The results of this study showed that the APS-Ce4+ complexes have some enzyme-like activities. Fucoidan and its complex with Ce4+ have activities similar to those of SOD. The activities of laminaran, alginic acid and their complexes are not measurable. The APS do not show measurable activities in the digestion of plasmid DNA. In contrast, the APS - Ce4+ complexes show these measurable activities under the comparable condition when APS bind Ce4+ and form homogenous solutions. The laminaran - Ce4+ complex shows the most obvious activity in the digestion of plasmid DNA, pNPP and chloropy-rifos under neutral conditions.

  18. Working memory brain activity and capacity link MAOA polymorphism to aggressive behavior during development.

    PubMed

    Ziermans, T; Dumontheil, I; Roggeman, C; Peyrard-Janvid, M; Matsson, H; Kere, J; Klingberg, T

    2012-02-28

    A developmental increase in working memory capacity is an important part of cognitive development, and low working memory (WM) capacity is a risk factor for developing psychopathology. Brain activity represents a promising endophenotype for linking genes to behavior and for improving our understanding of the neurobiology of WM development. We investigated gene-brain-behavior relationships by focusing on 18 single-nucleotide polymorphisms (SNPs) located in six dopaminergic candidate genes (COMT, SLC6A3/DAT1, DBH, DRD4, DRD5, MAOA). Visuospatial WM (VSWM) brain activity, measured with functional magnetic resonance imaging, and VSWM capacity were assessed in a longitudinal study of typically developing children and adolescents. Behavioral problems were evaluated using the Child Behavior Checklist (CBCL). One SNP (rs6609257), located ~6.6 kb downstream of the monoamine oxidase A gene (MAOA) on human chromosome X, significantly affected brain activity in a network of frontal, parietal and occipital regions. Increased activity in this network, but not in caudate nucleus or anterior prefrontal regions, was correlated with VSWM capacity, which in turn predicted externalizing (aggressive/oppositional) symptoms, with higher WM capacity associated with fewer externalizing symptoms. There were no direct significant correlations between rs6609257 and behavioral symptoms. These results suggest a mediating role of WM brain activity and capacity in linking the MAOA gene to aggressive behavior during development.

  19. MHC class II polymorphism is associated with a canine SLE-related disease complex.

    PubMed

    Wilbe, Maria; Jokinen, Päivi; Hermanrud, Christina; Kennedy, Lorna J; Strandberg, Erling; Hansson-Hamlin, Helene; Lohi, Hannes; Andersson, Göran

    2009-08-01

    Nova Scotia duck tolling retrievers are predisposed to a SLE-related disease complex including immune-mediated rheumatic disease (IMRD) and steroid-responsive meningitis-arteritis (SRMA). IMRD involves symptoms that resemble those seen in systemic autoimmune rheumatic diseases, such as systemic lupus erythematosus, SLE, or SLE-related diseases, in humans. This disease complex involves persistent lameness, stiffness, mainly after resting, and palpable pain from several joints of extremities. The majority of affected dogs display antinuclear autoantibody (ANA)-reactivity. SRMA is manifested in young dogs with high fever and neck stiffness and can be treated with corticosteroids. We have investigated the possible role of MHC class II as a genetic risk factor in IMRD and SRMA etiology. We performed sequence-based typing of the DLA-DRB1, -DQA1, and -DQB1 class II loci in a total of 176 dogs including 51 IMRD (33 ANA-positive), 49 SRMA cases, and 78 healthy controls (two dogs were both IMRD- and SRMA-affected). Homozygosity for the risk haplotype DRB1*00601/DQA1*005011/DQB1*02001 increased the risk for IMRD (OR = 4.9; ANA-positive IMRD: OR = 7.2) compared with all other genotypes. There was a general heterozygote advantage, homozygotes had OR = 4.4 (ANA-positive IMRD: OR = 8.9) compared with all heterozygotes. The risk haplotype contains the five amino acid epitope RARAA, known as the shared epitope for rheumatoid arthritis. No association was observed for SRMA. We conclude that DLA class II is a highly significant genetic risk factor for ANA-positive IMRD. The results indicate narrow diversity of DLA II haplotypes and identify an IMRD-related risk haplotype, which becomes highly significant in homozygous dogs.

  20. Complex, compound inversion/translocation polymorphism in an ape: presumptive intermediate stage in the karyotypic evolution of the agile gibbon Hylobates agilis.

    PubMed

    Van Tuinen, P; Mootnick, A R; Kingswood, S C; Hale, D W; Kumamoto, A T

    1999-10-01

    Karyotypic variation in five gibbon species of the subgenus Hylobates (2n = 44) was assessed in 63 animals, 23 of them wild born. Acquisition of key specimens of Hylobates agilis (agile gibbon), whose karyotype had been problematic due to unresolved structural polymorphisms, led to disclosure of a compound inversion/translocation polymorphism. A polymorphic region of chromosome 8 harboring two pericentric inversions, one nested within the other, was in turn bissected by one breakpoint of a reciprocal translocation. In double-inversion + translocation heterozygotes, the theoretical meiotic pairing configuration is a double inversion loop, with four arms of a translocation quadrivalent radiating from the loop. Electron-microscopic analysis of synaptonemal complex configurations consistently revealed translocation quadrivalents but no inversion loops. Rather, nonhomologous pairing was evident in the inverted region, a condition that should preclude crossing over and the subsequent production of duplication-deficiency gametes. This is corroborated by the existence of normal offspring of compound heterozygotes, indicating that fertility may not be reduced despite the topological complexity of this polymorphic system. The distribution of inversion and translocation morphs in these taxa suggests application of cytogenetics in identifying gibbon specimens and avoiding undesirable hybridization in captive breeding efforts.

  1. Relationship of plasminogen activator inhibitor 1 gene 4G/5G polymorphisms to hypertension in Korean women.

    PubMed

    Kim, Kyu-nam; Kim, Kwang-min; Kim, Bom-taeck; Joo, Nam-seok; Cho, Doo-yeoun; Lee, Duck-joo

    2012-04-01

    Hypertension (HTN) is a major determinant of various cardiovascular events. Plasma levels of plasminogen activator inhibitor 1 (PAI-1) modulate this risk. A deletion/insertion polymorphism within the PAI-1 loci (4G/4G, 4G/5G, 5G/5G) affects the expression of this gene. The present study investigated the association between PAI-1 loci polymorphisms and HTN in Korean women. Korean women (n = 1312) were enrolled in this study to evaluate the association between PAI-1 4G/5G gene polymorphisms and HTN as well as other metabolic risk factors. PAI-1 loci polymorphisms were investigated using polymerase chain reaction amplification and single-strand conformation polymorphism analysis. The three genotype groups differed with respect to systolic blood pressure (P = 0.043), and diastolic blood pressure (P = 0.009) but not with respect to age, body mass index, total cholesterol, low or high density lipoprotein cholesterol, triglycerides, or fasting blood glucose. Carriers of the PAI-1 4G allele had more hypertension significantly (PAI-1 4G/5G vs. PAI-1 5G/5G, P = 0.032; PAI-1 4G/4G vs. PAI-1 5G/5G, P = 0.034). When stratified according to PAI-1 4G/5G polymorphism, there was no significant difference in all metabolic parameters among PAI-1 genotype groups in patients with HTN as well as subjects with normal blood pressure. The estimated odds ratio of the 4G/4G genotype and 4G/5G for HTN was 1.7 (P = 0.005), and 1.6 (P = 0.015), respectively. These findings might indicate that PAI-1 loci polymorphisms independently contribute to HTN and that gene-environmental interaction may be not associated in Korean women.

  2. Lack of association between PCK1 polymorphisms and obesity, physical activity, and fitness in European Youth Heart Study (EYHS).

    PubMed

    Vimaleswaran, Karani S; Franks, Paul W; Brage, Soren; Grontved, Anders; Wareham, Nicholas J; Ekelund, Ulf; Loos, Ruth J F

    2010-10-01

    Phosphoenolpyruvate carboxykinase-1 (PCK1) is the rate-limiting enzyme in the hepatic gluconeogenic pathway. Studies have shown that overexpression of Pck1 in mice results in obesity-related traits and higher levels of physical activity (PA). Therefore, our aims were to investigate whether common genetic variation in the PCK1 gene influences obesity-related traits, PA, and fitness, and to examine whether PA and fitness attenuate the influence of the PCK1 polymorphisms on obesity in children. Analyses were undertaken on data from Danish and Estonian children (958 boys and 1,104 girls) from the European Youth Heart Study (EYHS), a school-based, cross-sectional study of children (mean ± s.d. age: 9.6 ± 0.4 years) and adolescents (15.5 ± 0.5 years). We genotyped eight polymorphisms that captured the common genetic variations in the PCK1 gene. The association between the PCK1 polymorphisms and BMI, waist circumference (WC), sum of four skinfolds, PA, and fitness was tested using an additive model adjusted for age, age-group, gender, maturity, and country. Interactions were tested by including interaction terms in the model. None of the polymorphisms were significantly associated with BMI, WC, sum of four skinfolds, PA, and fitness, and also with the risk of being overweight or obese (P > 0.05). The interactions between the polymorphisms and age-group, gender, PA, and fitness were not statistically significant. This is the first study to comprehensively examine the association of PCK1 polymorphisms with obesity, PA, and fitness. Despite strong evidence from animal studies, our study in the EYHS cohort failed to identify an association of PCK1 polymorphisms with obesity, PA, and fitness.

  3. A polymorphic microsatellite from the Squalius alburnoides complex (Osteichthyes, Cyprinidae) cloned by serendipity can be useful in genetic analysis of polyploids.

    PubMed

    Boto, Luis; Cunha, Carina; Doadrio, Ignacio

    2011-07-01

    A new microsatellite locus (SAS1) for Squalius alburnoides was obtained through cloning by serendipity. The possible usefulness of this new species-specific microsatellite in genetic studies of this hybrid-species complex, was explored. The polymorphism exhibited by SAS1 microsatellite is an important addition to the set of microsatellites previously used in genetic studies in S. alburnoides complex, that mostly relied in markers described for other species. Moreover, the SAS1 microsatellite could be used to identify the parental genomes of the complex, complementing other methods recently described for the same purpose..

  4. A polymorphic microsatellite from the Squalius alburnoides complex (Osteichthyes, Cyprinidae) cloned by serendipity can be useful in genetic analysis of polyploids

    PubMed Central

    Boto, Luis; Cunha, Carina; Doadrio, Ignacio

    2011-01-01

    A new microsatellite locus (SAS1) for Squalius alburnoides was obtained through cloning by serendipity. The possible usefulness of this new species-specific microsatellite in genetic studies of this hybrid-species complex, was explored. The polymorphism exhibited by SAS1 microsatellite is an important addition to the set of microsatellites previously used in genetic studies in S. alburnoides complex, that mostly relied in markers described for other species. Moreover, the SAS1 microsatellite could be used to identify the parental genomes of the complex, complementing other methods recently described for the same purpose.. PMID:21931529

  5. A functional polymorphism of the MAOA gene modulates spontaneous brain activity in pons.

    PubMed

    Lei, Hui; Zhang, Xiaocui; Di, Xin; Rao, Hengyi; Ming, Qingsen; Zhang, Jibiao; Guo, Xiao; Jiang, Yali; Gao, Yidian; Yi, Jinyao; Zhu, Xiongzhao; Yao, Shuqiao

    2014-01-01

    To investigate the effects of a functional polymorphism of the monoamine oxidase A (MAOA) gene on spontaneous brain activity in healthy male adolescents. Thirty-one healthy male adolescents with the low-activity MAOA genotype (MAOA-L) and 25 healthy male adolescents with the high-activity MAOA genotype (MAOA-H) completed the 11-item Barratt Impulsiveness Scale (BIS-11) questionnaire and were subjected to resting-state functional magnetic resonance imaging (rs-fMRI) scans. The amplitude of low-frequency fluctuation (ALFF) of the blood oxygen level-dependent (BOLD) signal was calculated using REST software. ALFF data were related to BIS scores and compared between genotype groups. Compared with the MAOA-H group, the MAOA-L group showed significantly lower ALFFs in the pons. There was a significant correlation between the BIS scores and the ALFF values in the pons for MAOA-L group, but not for the MAOA-H group. Further regression analysis showed a significant genotype by ALFF values interaction effect on BIS scores. Lower spontaneous brain activity in the pons of the MAOA-L male adolescents may provide a neural mechanism by which boys with the MAOA-L genotype confers risk for impulsivity and aggression.

  6. A Functional Polymorphism of the MAOA Gene Modulates Spontaneous Brain Activity in Pons

    PubMed Central

    Lei, Hui; Zhang, Xiaocui; Di, Xin; Rao, Hengyi; Ming, Qingsen; Zhang, Jibiao; Guo, Xiao; Jiang, Yali; Gao, Yidian; Yi, Jinyao; Zhu, Xiongzhao; Yao, Shuqiao

    2014-01-01

    Objective. To investigate the effects of a functional polymorphism of the monoamine oxidase A (MAOA) gene on spontaneous brain activity in healthy male adolescents. Methods. Thirty-one healthy male adolescents with the low-activity MAOA genotype (MAOA-L) and 25 healthy male adolescents with the high-activity MAOA genotype (MAOA-H) completed the 11-item Barratt Impulsiveness Scale (BIS-11) questionnaire and were subjected to resting-state functional magnetic resonance imaging (rs-fMRI) scans. The amplitude of low-frequency fluctuation (ALFF) of the blood oxygen level-dependent (BOLD) signal was calculated using REST software. ALFF data were related to BIS scores and compared between genotype groups. Results. Compared with the MAOA-H group, the MAOA-L group showed significantly lower ALFFs in the pons. There was a significant correlation between the BIS scores and the ALFF values in the pons for MAOA-L group, but not for the MAOA-H group. Further regression analysis showed a significant genotype by ALFF values interaction effect on BIS scores. Conclusions. Lower spontaneous brain activity in the pons of the MAOA-L male adolescents may provide a neural mechanism by which boys with the MAOA-L genotype confers risk for impulsivity and aggression. PMID:24971323

  7. PPARα gene polymorphisms modulate the association between physical activity and cardiometabolic risk.

    PubMed

    Halder, I; Champlin, J; Sheu, L; Goodpaster, B H; Manuck, S B; Ferrell, R E; Muldoon, M F

    2014-07-01

    Habitual physical activity is understood to help prevent type 2 diabetes and atherosclerotic cardiovascular disease via beneficial effects on both metabolism and the vascular system. However, individuals do not have uniform cardiometabolic responses to physical activity. Here we explore the extent to which variation in the proliferator-activated receptor-alpha (PPARα) gene, which modulates carbohydrate and lipid metabolism, vascular function, and inflammation, predicts the overall cardiometabolic risk (CMR) profile of individuals engaging in various levels of physical activity. 917 unrelated, community volunteers (52% female, of Non-Hispanic European ancestry) aged 30-54 years, participated in the cross-sectional study. Subjects were genotyped for 5 single nucleotide polymorphisms in the PPARα gene, from which common haplotypes were defined. A continuous measure of CMR was calculated as an aggregate of 5 traditional risk factors: waist circumference, resting blood pressure, fasting serum triglycerides, HDL-cholesterol and glucose. Regression models were used to examine the main and interactive effects of physical activity and genetic variation on CMR. One common PPARα haplotype (H-23) was associated with a higher CMR. This association was moderated by daily physical activity (B = -0.11, SE = 0.053, t = -2.05, P = 0.04). Increased physical activity was associated with a steeper reduction of CMR in persons carrying the otherwise detrimental H-23 haplotype. Variations in the PPARα gene appear to magnify the cardiometabolic benefits of habitual physical activity. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. DRD4 and TH gene polymorphisms are associated with activity, impulsivity and inattention in Siberian Husky dogs.

    PubMed

    Wan, Michele; Hejjas, Krisztina; Ronai, Zsolt; Elek, Zsuzsanna; Sasvari-Szekely, Maria; Champagne, Frances A; Miklósi, Adám; Kubinyi, Enikő

    2013-12-01

    Both dopamine receptor D4 (DRD4) exon 3 and tyrosine hydroxylase (TH) intron 4 repeat polymorphisms have been linked to activity and impulsivity in German Shepherd dogs (GSDs). However, the results in GSDs may not be generalisable to other breeds, as allelic frequencies vary markedly among breeds. We selected the Siberian Husky for further study, because it is highly divergent from most dog breeds, including the GSD. The study sample consisted of 145 racing Siberian Huskies from Europe and North America. We found that this breed possesses seven DRD4 length variants, two to five more variants than found in other breeds. Among them was the longest known allele, previously described only in wolves. Short alleles of the DRD4 and TH repeat polymorphisms were associated with higher levels of activity, impulsivity and inattention. Siberian Huskies possessing at least one short allele of the DRD4 polymorphism displayed greater activity in a behavioural test battery than did those with two long alleles. However, the behavioural test was brief and may not have registered variation in behaviour across time and situations. Owners also completed the Dog-Attention Deficit Hyperactivity Disorder Rating Scale (Dog-ADHD RS), a more general measure of activity and attention. Siberian Huskies from Europe with two short alleles of the TH polymorphism received higher ratings of inattention on the Dog-ADHD RS than did those with the long allele. Investigation of the joint effect of DRD4 and TH showed that dogs possessing long alleles at both sites were scored as less active-impulsive than were others. Our results are aligned with previous studies showing that DRD4 and TH polymorphisms are associated with activity-impulsivity related traits in dogs. However, the prevalence of variants of these genes differs across breeds, and the functional role of specific variants is unclear.

  9. Interactions between Aβ and Mutated Tau Lead to Polymorphism and Induce Aggregation of Aβ-Mutated Tau Oligomeric Complexes

    PubMed Central

    Raz, Yoav; Miller, Yifat

    2013-01-01

    One of the main hallmarks of the fronto-temporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) is the accumulation of neurofibrillary tangles in the brain as an outcome of the aggregation of mutated tau protein. This process occurs due to a number of genetic mutations in the MAPT gene. One of these mutations is the ∆K280 mutation in the tau R2 repeat domain, which promotes the aggregation vis-à-vis that for the wild-type tau. Experimental studies have shown that in Alzheimer’s disease Aβ peptide forms aggregates both with itself and with wild-type tau. By analogy, in FTDP-17, it is likely that there are interactions between Aβ and mutated tau, but the molecular mechanisms underlying such interactions remain to be elucidated. Thus, to investigate the interactions between Aβ and mutated tau, we constructed fourteen ∆K280 mutated tau-Aβ17-42 oligomeric complexes. In seven of the mutated tau-Aβ17-42 oligoemric complexes the mutated tau oligomers exhibited hydrophobic interactions in their core domain, and in the other seven mutated tau-Aβ17-42 oligoemric complexes the mutated tau oligomers exhibited salt-bridge interactions in their core domain. We considered two types of interactions between mutated tau oligomers and Aβ oligomers: interactions of one monomer of the Aβ oligomer with one monomer of the mutated tau oligomer to form a single-layer conformation, and interactions of the entire Aβ oligomer with the entire mutated tau oligomer to form a double-layer conformation. We also considered parallel arrangements of Aβ trimers alternating with mutated tau trimers in a single-layer conformation. Our results demonstrate that in the interactions of Aβ and mutated tau oligomers, polymorphic mutated tau-Aβ17-42 oligomeric complexes were observed, with a slight preference for the double-layer conformation. Aβ trimers alternating with mutated tau trimers constituted a structurally stable confined β-structure, albeit one that was

  10. Genotyping of peroxisome proliferator-activated receptor gamma (PPAR-γ) polymorphism (Pro12Ala) in Iranian population

    PubMed Central

    Namvaran, Fatemeh; Rahimi-Moghaddam, Parvaneh; Azarpira, Negar

    2011-01-01

    BACKGROUND: The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear hormone receptor. It is predominantly expressed in adipose tissue and as a receptor for thiazolidinediones, it has drawn attentions towards itself as a key molecule to trigger pathways involving in some diseases such as cancers, type 2 diabetes, inflammations and osteoporosis. A proline changed to alanine in codon 12 of PPAR-γ gene (Pro12Ala) has been known to be responsible for decreased risk of type 2 diabetes. The aim of the present study is to investigate the frequency of Pro12Ala polymorphism in PPAR-γ in healthy Iranian population to compare with other populations. Understanding this polymorphism may help us in better diagnosis, prevention, and therapeutic approaches toward a better management of diseases such as type 2 diabetes and osteoporosis. METHODS: 128 healthy volunteers were enrolled in this study. To determine single nucleotide polymorphisms (SNPs), we did real time polymerase chain reaction (RT-PCR), using TaqMan allelic discrimination assays. RESULTS: Genotype frequencies for PPAR-γ gene Pro12Ala (rs1801282) polymorphism were 0.86 for CC, 0.14 for CG, 0.00 for GG while allelic frequencies were 0.93 and 0.0.07 for C and G, respectively. CONCLUSIONS: There are statistical differences between the distribution of the PPAR-γ-2 Pro12Ala polymorphism in other populations and Iranian population. PMID:22091247

  11. Association of peroxisome proliferator-activated receptor-gamma 2 Pro12Ala polymorphism with advanced-stage endometriosis.

    PubMed

    Hwang, Kyu Ri; Choi, Young Min; Kim, Jong Mee; Lee, Gyoung Hoon; Kim, Jin Ju; Chae, Soo Jin; Moon, Shin Yong

    2010-11-01

    To investigate whether the peroxisome proliferator-activated receptor (PPAR)-γ2 Pro12Ala polymorphism is associated with a risk of advanced-stage endometriosis in a Korean population.   Case-control study in a collective of 446 patients and 427 controls. The Pro12Ala polymorphism of PPAR-γ2 gene was genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. The distribution of the PPAR-γ2 Pro12Ala polymorphism was different between the advanced-stage endometriosis group and the control group (non-CC rates were 5.2% for patients with advanced endometriosis and 10.1% for the control group, respectively, P = 0.006). The frequency for the Ala-12 allele variant was significantly lower in patients with advanced stage of endometriosis (2.7%) than in the control group (5.3%) (P = 0.006). These findings suggest that the PPAR-γ2 Pro12Ala polymorphism is associated with advanced-stage endometriosis in the Korean population. Unlike results from other studies reported so far, the Ala-12 allele may have protective effects against advanced-stage endometriosis in the Korean population. © 2010 John Wiley & Sons A/S.

  12. Genotyping of peroxisome proliferator-activated receptor gamma (PPAR-γ) polymorphism (Pro12Ala) in Iranian population.

    PubMed

    Namvaran, Fatemeh; Rahimi-Moghaddam, Parvaneh; Azarpira, Negar

    2011-03-01

    The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear hormone receptor. It is predominantly expressed in adipose tissue and as a receptor for thiazolidinediones, it has drawn attentions towards itself as a key molecule to trigger pathways involving in some diseases such as cancers, type 2 diabetes, inflammations and osteoporosis. A proline changed to alanine in codon 12 of PPAR-γ gene (Pro12Ala) has been known to be responsible for decreased risk of type 2 diabetes. The aim of the present study is to investigate the frequency of Pro12Ala polymorphism in PPAR-γ in healthy Iranian population to compare with other populations. Understanding this polymorphism may help us in better diagnosis, prevention, and therapeutic approaches toward a better management of diseases such as type 2 diabetes and osteoporosis. 128 healthy volunteers were enrolled in this study. To determine single nucleotide polymorphisms (SNPs), we did real time polymerase chain reaction (RT-PCR), using TaqMan allelic discrimination assays. Genotype frequencies for PPAR-γ gene Pro12Ala (rs1801282) polymorphism were 0.86 for CC, 0.14 for CG, 0.00 for GG while allelic frequencies were 0.93 and 0.0.07 for C and G, respectively. There are statistical differences between the distribution of the PPAR-γ-2 Pro12Ala polymorphism in other populations and Iranian population.

  13. Association of Plasminogen Activator Inhibitor-1 Gene Polymorphism with Inflammatory Bowel Disease in Iranian Azeri Turkish Patients

    PubMed Central

    Shaghaghi, Zeynab; Bonyadi, Mortaza; Somi, Mohammad H.; Khoshbaten, Manouchehr

    2014-01-01

    Background/Aim: Previous studies have shown the association of some genetic factors, such as Plasminogen activator inhibitor type-1 (PAI-1) 4G/5G polymorphism, with the development of inflammatory bowel disease (IBD). We aimed to study this polymorphism as a risk factor in IBD patients in this cohort. Patients and Methods: One hundred and fifteen IBD patients and 95 healthy controls were selected from Iranian Azeri Turks and -6754G/5G polymorphism of PAI-1 gene was tested by polymerase chain reaction using allele-specific primers confirmed by sequencing. Results: There was no significant difference of PAI-1 polymorphism between IBD patients and the control group (P > 0.05). Furthermore, these data showed no significant difference between Crohn's disease and ulcerative colitis patients. However, 4G/4G homozygotes have reduced probability to progression of loss of appetite, whereas 5G/5G genotypes have increased risk for development of chronic diarrhea without blood, nausea, and loss of appetite. Conclusions: Although our study showed no significant association of PAI-1 polymorphism between patients and control group, the carriers of 4G/4G genotype and 4G allele had reduced risk for the progression of IBD features in this cohort. PMID:24496159

  14. Meta-Analysis of the Association between Plasminogen Activator Inhibitor-1 4G/5G Polymorphism and Recurrent Pregnancy Loss

    PubMed Central

    Li, Xuejiao; Liu, Yukun; Zhang, Rui; Tan, Jianping; Chen, Libin; Liu, Yinglin

    2015-01-01

    Background The association between plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism and recurrent pregnancy loss (RPL) risk is still contradictory. We thus performed a meta-analysis. Material/Methods Relevant studies were searched for in PubMed, Web of Science, Embase, and Cochrane Library. An odds ratio (OR) with a 95% confidence interval (CI) was used to assess the association between PAI-1 4G/5G polymorphism and RPL risk. Results A total of 22 studies with 4306 cases and 3076 controls were included in this meta-analysis. We found that PAI-1 4G/5G polymorphism was significantly associated with an increased RPL risk (OR=1.89; 95% CI 1.34–2.67; P=0.0003). In the subgroup analysis by race, PAI-1 4G/5G polymorphism was significantly associated with an increased RPL risk in Caucasians (OR=2.23; 95% CI 1.44–3.46; P=0.0003). However, no significant association was observed in Asians (OR=1.47; 95% CI 0.84–2.59; P=0.18). Conclusions In conclusion, this meta-analysis suggests that PAI-1 4G/5G polymorphism might be associated with RPL development in Caucasians. PMID:25862335

  15. Meta-analysis of the association between plasminogen activator inhibitor-1 4G/5G polymorphism and recurrent pregnancy loss.

    PubMed

    Li, Xuejiao; Liu, Yukun; Zhang, Rui; Tan, Jianping; Chen, Libin; Liu, Yinglin

    2015-04-11

    The association between plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism and recurrent pregnancy loss (RPL) risk is still contradictory. We thus performed a meta-analysis. Relevant studies were searched for in PubMed, Web of Science, Embase, and Cochrane Library. An odds ratio (OR) with a 95% confidence interval (CI) was used to assess the association between PAI-1 4G/5G polymorphism and RPL risk. A total of 22 studies with 4306 cases and 3076 controls were included in this meta-analysis. We found that PAI-1 4G/5G polymorphism was significantly associated with an increased RPL risk (OR=1.89; 95% CI 1.34-2.67; P=0.0003). In the subgroup analysis by race, PAI-1 4G/5G polymorphism was significantly associated with an increased RPL risk in Caucasians (OR=2.23; 95% CI 1.44-3.46; P=0.0003). However, no significant association was observed in Asians (OR=1.47; 95% CI 0.84-2.59; P=0.18). In conclusion, this meta-analysis suggests that PAI-1 4G/5G polymorphism might be associated with RPL development in Caucasians.

  16. Sequences, annotation and single nucleotide polymorphism of the major histocompatibility complex in the domestic cat.

    PubMed

    Yuhki, Naoya; Mullikin, James C; Beck, Thomas; Stephens, Robert; O'Brien, Stephen J

    2008-07-16

    Two sequences of major histocompatibility complex (MHC) regions in the domestic cat, 2.976 and 0.362 Mbps, which were separated by an ancient chromosome break (55-80 MYA) and followed by a chromosomal inversion were annotated in detail. Gene annotation of this MHC was completed and identified 183 possible coding regions, 147 human homologues, possible functional genes and 36 pseudo/unidentified genes) by GENSCAN and BLASTN, BLASTP RepeatMasker programs. The first region spans 2.976 Mbp sequence, which encodes six classical class II antigens (three DRA and three DRB antigens) lacking the functional DP, DQ regions, nine antigen processing molecules (DOA/DOB, DMA/DMB, TAPASIN, and LMP2/LMP7,TAP1/TAP2), 52 class III genes, nineteen class I genes/gene fragments (FLAI-A to FLAI-S). Three class I genes (FLAI-H, I-K, I-E) may encode functional classical class I antigens based on deduced amino acid sequence and promoter structure. The second region spans 0.362 Mbp sequence encoding no class I genes and 18 cross-species conserved genes, excluding class I, II and their functionally related/associated genes, namely framework genes, including three olfactory receptor genes. One previously identified feline endogenous retrovirus, a baboon retrovirus derived sequence (ECE1) and two new endogenous retrovirus sequences, similar to brown bat endogenous retrovirus (FERVmlu1, FERVmlu2) were found within a 140 Kbp interval in the middle of class I region. MHC SNPs were examined based on comparisons of this BAC sequence and MHC homozygous 1.9x WGS sequences and found that 11,654 SNPs in 2.84 Mbp (0.00411 SNP per bp), which is 2.4 times higher rate than average heterozygous region in the WGS (0.0017 SNP per bp genome), and slightly higher than the SNP rate observed in human MHC (0.00337 SNP per bp).

  17. Structural insight of dopamine β-hydroxylase, a drug target for complex traits, and functional significance of exonic single nucleotide polymorphisms.

    PubMed

    Kapoor, Abhijeet; Shandilya, Manish; Kundu, Suman

    2011-01-01

    Human dopamine β-hydroxylase (DBH) is an important therapeutic target for complex traits. Several single nucleotide polymorphisms (SNPs) have also been identified in DBH with potential adverse physiological effect. However, difficulty in obtaining diffractable crystals and lack of a suitable template for modeling the protein has ensured that neither crystallographic three-dimensional structure nor computational model for the enzyme is available to aid rational drug design, prediction of functional significance of SNPs or analytical protein engineering. Adequate biochemical information regarding human DBH, structural coordinates for peptidylglycine alpha-hydroxylating monooxygenase and computational data from a partial model of rat DBH were used along with logical manual intervention in a novel way to build an in silico model of human DBH. The model provides structural insight into the active site, metal coordination, subunit interface, substrate recognition and inhibitor binding. It reveals that DOMON domain potentially promotes tetramerization, while substrate dopamine and a potential therapeutic inhibitor nepicastat are stabilized in the active site through multiple hydrogen bonding. Functional significance of several exonic SNPs could be described from a structural analysis of the model. The model confirms that SNP resulting in Ala318Ser or Leu317Pro mutation may not influence enzyme activity, while Gly482Arg might actually do so being in the proximity of the active site. Arg549Cys may cause abnormal oligomerization through non-native disulfide bond formation. Other SNPs like Glu181, Glu250, Lys239 and Asp290 could potentially inhibit tetramerization thus affecting function. The first three-dimensional model of full-length human DBH protein was obtained in a novel manner with a set of experimental data as guideline for consistency of in silico prediction. Preliminary physicochemical tests validated the model. The model confirms, rationalizes and provides

  18. Characterization and activity of cephalosporin metal complexes.

    PubMed

    Auda, S H; Mrestani, Y; Fetouh, M I; Neubert, R H H

    2008-08-01

    Semi-synthetic cephalosporin antibiotics have structures similar to that of penicillins, and both groups of compounds are characterized by similar properties and determined by the same methods. Most antibiotics, including cephalosporins and their decomposition products, contain electron donor groups that can bind naturally occurring metal ions in vivo. Cephalosporin antibiotics exhibit a change in their toxicological properties and biological performance when they were tested as metal complexes. The proposed reason for such a behavior is the capability of chelate binding of the cephalosporins to the metals. In an attempt to understand the coordination mode of metals with cephalosporins, different spectroscopic techniques such as IR, UV-visible, NMR spectroscopy and voltammetric measurements were carried out to elucidate the structure of the metal-cephalosporin complexes. Synthesis, characterization and biological screening of the cephalosporins and of the cephalosporin-metal complexes are discussed in this review. However, little information is available on the influence of the metal ions on the pharmacokinetics of the cephalosporin derivatives.

  19. Noise enhanced activity in a complex network

    NASA Astrophysics Data System (ADS)

    Choudhary, Anshul; Kohar, Vivek; Sinha, Sudeshna

    2014-09-01

    We consider the influence of local noise on a generalized network of populations having positive and negative feedbacks. The population dynamics at the nodes is nonlinear, typically chaotic, and allows cessation of activity if the population falls below a threshold value. We investigate the global stability of this large interactive system, as indicated by the average number of nodal populations that manage to remain active. Our central result is that the probability of obtaining active nodes in this network is significantly enhanced under fluctuations. Further, we find a sharp transition in the number of active nodes as noise strength is varied, along with clearly evident scaling behaviour near the critical noise strength. Lastly, we also observe noise induced temporal coherence in the active sub-network, namely, there is an enhancement in synchrony among the nodes at an intermediate noise strength.

  20. Angiotensinogen and Plasminogen Activator Inhibitor-1 Gene Polymorphism in Relation to Renovascular Disease

    SciTech Connect

    Reis, Kadriye Altok Onal, Baran; Gonen, Sevim; Arinsoy, Turgay; Erten, Yasemin; Ilgit, Erhan; Soylemezoglu, Oguz; Derici, Ulver; Guz, Galip; Bali, Musa; Sindel, Sukru

    2006-02-15

    The present study was designed to evaluate angiotensinogen (AGT) M235T and plasminogen activator inhibitor-1 (PAI-1) (4G/5G) polymorphisims in relation to the occurrence of atherosclerotic renal artery stenosis (ARAS) and recurrent stenosis. In this study, 30 patients were enrolled after angiographic demonstration of ARAS; 100 healthy subjects for AGT polymorphism and 80 healthy subjects for PAI-1 polymorphism were considered the control group. The patients were followed for a mean 46.1 {+-} 9.2 months. The patients had significantly higher frequencies of the MT genotype and the T allele than control group ({chi}{sup 2} = 18.2, p < 0.001 and {chi}{sup 2} = 11.5 p < 0.001). There were no significant differences in the PAI-1 genotype and allele findings when the data for all patients were compared with that for the controls ({chi}{sup 2}= 2.45, p = 0.29 and {chi}{sup 2} = 0.019, p = 0.89). There were no significant differences in the genotype and allele findings for the patients with and without restenosis (p > 0.05). The C-reactive protein (CRP) level was higher in the patients with restenosis than in the patients without restenosis (7.694 {+-} 0.39 mg/L and 1.56 {+-} 1.08 mg/L) (p = 0.001). Our results suggest that the M235T MT genotype and T allele might be associated with increased risk of atherosclerotic renal artery stenosis. The CRP level might be an independent predictor for recurrent stenosis.

  1. Polymorph characterization of active pharmaceutical ingredients (APIs) using low-frequency Raman spectroscopy.

    PubMed

    Larkin, Peter J; Dabros, Marta; Sarsfield, Beth; Chan, Eric; Carriere, James T; Smith, Brian C

    2014-01-01

    Polymorph detection, identification, and quantitation in crystalline materials are of great importance to the pharmaceutical industry. Vibrational spectroscopic techniques used for this purpose include Fourier transform mid-infrared (FT-MIR) spectroscopy, Fourier transform near-infrared (FT-NIR) spectroscopy, Raman spectroscopy, and terahertz (THz) and far-infrared (FIR) spectroscopy. Typically, the fundamental molecular vibrations accessed using high-frequency Raman and MIR spectroscopy or the overtone and combination of bands in the NIR spectra are used to monitor the solid-state forms of active pharmaceutical ingredients (APIs). The local environmental sensitivity of the fundamental molecular vibrations provides an indirect probe of the long-range order in molecular crystals. However, low-frequency vibrational spectroscopy provides access to the lattice vibrations of molecular crystals and, hence, has the potential to more directly probe intermolecular interactions in the solid state. Recent advances in filter technology enable high-quality, low-frequency Raman spectra to be acquired using a single-stage spectrograph. This innovation enables the cost-effective collection of high-quality Raman spectra in the 200-10 cm(-1) region. In this study, we demonstrate the potential of low-frequency Raman spectroscopy for the polymorphic characterization of APIs. This approach provides several benefits over existing techniques, including ease of sampling and more intense, information-rich band structures that can potentially discriminate among crystalline forms. An improved understanding of the relationship between the crystalline structure and the low-frequency vibrational spectrum is needed for the more widespread use of the technique.

  2. ABCG2 regulatory single-nucleotide polymorphisms alter in-vivo enhancer activity and expression.

    PubMed

    Eclov, Rachel J; Kim, Mee J; Chhibber, Aparna; Smith, Robin P; Ahituv, Nadav; Kroetz, Deanna L

    2017-09-18

    The expression and activity of the breast cancer resistance protein (ABCG2) contributes toward the pharmacokinetics of endogenous and xenobiotic substrates. The effect of genetic variation on the activity of cis-regulatory elements and nuclear response elements in the ABCG2 locus and their contribution toward ABCG2 expression have not been investigated systematically. In this study, the effect of genetic variation on the in-vitro and in-vivo enhancer activity of six previously identified liver enhancers in the ABCG2 locus was examined. Reference and variant liver enhancers were tested for their ability to alter luciferase activity in vitro in HepG2 and HEK293T cell lines and in vivo using a hydrodynamic tail vein assay. Positive in-vivo single-nucleotide polymorphisms (SNPs) were tested for association with gene expression and for altered protein binding in electrophoretic mobility shift assays. Multiple SNPs were found to alter enhancer activity in vitro. Four of these variants (rs9999111, rs12508471, ABCG2RE1*2, and rs149713212) decreased and one (rs2725263) increased enhancer activity in vivo. In addition, rs9999111 and rs12508471 were associated with ABCG2 expression in lymphoblastoid cell lines, lymphocytes, and T cells, and showed increased HepG2 nuclear protein binding. This study identifies SNPs within regulatory regions of the ABCG2 locus that alter enhancer activity in vitro and in vivo. Several of these SNPs correlate with tissue-specific ABCG2 expression and alter DNA/protein binding. These SNPs could contribute toward reported tissue-specific variability in ABCG2 expression and may influence the correlation between ABCG2 expression and disease risk or the pharmacokinetics and pharmacodynamics of breast cancer resistance protein substrates.

  3. Correlations among obesity-associated gene polymorphisms, body composition, and physical activity in patients with type 2 diabetes mellitus

    PubMed Central

    Saitoh, Sanae; Shimoda, Taeko; Hamamoto, Yukie; Nakaya, Yutaka; Nakajima, Shigeru

    2015-01-01

    Context: Various studies have focused on the correlation between β2-adrenergic receptor (β2AR), the β3-adrenergic receptor (β3AR), and the uncoupling protein 1 (UCP1) polymorphisms and obesity in patients with type 2 diabetes mellitus (T2DM). Aims: We examined the correlation between these polymorphisms and body composition variables and between body composition and lifestyle variables in Japanese T2DM patients. Materials and Methods: Of the 48, T2DM outpatients in Kanagawa prefecture recruited for participation, 32 (6 men and 26 women) met the study criteria and were enrolled. Obesity-related gene polymorphisms were identified in 3 genes β3AR, UCP1, and β2AR using the SMart amplification process. Body composition variables were measured using a body composition analyzer. Data regarding food and nutrient consumption, family history, and lifestyle factors were collected via administration of questionnaires. Results: Because significant differences in body composition variables were found between men and women, statistical analysis was performed with data from the 25 female subjects only. On the basis of results of genetic testing, the subjects were divided into genotype groups for two-group and three-group comparison. The β3AR, UCP1, and β2AR polymorphisms and body composition significantly correlated with the percentage of subcutaneous fat in both arms as compared with the wild type or hetero groups with β3AR polymorphisms. However, physical activity correlated with several body composition variables. Conclusions: These results suggest that obesity in T2DM patients is not the result of presence of an obesity-related gene polymorphism but rather the absence of daily physical activity. PMID:25593829

  4. Association of ADAM33 gene polymorphism and arginase activity with susceptibility to ventilatory impairment in wood dust-exposed workers.

    PubMed

    Saad-Hussein, A; Thabet, E H; Taha, M M; Shahy, E M; Mahdy-Abdallah, H

    2016-09-01

    ADAM33 represents an important gene of susceptibility for lung function impairment. This work aimed to evaluate the association between genetic polymorphism of ADAM33 at four single nucleotide polymorphisms (T1, T2, S1, and Q1) and arginase activity with respiratory functions impairment in wood workers. The study was done to compare ventilatory functions and arginase activity of 82 wood workers and 81 controls. Genotyping was determined by using the polymerase chain restriction fragment length polymorphism method. Forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), and peak expiratory flow rate (PEF) of the workers were significantly reduced compared with the controls. T1 single nucleotide polymorphism (SNP) was associated with obvious decline in the FEV1, FVC, and PEF in wood workers, while T2 SNP was associated with decline in FEV1 and PEF. A significant increase in arginase activity was found in T2 and S1 SNPs of the exposed workers. Increase in duration of exposure was correlated with the decline in ventilatory functions. This inverse correlation was significant for pulmonary function indices in AA and GG genotypes of T1 and T2, respectively. Moreover, significance was detected for FVC and FEV1 in AA and GA genotypes of S1 and Q1. A positive correlation between arginase activity and duration of exposure was found to be significant in GG genotype of S1 SNP. An association between ADAM33 gene polymorphism and impaired lung functions was detected in wood dust-exposed workers. Arginase activity may play an associated important role in increasing this impairment in wood workers.

  5. An active particle in a complex fluid

    NASA Astrophysics Data System (ADS)

    Datt, Charu; Natale, Giovanniantonio; Hatzikiriakos, Savvas G.; Elfring, Gwynn J.

    2016-11-01

    Active particles are self-driven units capable of converting stored or ambient free-energy into systematic movement. We discuss here the case when such particles move through non-Newtonian fluids. Neglecting inertial forces, we employ the reciprocal theorem to calculate the propulsion velocity of a single swimmer in a weakly non-Newtonian fluid with background flow. We also derive a general expression for the velocity of an active particle modelled as a squirmer in a second-order fluid. We then discuss how active colloids are affected by the medium rheology, namely viscoelasticity and shear-thinning.

  6. Association of autophagy-related IRGM polymorphisms with latent versus active tuberculosis infection in a Chinese population.

    PubMed

    Lu, Yanjun; Li, Qian; Peng, Jing; Zhu, Yaowu; Wang, Feng; Wang, Chunyu; Wang, Xiong

    2016-03-01

    The autophagy-related immunity-related GTPase family M protein, IRGM, plays an important role in the defense against tuberculosis (TB) infection. IRGM polymorphisms are associated with TB infection susceptibility, and recent studies demonstrate host genetic differences between active and latent TB. Here, we investigated the association between IRGM polymorphisms and TB infection type in a Chinese population. We recruited 268 and 321 patients with confirmed or latent TB, respectively, and 475 TB-free healthy controls. Three single nucleotide polymorphisms, rs10065172, rs10051924, and rs13361189 within IRGM were genotyped using TaqMan-based assays. Interferon-gamma release levels were tested by T-SPOT. rs10065172 (P = 0.024, OR 0.67 (95% CI 0.48-0.95)), rs10051924 (P = 0.01, OR 0.64 (95% CI 0.46-0.90)), and rs13361189 (P = 0.055, OR 0.72 (95% CI 0.51-1.01)) were associated with a protective role against latent TB progression. Haplotype analysis showed that TCC was protective for latent TB (P = 0.022, OR 0.74 (95% CI 0.57-0.96)) whereas TTC conferred a higher risk of active TB. Additionally, patients with the rs10065172 TT genotype had a higher response to TB specific antigens. Thus, IRGM polymorphism differences between latent and active TB suggests that genetic differences in autophagy might partly affect host TB infection status.

  7. Lack of Association Between ACE Indel Polymorphism and Cardiorespiratory Fitness in Physically Active and Sedentary Young Women

    PubMed Central

    Verlengia, Rozangela; Rebelo, Ana C.; Crisp, Alex H.; Kunz, Vandeni C.; dos Santos Carneiro Cordeiro, Marco A.; Hirata, Mario H.; Crespo Hirata, Rosario D.; Silva, Ester

    2014-01-01

    Background: Polymorphisms at the angiotensin-converting enzyme gene (ACE), such as the indel [rs1799752] variant in intron 16, have been shown to be associated with aerobic performance of athletes and non-athletes. However, the relationship between ACE indel polymorphism and cardiorespiratory fitness has not been always demonstrated. Objectives: The relationship between ACE indel polymorphism and cardiorespiratory fitness was investigated in a sample of young Caucasian Brazilian women. Patients and Methods: This study investigated 117 healthy women (aged 18 to 30 years) who were grouped as physically active (n = 59) or sedentary (n = 58). All subjects performed an incremental exercise test (ramp protocol) on a cycle-ergometer with 20-25 W/min increments. Blood samples were obtained for DNA extraction and to analyze metabolic and hormonal profiles. ACE indel polymorphism was determined by polymerase chain reaction (PCR) and fragment size analysis. Results: The physically active group had higher values of peak oxygen uptake (VO2 peak), carbon dioxide output (VCO2), ventilation (VE) and power output than the sedentary group (P < 0.05) at the peak of the exercise test. However, heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) did not differ between groups. There was no relationship between ACE indel polymorphism and cardiorespiratory variables during the test in both the physically active and sedentary groups, even when the dominant (DD vs. D1 + 2) and recessive (2 vs. DI + DD) models of inheritance were tested. Conclusions: These results do not support the concept that the genetic variation at the ACE locus contributes to the cardiorespiratory responses at the peak of exercise test in physically active or sedentary healthy women. This indicates that other factors might mediate these responses, including the physical training level of the women. PMID:25520764

  8. GSTP1 Polymorphisms and their Association with Glutathione Transferase and Peroxidase Activities in Patients with Motor Neuron Disease.

    PubMed

    Gajewska, Beata; Kaźmierczak, Beata; Kuźma-Kozakiewicz, Magdalena; Jamrozik, Zygmunt; Barańczyk-Kuźma, Anna

    2015-01-01

    Glutathione S-transferase pi (GSTP1) is a crucial enzyme in detoxification of electrophilic compounds and organic peroxides. Together with Se-dependent glutathione peroxidase (Se-GSHPx) it protects cells against oxidative stress which may be a primary factor implicated in motor neuron disease (MND) pathogenesis. We investigated GSTP1 polymorphisms and their relationship with GST and Se-GSTPx activities in a cohort of Polish patients with MND. Results were correlated with clinical phenotypes. The frequency of genetic variants for GSTP1 exon 5 (I105V) and exon 6 (A114V) was studied in 104 patients and 100 healthy controls using real-time polymerase chain reaction. GST transferase activity was determined in serum with 1-chloro-2,4-dinitrobenzene, its peroxidase activity with cumene hydroperoxide, and Se-GSHPx activity with hydrogen peroxide. There were no differences in the prevalence of GSTP1 polymorphism I105V and A114V between MND and controls, however the occurrence of CT variant in codon 114 was associated with a higher risk for MND. GSTP1 polymorphisms were less frequent in classic ALS than in progressive bulbar palsy. In classic ALS C* (heterozygous I /V and A /V) all studied activities were significantly lower than in classic ALS A* (homozygous I /I and A/A). GST peroxidase activity and Se-GSHPx activity were lower in classic ALS C* than in control C*, but in classic ALS A* Se-GSHPx activity was significantly higher than in control A*. It can be concluded that the presence of GSTP1 A114V but not I105V variant increases the risk of MND, and combined GSTP1 polymorphisms in codon 105 and 114 may result in lower protection of MND patients against the toxicity of electrophilic compounds, organic and inorganic hydroperoxides.

  9. Effects of omeprazole and genetic polymorphism of CYP2C19 on the clopidogrel active metabolite.

    PubMed

    Boulenc, Xavier; Djebli, Nassim; Shi, Juan; Perrin, Laurent; Brian, William; Van Horn, Robert; Hurbin, Fabrice

    2012-01-01

    Clopidogrel is an antiplatelet agent widely used in cardiovascular diseases and an inactive prodrug that needs to be converted to an active metabolite in two sequential metabolic steps. Several CYP450 isoforms involved in these two steps have been described, although the relative contribution in vivo of each enzyme is still under debate. CYP2C19 is considered to be the major contributor to active metabolite formation. In the current study, net CYP2C19 contribution to the active metabolite formation was determined from exposure of the active metabolite in two clinical studies (one phase I study with well balanced genetic polymorphic populations and a meta-analysis with a total of 396 healthy volunteers) at different clopidogrel doses. CYP2C19 involvements were estimated to be from 58 to 67% in intermediate metabolizers (IMs), from 58 to 72% in extensive metabolizers (EMs), and from 56 to 74% in ultrarapid metabolizers (UMs), depending on the study and the dose. For this purpose, a static model was proposed to estimate the net contribution of a given enzyme to the secondary metabolite formation. This static model was compared with a dynamic approach (Simcyp model) and showed good consistency. In parallel, in vitro investigations showed that omeprazole is a mechanism-based inhibitor of CYP2C19 with K(I) of 8.56 μM and K(inact) of 0.156 min(-1). These values were combined with the net CYP2C19 contribution to the active metabolite formation, through a static approach, to predict the inhibitory effect at 80-mg omeprazole doses in EM, IM, and UM CYP2C19 populations, with good consistency, compared with observed clinical values.

  10. Unveiling causal activity of complex networks

    NASA Astrophysics Data System (ADS)

    Williams-García, Rashid V.; Beggs, John M.; Ortiz, Gerardo

    2017-07-01

    We introduce a novel tool for analyzing complex network dynamics, allowing for cascades of causally-related events, which we call causal webs (c-webs), to be separated from other non-causally-related events. This tool shows that traditionally-conceived avalanches may contain mixtures of spatially-distinct but temporally-overlapping cascades of events, and dynamical disorder or noise. In contrast, c-webs separate these components, unveiling previously hidden features of the network and dynamics. We apply our method to mouse cortical data with resulting statistics which demonstrate for the first time that neuronal avalanches are not merely composed of causally-related events. The original version of this article was uploaded to the arXiv on March 17th, 2016 [1].

  11. Active Control of Complex Physical Systems: An Overview

    DTIC Science & Technology

    1992-09-01

    release; distribution is unlimited. 13. ABSTRACT (Maxtmum 200 words) Active control of complex systems imposes unique requirements for physical models and...months after the meeting, SPrinte In USA. Acceslon For NTIS CRA&W DTIC TAB Unlannounced ] Active Control of Complex Physical Systems Justificatton An...control strategies. Physical models This work on the active control of which are adequate to predict the influence of specific physical systems has been

  12. Effect of Proliferator-Activated Receptor-γ Pro12Ala Polymorphism on Colorectal Cancer Risk: A Meta-Analysis

    PubMed Central

    Wei, Zhijiang; Han, Guoda; Bai, Xiyong

    2015-01-01

    Background The association between peroxisome proliferators-activated receptor γ (PPARγ) Pro12Ala polymorphism and colorectal cancer (CRC) risk is still controversial. A meta-analysis was performed. Material/Methods We conducted a literature search using PubMed, EMBASE, and Cochran databases. The pooled odds ratio (OR) with 95% confidence intervals (CIs) were calculated. Fixed-effects and random-effects models were used. Dominant model, recessive model, and additive model were used in this meta-analysis. Results Fifteen studies including 13575 cases and 17085 controls were included in our meta-analysis. Result of this meta-analysis found that PPARγ Pro12Ala polymorphism was significantly associated with a reduced risk of CRC (OR=0.90; 95% CI 0.83–0.98; P=0.01). No significant association was found between PPARγ Pro12Ala polymorphism and CRC risk in Asians (OR=0.80; 95% CI 0.60–1.09; P=0.15). However, PPARγ Pro12Ala polymorphism was significantly associated with a reduced risk of CRC in Caucasians (OR=0.91; 95% CI 0.83–0.99; P=0.03). When stratified analysis was performed by CRC site, no positive association was found between PPARγ Pro12Ala polymorphism and rectal cancer (OR=0.95; 95% CI 0.74–1.22; P=0.71). However, a reduced risk of colon cancer was observed (OR=0.85; 95% CI 0.76–0.94; P=0.002). Conclusions In summary, this study suggests that PPARγ Pro12Ala polymorphism was a protective factor of CRC. PMID:26049557

  13. Effect of Proliferator-Activated Receptor-γ Pro12Ala Polymorphism on Colorectal Cancer Risk: A Meta-Analysis.

    PubMed

    Wei, Zhijiang; Han, Guoda; Bai, Xiyong

    2015-06-02

    The association between peroxisome proliferators-activated receptor γ (PPARγ) Pro12Ala polymorphism and colorectal cancer (CRC) risk is still controversial. A meta-analysis was performed. We conducted a literature search using PubMed, EMBASE, and Cochran databases. The pooled odds ratio (OR) with 95% confidence intervals (CIs) were calculated. Fixed-effects and random-effects models were used. Dominant model, recessive model, and additive model were used in this meta-analysis. Fifteen studies including 13575 cases and 17085 controls were included in our meta-analysis. Result of this meta-analysis found that PPARγ Pro12Ala polymorphism was significantly associated with a reduced risk of CRC (OR=0.90; 95% CI 0.83-0.98; P=0.01). No significant association was found between PPARγ Pro12Ala polymorphism and CRC risk in Asians (OR=0.80; 95% CI 0.60-1.09; P=0.15). However, PPARγ Pro12Ala polymorphism was significantly associated with a reduced risk of CRC in Caucasians (OR=0.91; 95% CI 0.83-0.99; P=0.03). When stratified analysis was performed by CRC site, no positive association was found between PPARγ Pro12Ala polymorphism and rectal cancer (OR=0.95; 95% CI 0.74-1.22; P=0.71). However, a reduced risk of colon cancer was observed (OR=0.85; 95% CI 0.76-0.94; P=0.002). In summary, this study suggests that PPARγ Pro12Ala polymorphism was a protective factor of CRC.

  14. Global fibrinolytic activity, PAI-1 level, and 4G/5G polymorphism in Thai children with arterial ischemic stroke.

    PubMed

    Natesirinilkul, Rungrote; Sasanakul, Werasak; Chuansumrit, Ampaiwan; Kadegasem, Praguywan; Visudtibhan, Anannit; Wongwerawattanakoon, Pakawan; Sirachainan, Nongnuch

    2014-01-01

    Prolonged euglobulin clot lysis time (ECLT) and increased level of plasminogen activator inhibitor-1 (PAI-1) were reported to be risk factors of arterial ischemic stroke (AIS) by some studies; however, these findings were not supported by other studies. The objective of this study was to determine the association of ECLT, PAI-1 level, and polymorphisms of 4G and 5G of PAI-1 gene to the development of AIS in Thai children. This study included patients aged 1-18 years old. Diagnosis of AIS was confirmed by imaging study. The control group was age- and sex-matched healthy subjects. Demographic data were recorded, and blood was tested for ECLT, PAI-1 level, lipid profiles, fasting blood sugar (FBS), and 4G and 5G polymorphisms of PAI-1 gene. There were 70 subjects participating in this study, consisting of 30 patients and 40 controls. Demographic data, lipid profiles, and FBS were similar between the 2 groups. Furthermore, ECLT and PAI-1 level did not differ between patient and control groups; however, both showed significant correlation (r = .352, P = .006). The 4G/5G polymorphism was the most common genotype in both patient and control groups (69.0% vs. 80.0%). However, 4G and 5G polymorphisms of PAI-1 gene did not correlate with PAI-1 level in this study (P = .797). The PAI-1 level and 4G/5G polymorphism may not be a risk factor of AIS in this population. It was also found that the 4G/5G polymorphism was the most common PAI-1 genotype in this study. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  15. Clinicopathological significance of plasminogen activator inhibitor-1 promoter 4G/5G polymorphism in breast cancer: a meta-analysis.

    PubMed

    Lee, Ju-Han; Kim, Younghye; Choi, Jung-Woo; Kim, Young-Sik

    2013-01-01

    Plasminogen activator inhibitor type 1 (PAI-1) is associated with poor prognosis in breast cancer. Transcriptional expression of the PAI-1 can be controlled by PAI-1 promoter 4G/5G polymorphism. However, the significance of PAI-1 promoter 4G/5G polymorphism in breast cancer patients is contentious. To address this controversy, we conducted a meta-analysis for the relationships between PAI-1 promoter polymorphism and clinicopathological characteristics of breast cancer. Relevant published studies were identified using a search of PubMed, Embase, and the ISI Web of Science. The effect sizes of PAI-1 promoter 4G/5G polymorphism on breast cancer risk, lymph node metastasis, histologic grade, and overall survival were calculated by odds ratio (OR) or hazard ratio. The effect sizes were combined using a random-effects model. Individuals with 4G/4G genotype had a higher risk of breast cancer than those with the combined 4G/5G and 5G/5G genotypes (OR = 1.388; p = 0.031). Breast cancer patients with the 5G/5G genotype displayed lymph node metastasis more than patients with either the combined other genotypes (OR = 1.495; p = 0.027) or with the 4G/4G genotype (OR = 1.623; p = 0.018). However, the PAI-1 promoter 4G/5G polymorphism was not associated with histological grade or overall survival. PAI-1 promoter 4G/5G polymorphism is associated with a relatively increased risk of breast cancer development and lymph node metastasis. Copyright © 2013 IMSS. Published by Elsevier Inc. All rights reserved.

  16. Selection, trans-species polymorphism, and locus identification of major histocompatibility complex class IIβ alleles of New World ranid frogs.

    PubMed

    Kiemnec-Tyburczy, Karen M; Richmond, Jonathan Q; Savage, Anna E; Zamudio, Kelly R

    2010-12-01

    Genes encoded by the major histocompatibility complex (MHC) play key roles in the vertebrate immune system. However, our understanding of the evolutionary processes and underlying genetic mechanisms shaping these genes is limited in many taxa, including amphibians, a group currently impacted by emerging infectious diseases. To further elucidate the evolution of the MHC in frogs (anurans) and develop tools for population genetics, we surveyed allelic diversity of the MHC class II β1 domain in both genomic and complementary DNA of seven New World species in the genus Rana (Lithobates). To assign locus affiliation to our alleles, we used a "gene walking" technique to obtain intron 2 sequences that flanked MHC class IIβ exon 2. Two distinct intron sequences were recovered, suggesting the presence of at least two class IIβ loci in Rana. We designed a primer pair that successfully amplified an orthologous locus from all seven Rana species. In total, we recovered 13 alleles and documented trans-species polymorphism for four of the alleles. We also found quantitative evidence of selection acting on amino acid residues that are putatively involved in peptide binding and structural stability of the β1 domain of anurans. Our results indicated that primer mismatch can result in polymerase chain reaction (PCR) bias, which influences the number of alleles that are recovered. Using a single locus may minimize PCR bias caused by primer mismatch, and the gene walking technique was an effective approach for generating single-copy orthologous markers necessary for future studies of MHC allelic variation in natural amphibian populations.

  17. Selection, trans-species polymorphism, and locus identification of major histocompatibility complex class IIβ alleles of New World ranid frogs

    USGS Publications Warehouse

    Kiemnec-Tyburczy, Karen M.; Richmond, Jonathan Q.; Savage, Anna E.; Zamudio, Kelly R.

    2010-01-01

    Genes encoded by the major histocompatibility complex (MHC) play key roles in the vertebrate immune system. However, our understanding of the evolutionary processes and underlying genetic mechanisms shaping these genes is limited in many taxa, including amphibians, a group currently impacted by emerging infectious diseases. To further elucidate the evolution of the MHC in frogs (anurans) and develop tools for population genetics, we surveyed allelic diversity of the MHC class II ??1 domain in both genomic and complementary DNA of seven New World species in the genus Rana (Lithobates). To assign locus affiliation to our alleles, we used a "gene walking" technique to obtain intron 2 sequences that flanked MHC class II?? exon 2. Two distinct intron sequences were recovered, suggesting the presence of at least two class II?? loci in Rana. We designed a primer pair that successfully amplified an orthologous locus from all seven Rana species. In total, we recovered 13 alleles and documented trans-species polymorphism for four of the alleles. We also found quantitative evidence of selection acting on amino acid residues that are putatively involved in peptide binding and structural stability of the ??1 domain of anurans. Our results indicated that primer mismatch can result in polymerase chain reaction (PCR) bias, which influences the number of alleles that are recovered. Using a single locus may minimize PCR bias caused by primer mismatch, and the gene walking technique was an effective approach for generating single-copy orthologous markers necessary for future studies of MHC allelic variation in natural amphibian populations. ?? 2010 Springer-Verlag.

  18. Whole-genome scan, in a complex disease, using 11,245 single-nucleotide polymorphisms: comparison with microsatellites.

    PubMed

    John, Sally; Shephard, Neil; Liu, Guoying; Zeggini, Eleftheria; Cao, Manqiu; Chen, Wenwei; Vasavda, Nisha; Mills, Tracy; Barton, Anne; Hinks, Anne; Eyre, Steve; Jones, Keith W; Ollier, William; Silman, Alan; Gibson, Neil; Worthington, Jane; Kennedy, Giulia C

    2004-07-01

    Despite the theoretical evidence of the utility of single-nucleotide polymorphisms (SNPs) for linkage analysis, no whole-genome scans of a complex disease have yet been published to directly compare SNPs with microsatellites. Here, we describe a whole-genome screen of 157 families with multiple cases of rheumatoid arthritis (RA), performed using 11,245 genomewide SNPs. The results were compared with those from a 10-cM microsatellite scan in the same cohort. The SNP analysis detected HLA*DRB1, the major RA susceptibility locus (P=.00004), with a linkage interval of 31 cM, compared with a 50-cM linkage interval detected by the microsatellite scan. In addition, four loci were detected at a nominal significance level (P<.05) in the SNP linkage analysis; these were not observed in the microsatellite scan. We demonstrate that variation in information content was the main factor contributing to observed differences in the two scans, with the SNPs providing significantly higher information content than the microsatellites. Reducing the number of SNPs in the marker set to 3,300 (1-cM spacing) caused several loci to drop below nominal significance levels, suggesting that decreases in information content can have significant effects on linkage results. In contrast, differences in maps employed in the analysis, the low detectable rate of genotyping error, and the presence of moderate linkage disequilibrium between markers did not significantly affect the results. We have demonstrated the utility of a dense SNP map for performing linkage analysis in a late-age-at-onset disease, where DNA from parents is not always available. The high SNP density allows loci to be defined more precisely and provides a partial scaffold for association studies, substantially reducing the resource requirement for gene-mapping studies.

  19. Gene Network Polymorphism Illuminates Loss and Retention of Novel RNAi Silencing Components in the Cryptococcus Pathogenic Species Complex

    PubMed Central

    Clancey, Shelly Applen; Wang, Xuying; Heitman, Joseph

    2016-01-01

    RNAi is a ubiquitous pathway that serves central functions throughout eukaryotes, including maintenance of genome stability and repression of transposon expression and movement. However, a number of organisms have lost their RNAi pathways, including the model yeast Saccharomyces cerevisiae, the maize pathogen Ustilago maydis, the human pathogen Cryptococcus deuterogattii, and some human parasite pathogens, suggesting there may be adaptive benefits associated with both retention and loss of RNAi. By comparing the RNAi-deficient genome of the Pacific Northwest Outbreak C. deuterogattii strain R265 with the RNAi-proficient genomes of the Cryptococcus pathogenic species complex, we identified a set of conserved genes that were lost in R265 and all other C. deuterogattii isolates examined. Genetic and molecular analyses reveal several of these lost genes play roles in RNAi pathways. Four novel components were examined further. Znf3 (a zinc finger protein) and Qip1 (a homolog of N. crassa Qip) were found to be essential for RNAi, while Cpr2 (a constitutive pheromone receptor) and Fzc28 (a transcription factor) are involved in sex-induced but not mitosis-induced silencing. Our results demonstrate that the mitotic and sex-induced RNAi pathways rely on the same core components, but sex-induced silencing may be a more specific, highly induced variant that involves additional specialized or regulatory components. Our studies further illustrate how gene network polymorphisms involving known components of key cellular pathways can inform identification of novel elements and suggest that RNAi loss may have been a core event in the speciation of C. deuterogattii and possibly contributed to its pathogenic trajectory. PMID:26943821

  20. Different applications of polymerases with and without proofreading activity in single-nucleotide polymorphism analysis.

    PubMed

    Zhang, Jia; Li, Kai; Liao, Duanfang; Pardinas, Jose R; Chen, Linling; Zhang, Xu

    2003-08-01

    With the completion of the human genome project, single-nucleotide polymorphisms (SNPs) have become the focus of intense study in biomedical research. Polymerase-mediated primer extension has been employed in a variety of SNP assays. However, these SNP assays using polymerase without proofreading function are compromised by their low reliability. Using a newly developed short amplicon harboring restriction enzyme site, EcoR-I, we were able to compare the single-base discrimination abilities of polymerases with and without proofreading function in primer extension in a broad range of annealing temperatures. Thermodynamic analysis demonstrated a striking single-nucleotide discrimination ability of polymerases with proofreading function. Using unmodified 3'-end allele-specific primers, only template-dependent products were generated by polymerase with proofreading activity. This powerful single-base discrimination ability of exo(+) polymerases was further evaluated in primer extension using three types of 3' terminally modified allele-specific primers. As compared with the poor fidelity in primer extension of polymerases lacking 3' exonuclease activity, this study provides convincing evidence that the use of proofreading polymerases in combination with 3'-end modified allele-specific primers can be a powerful new strategy for the development of SNP assays.

  1. Polymorphisms and the Differential Antiviral Activity of the Chicken Mx Gene

    PubMed Central

    Ko, Jae-Hong; Jin, Hee-Kyung; Asano, Atsushi; Takada, Ayato; Ninomiya, Ai; Kida, Hiroshi; Hokiyama, Hironao; Ohara, Mutsuo; Tsuzuki, Masaoki; Nishibori, Masahide; Mizutani, Makoto; Watanabe, Tomomasa

    2002-01-01

    The nucleotide sequence of chicken Mx cDNA was reported earlier using the White Leghorn breed in Germany, but it showed no enhanced resistance to viruses. In this study, the nucleotide sequences of chicken Mx cDNA were determined in many breeds. A total of 25 nucleotide substitutions, of which 14 were deduced to cause amino acid exchanges, were detected, suggesting that the chicken Mx gene is very polymorphic. Transfected cell clones expressing chicken Mx mRNA were established after the Mx cDNA was constructed with an expression vector and introduced into mouse 3T3 cells, and the Mx genes from some breeds were demonstrated to confer positive antiviral responses to influenza virus and vesicular stomatitis virus. On the basis of the comparison among the antiviral activities associated with many Mx variations, a specific amino acid substitution at position 631 (Ser to Asn) was considered to determine the antivirally positive or negative Mx gene. Thus, a single amino acid substitution influences the antiviral activity of Mx in domesticated chickens. PMID:11932243

  2. Inhibition of Proteasome Activity Induces Formation of Alternative Proteasome Complexes*

    PubMed Central

    Welk, Vanessa; Coux, Olivier; Kleene, Vera; Abeza, Claire; Trümbach, Dietrich; Eickelberg, Oliver; Meiners, Silke

    2016-01-01

    The proteasome is an intracellular protease complex consisting of the 20S catalytic core and its associated regulators, including the 19S complex, PA28αβ, PA28γ, PA200, and PI31. Inhibition of the proteasome induces autoregulatory de novo formation of 20S and 26S proteasome complexes. Formation of alternative proteasome complexes, however, has not been investigated so far. We here show that catalytic proteasome inhibition results in fast recruitment of PA28γ and PA200 to 20S and 26S proteasomes within 2–6 h. Rapid formation of alternative proteasome complexes did not involve transcriptional activation of PA28γ and PA200 but rather recruitment of preexisting activators to 20S and 26S proteasome complexes. Recruitment of proteasomal activators depended on the extent of active site inhibition of the proteasome with inhibition of β5 active sites being sufficient for inducing recruitment. Moreover, specific inhibition of 26S proteasome activity via siRNA-mediated knockdown of the 19S subunit RPN6 induced recruitment of only PA200 to 20S proteasomes, whereas PA28γ was not mobilized. Here, formation of alternative PA200 complexes involved transcriptional activation of the activator. Alternative proteasome complexes persisted when cells had regained proteasome activity after pulse exposure to proteasome inhibitors. Knockdown of PA28γ sensitized cells to proteasome inhibitor-mediated growth arrest. Thus, formation of alternative proteasome complexes appears to be a formerly unrecognized but integral part of the cellular response to impaired proteasome function and altered proteostasis. PMID:27129254

  3. First functional polymorphism in CFTR promoter that results in decreased transcriptional activity and Sp1/USF binding

    SciTech Connect

    Taulan, M. Lopez, E.; Guittard, C.; Rene, C.; Baux, D.; Altieri, J.P.; DesGeorges, M.; Claustres, M.; Romey, M.C.

    2007-09-28

    Growing evidences show that functionally relevant polymorphisms in various promoters alter both transcriptional activity and affinities of existing protein-DNA interactions, and thus influence disease progression in humans. We previously reported the -94G>T CFTR promoter variant in a female CF patient in whom any known disease-causing mutation has been detected. To investigate whether the -94G>T could be a regulatory variant, we have proceeded to in silico analyses and functional studies including EMSA and reporter gene assays. Our data indicate that the promoter variant decreases basal CFTR transcriptional activity in different epithelial cells and alters binding affinities of both Sp1 and USF nuclear proteins to the CFTR promoter. The present report provides evidence for the first functional polymorphism that negatively affects the CFTR transcriptional activity and demonstrates a cooperative role of Sp1 and USF transcription factors in transactivation of the CFTR gene promoter.

  4. Two mammalian MOF complexes regulate transcription activation by distinct mechanisms.

    PubMed

    Li, Xiangzhi; Wu, Lipeng; Corsa, Callie Ann Sprunger; Kunkel, Steve; Dou, Yali

    2009-10-23

    In mammals, MYST family histone acetyltransferase MOF plays important roles in transcription activation by acetylating histone H4 on K16, a prevalent mark associated with chromatin decondensation, and transcription factor p53 on K120, which is important for activation of proapoptotic genes. However, little is known about MOF regulation in higher eukaryotes. Here, we report that the acetyltransferase activity of MOF is tightly regulated in two different but evolutionarily conserved complexes, MSL and MOF-MSL1v1. Importantly, we demonstrate that while the two MOF complexes have indistinguishable activity on histone H4 K16, they differ dramatically in acetylating nonhistone substrate p53. We further demonstrate that MOF-MSL1v1 is specifically required for optimal transcription activation of p53 target genes both in vitro and in vivo. Our results support a model that these two MOF complexes regulate distinct stages of transcription activation in cooperation with other histone modifying activities.

  5. [Oral fluid bacteriocidal activity in complex diagnostics of oral disbiosis].

    PubMed

    Rabinovich, O F; Abramova, E S

    2012-01-01

    The possibility of examination of oral fluid bacteriocidal activity in complex diagnostics of oral mucosa disbiosis was evaluated. Thirty-seven patients were included in complex clinical and laboratory studies. The patients were divided in two groups: main group (30 patients exhibiting various grades of oral mucosa disbiosis) and control group (7 patients with no signs of oral disbiosis). The oral fluid bacteriocidal activity was examined by means of laser flow cytometry. Study results proved oral fluid bacteriocidal activity increase to correlate with the grade of oral mucosa disbiosis thus confirming the usefulness of the method in complex diagnostics of oral disbiosis.

  6. Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma (PPARgamma) gene in inflammatory bowel disease.

    PubMed

    Atug, Ozlen; Tahan, Veysel; Eren, Fatih; Tiftikci, Arzu; Imeryuz, Nese; Hamzaoglu, Hulya Over; Tozun, Nurdan

    2008-12-01

    Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has recently been implicated as an endogenous regulator of cellular proliferation and inflammation. Impaired expression of PPAR-gamma in colonic epithelial cells in ulcerative colitis (UC) and increased expression in hypertrophic mesenteric adipose tissue in Crohn's disease (CD) have been reported. Furthermore, PPAR-gamma ligands have been shown to inhibit tissue injury associated with immune activation in UC. Any mutation in PPAR-gamma gene may be responsible for the increase in inflammatory mediators and hence the perpetuation of inflammation in inflammatory bowel disease (IBD) patients. One common polymorphism in PPAR-gamma gene is proline to alanine substitution (Pro12Ala) which results from a CCA to GCA missense substitution in codon 12 of exon 2 of the PPAR-gamma gene. In this study, we aimed to explore Pro12Ala polymorphism in PPAR-gamma gene in IBD in Turkish patients. 69 patients with CD, 45 with UC and 100 controls of similar age and sex were studied. Genomic DNA was isolated from peripheral blood leucocytes and mutagenically separated-polymerase chain reaction (PCR) analyses were performed to determine the Pro12Ala polymorphism of the PPAR-gamma gene. We observed no significant differences in the frequency of the Pro12Ala polymorphism in the PPAR-gamma gene among subjects with CD, UC and controls (15.9%, 15.5% and 13%, respectively, p>0.05). These results suggest that Pro12Ala polymorphism in the PPAR-gamma gene relates neither to the risk of the development of inflammatory bowel disease nor to the clinical subtypes of CD in the Turkish population.

  7. Expression of ICAM1 and VCAM1 Serum Levels in Rheumatoid Arthritis Clinical Activity. Association with Genetic Polymorphisms

    PubMed Central

    Navarro-Hernández, Rosa Elena; Oregon-Romero, Edith; Vázquez-Del Mercado, Mónica; Rangel-Villalobos, Héctor; Palafox-Sánchez, Claudia Azucena; Muñoz-Valle, José Francisco

    2009-01-01

    To investigate the association of sICAM-1 and sVCAM-1 with ICAM1 721G>A and VCAM1 1238G>C polymorphisms and rheumatoid arthritis (RA) clinical activity, sixty RA patients and 60 healthy non-related subjects (HS) matched for age and sex were recruited. Soluble adhesion molecules were determined by ELISA technique. Rheumatoid factor (RF), C reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) were measured by routine methods. Disability and clinical activity was measured with Spanish-HAQ-DI and DAS28 scores, respectively. The ICAM1 and VCAM1 polymorphism were identified using the PCR-RFLP procedure. Inter-group comparison showed increased levels of sICAM-1 and sVCAM-1 in RA patients (284 and 481 ng/mL) versus HS (132 and 280 ng/mL); in the RA group, significant correlations between sVCAM-1 and RF (r = 0.402), ESR (r = 0.426), Spanish-HAQ-DI (r = 0.276), and DAS28 (r = 0.342) were found, whereas sICAM-1 only correlated with RF (r = 0.445). In RA patients, a significant association with the 721A allele of ICAM1 polymorphism (p = 0.04), was found. In addition, the allele impact (G/A + A/A) of this polymorphism was confirmed, (p = 0.038, OR = 2.3, C.I. 1.1–5.0). sVCAM-1 and sICAM-1 serum levels reflected the clinical status in RA, independently of the ICAM1 and VCAM1 polymorphism. However, the ICAM1 721A allele could be a genetic marker to RA susceptibility. PMID:19597294

  8. Expression of ICAM1 and VCAM1 serum levels in rheumatoid arthritis clinical activity. Association with genetic polymorphisms.

    PubMed

    Navarro-Hernández, Rosa Elena; Oregon-Romero, Edith; Vázquez-Del Mercado, Mónica; Rangel-Villalobos, Héctor; Palafox-Sánchez, Claudia Azucena; Muñoz-Valle, José Francisco

    2009-01-01

    To investigate the association of sICAM-1 and sVCAM-1 with ICAM1 721G>A and VCAM1 1238G>C polymorphisms and rheumatoid arthritis (RA) clinical activity, sixty RA patients and 60 healthy non-related subjects (HS) matched for age and sex were recruited. Soluble adhesion molecules were determined by ELISA technique. Rheumatoid factor (RF), C reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) were measured by routine methods. Disability and clinical activity was measured with Spanish-HAQ-DI and DAS28 scores, respectively. The ICAM1 and VCAM1 polymorphism were identified using the PCR-RFLP procedure. Inter-group comparison showed increased levels of sICAM-1 and sVCAM-1 in RA patients (284 and 481 ng/mL) versus HS (132 and 280 ng/mL); in the RA group, significant correlations between sVCAM-1 and RF (r = 0.402), ESR (r = 0.426), Spanish-HAQ-DI (r = 0.276), and DAS28 (r = 0.342) were found, whereas sICAM-1 only correlated with RF (r = 0.445). In RA patients, a significant association with the 721A allele of ICAM1 polymorphism (p = 0.04), was found. In addition, the allele impact (G/A+A/A) of this polymorphism was confirmed, (p = 0.038, OR = 2.3, C.I. 1.1-5.0). sVCAM-1 and sICAM-1 serum levels reflected the clinical status in RA, independently of the ICAM1 and VCAM1 polymorphism. However, the ICAM1 721A allele could be a genetic marker to RA susceptibility.

  9. The Plasminogen Activator Inhibitor 1 4G/5G Polymorphism and the Risk of Alzheimer's Disease.

    PubMed

    Fekih-Mrissa, Najiba; Mansour, Malek; Sayeh, Aicha; Bedoui, Ines; Mrad, Meriem; Riahi, Anis; Mrissa, Ridha; Nsiri, Brahim

    2017-09-01

    The aim of this study was to determine whether plasminogen activator inhibitor 1 (PAI-1) is associated with the risk of Alzheimer's disease (AD) in Tunisian patients. We analyzed the genotype and allele frequency distribution of the PAI-1 polymorphism in 60 Tunisian patients with AD and 120 healthy controls. The results show a significantly increased risk of AD in carriers of the 4G/4G and 4G/5G genotypes versus the wild-type 5G/5G genotype (4G/4G: 28.33% in patients vs 10.0% in controls; P < 10(-3); OR = 8.78; 4G/5G: 55.0% in patients vs 38.33% in controls; OR = 4.45; P < 10(-3)). The 4G allele was also more frequently found in patients compared with controls; P < 10(-3); OR = 3.07. For all participants and by gender, homozygotic carriers (4G/4G) were at an increased risk of AD over heterozygotes and women were at an increased risk over their male genotype counterparts. The odds ratio for AD among 4G/4G carriers for any group was approximately twice that of heterozygotes in the same group. Women homozygotes ranked highest for AD risk (OR = 20.8) and, in fact, women heterozygotes (OR = 9.03) ranked higher for risk than male homozygotes (OR = 6.12). These preliminary exploratory results should be confirmed in a larger study.

  10. Peroxisome proliferator-activated receptor Pro12Ala polymorphism and the risks of gestational diabetes mellitus

    PubMed Central

    Wang, Lihong; Xu, Wenting; Wang, Xu

    2016-01-01

    Abstract Background: Peroxisome proliferator-activated receptors-λ (PPAR-λ) is a member of nuclear receptor superfamily and acts as a ligand-dependent transcription factor often found in the adrenal gland, the spleen, and adipose tissue. The Pro12Ala polymorphism of PPAR-λ has been associated with the risks of gestational diabetes mellitus (GDM); however, association studies have provided conflicting results. The aim of this Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) compliant meta-analysis is to reach a more up-to-date and accurate estimation of the relationship between Pro12Ala genetic polymorphisms and the risks of GDM. Methods: Eligible studies were retrieved by searching PubMed, EMBASE, Web of Science, Ovid, WanFang, and Chinese National Knowledge Databases and selected according to a pre-defined inclusion criterion. The risk of bias was assessed using the Newcastle-Ottawa quality assessment scale. The per-allele odds ratio (OR) of risk allele proline (Pro) was compared between cases and controls in each study to describe the association between the Pro allele and an individual's risk of GDM. The ORs were pooled using both the random-effects model (the DerSimonian and Laird method) and the fixed effects model (the Mantel-Haenszel method) and the 95% confidence interval (95% CI) was calculated using Woolf method. Results: The final meta-analysis included a total of 11 articles of 12 data sets consisting of 7054 controls and 2980 GDM cases. Our results demonstrate that the Pro allele is not associated with GDM [OR: across multiple populations, 95% CI: 0.98–1.24; P(Z) = 0.01; P(Q) = 0.003]. In the stratified analysis by ethnicity, significantly increased risks were found for the Chinese (OR = 2.36; 95% CI: 1.47–3.78) and Korean (OR = 1.39; 95% CI: 1.00–1.93) populations. Conclusion: These data suggest the potential role of Pro allele in the pathogenesis of GDM in Asian populations. Although the funnel plot

  11. Anticancer activity assessment of two novel binuclear platinum (II) complexes.

    PubMed

    Shahsavani, Mohammad Bagher; Ahmadi, Shamseddin; Aseman, Marzieh Dadkhah; Nabavizadeh, S Masoud; Rashidi, Mehdi; Asadi, Zahra; Erfani, Nasrollah; Ghasemi, Atiyeh; Saboury, Ali Akbar; Niazi, Ali; Bahaoddini, Aminollah; Yousefi, Reza

    2016-08-01

    In the current study, two binuclear Pt (II) complexes, containing cis, cis-[Me2Pt (μ-NN) (μ-dppm) PtMe2] (1), and cis,cis-[Me2Pt(μ-NN)(μ dppm) Pt((CH2)4)] (2) in which NN=phthalazine and dppm=bis (diphenylphosphino) methane were evaluated for their anticancer activities and DNA/purine nucleotide binding properties. These Pt (II) complexes, with the non-classical structures, demonstrated a significant anticancer activity against Jurkat and MCF-7 cancer cell lines. The results of ethidium bromide/acridine orange staining and Caspase-III activity suggest that these complexes were capable to stimulate an apoptotic mechanism of cell death in the cancer cells. Using different biophysical techniques and docking simulation analysis, we indicated that these complexes were also capable to interact efficiently with DNA via a non-intercalative mechanism. According to our results, substitution of cyclopentane (in complex 2) with two methyl groups (in complex 1) results in significant improvement of the complex ability to interact with DNA and subsequently to induce the anticancer activity. Overall, these binuclear Pt (II) complexes are promising group of the non-classical potential anticancer agents which can be considered as molecular templates in designing of highly efficient platinum anticancer drugs.

  12. Sex, Drugs, and Rock ‘N’ Roll: Hypothesizing Common Mesolimbic Activation as a Function of Reward Gene Polymorphisms

    PubMed Central

    Blum, Kenneth; Werner, Tonia; Carnes, Stefanie; Carnes, Patrick; Bowirrat, Abdalla; Giordano, John; Marlene-Oscar-Berman; Gold, Mark

    2014-01-01

    The nucleus accumbens, a site within the ventral striatum, plays a prominent role in mediating the reinforcing effects of drugs of abuse, food, sex, and other addictions. Indeed, it is generally believed that this structure mandates motivated behaviors such as eating, drinking, and sexual activity, which are elicited by natural rewards and other strong incentive stimuli. This article focuses on sex addiction, but we hypothesize that there is a common underlying mechanism of action for the powerful effects that all addictions have on human motivation. That is, biological drives may have common molecular genetic antecedents, which if impaired, lead to aberrant behaviors. Based on abundant scientific support, we further hypothesize that dopaminergic genes, and possibly other candidate neurotransmitter-related gene polymorphisms, affect both hedonic and anhedonic behavioral outcomes. Genotyping studies already have linked gene polymorphic associations with alcohol and drug addictions and obesity, and we anticipate that future genotyping studies of sex addicts will provide evidence for polymorphic associations with specific clustering of sexual typologies based on clinical instrument assessments. We recommend that scientists and clinicians embark on research coupling the use of neuroimaging tools with dopaminergic agonistic agents to target specific gene polymorphisms systematically for normalizing hyper- or hypo-sexual behaviors. PMID:22641964

  13. Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms.

    PubMed

    Blum, Kenneth; Werner, Tonia; Carnes, Stefanie; Carnes, Patrick; Bowirrat, Abdalla; Giordano, John; Oscar-Berman, Marlene; Gold, Mark

    2012-01-01

    The nucleus accumbens, a site within the ventral striatum, plays a prominent role in mediating the reinforcing effects of drugs of abuse, food, sex, and other addictions. Indeed, it is generally believed that this structure mandates motivated behaviors such as eating, drinking, and sexual activity, which are elicited by natural rewards and other strong incentive stimuli. This article focuses on sex addiction, but we hypothesize that there is a common underlying mechanism of action for the powerful effects that all addictions have on human motivation. That is, biological drives may have common molecular genetic antecedents, which if impaired, lead to aberrant behaviors. Based on abundant scientific support, we further hypothesize that dopaminergic genes, and possibly other candidate neurotransmitter-related gene polymorphisms, affect both hedonic and anhedonic behavioral outcomes. Genotyping studies already have linked gene polymorphic associations with alcohol and drug addictions and obesity, and we anticipate that future genotyping studies of sex addicts will provide evidence for polymorphic associations with specific clustering of sexual typologies based on clinical instrument assessments. We recommend that scientists and clinicians embark on research coupling the use of neuroimaging tools with dopaminergic agonistic agents to target specific gene polymorphisms systematically for normalizing hyper- or hypo-sexual behaviors.

  14. Association between Plasminogen Activator Inhibitor-1 -675 4G/5G Polymorphism and Sepsis: A Meta-Analysis

    PubMed Central

    Yuan, Weifeng; Li, Weifeng; Huang, Wenjie

    2013-01-01

    Background Several studies have evaluated the association between plasminogen activator inhibitor-1 (PAI-1) -675 4G/5G polymorphism and sepsis in different populations. However, the available results are conflicting. Methods A search of Pubmed and EMBASE databases was performed to identify relevant studies for inclusion in the meta-analysis. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were determined using a random-effects model. Results Twelve case-control studies and three cohort studies were included. Overall, a significant association between 4G/5G polymorphism and sepsis risk was observed for 4G/4G vs. 4G/5G +5G/5G (OR = 1.30, 95% CI 1.08–1.56, P = 0.006). In addition, there was a significant association between PAI-1 4G/5G polymorphism and sepsis-related mortality (OR = 1.72, 95% CI 1.27–2.33, P = 0.0005). In subgroup analyses, increased sepsis risk and mortality risk were found in Caucasians and in patients with sepsis. Conclusions This meta-analysis suggested that the PAI-1 -675 4G/5G polymorphism was a risk factor for sepsis and sepsis mortality. PMID:23382992

  15. Association between plasminogen activator inhibitor-1 -675 4G/5G polymorphism and sepsis: a meta-analysis.

    PubMed

    Li, Li; Nie, Wei; Zhou, Hongfeng; Yuan, Weifeng; Li, Weifeng; Huang, Wenjie

    2013-01-01

    Several studies have evaluated the association between plasminogen activator inhibitor-1 (PAI-1) -675 4G/5G polymorphism and sepsis in different populations. However, the available results are conflicting. A search of Pubmed and EMBASE databases was performed to identify relevant studies for inclusion in the meta-analysis. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were determined using a random-effects model. Twelve case-control studies and three cohort studies were included. Overall, a significant association between 4G/5G polymorphism and sepsis risk was observed for 4G/4G vs. 4G/5G +5G/5G (OR = 1.30, 95% CI 1.08-1.56, P = 0.006). In addition, there was a significant association between PAI-1 4G/5G polymorphism and sepsis-related mortality (OR = 1.72, 95% CI 1.27-2.33, P = 0.0005). In subgroup analyses, increased sepsis risk and mortality risk were found in Caucasians and in patients with sepsis. This meta-analysis suggested that the PAI-1 -675 4G/5G polymorphism was a risk factor for sepsis and sepsis mortality.

  16. Influence of PAI-1 gene promoter-675 (4G/5G) polymorphism on fibrinolytic activity after cardiac surgery employing cardiopulmonary bypass.

    PubMed

    Ozolina, Agnese; Strike, Eva; Jaunalksne, Inta; Serova, Jelena; Romanova, Tatjana; Zake, Liene Nikitina; Sabelnikovs, Olegs; Vanags, Indulis

    2012-01-01

    The plasminogen activator inhibitor type-1 (PAI-1) gene promoter contains 675 (4G/5G) polymorphism. The aim of this study was evaluate the effect of the PAI-1 promoter-675 (4G/5G) polymorphism on the concentrations of PAI-1 and tissue plasminogen activator/PAI-1 (t-PA/PAI-1) complex and bleeding volume after on-pump cardiac surgery. A total of 90 patients were included in the study at Pauls Stradins Clinical University Hospital. Seven patients were excluded due to surgical bleeding. Eighty-three patients were classified according to the PAI-1 genotype: 21 patients had the 4G/4G genotype; 42, the 4G/5G genotype; and 20, the 5G/5G genotype. The following fibrinolysis parameters were recorded: the PAI-1 level preoperatively, D-dimer level at 0, 6, and 24 hours after surgery, and t-PA/PAI-1 complex level 24 hours postoperatively. A postoperative bleeding volume was registered in mL 24 hours after surgery. The patients with the 5G/5G genotype had significantly lower preoperative PAI-1 levels (17 [SD, 10.8] vs. 24 ng/mL [SD, 9.6], P=0.04), higher D-dimer levels at 6 hours (371 [SD, 226] vs. 232 ng/mL [SD, 185], P=0.03) and 24 hours (326 [SD, 207] vs. 209 ng/mL [SD, 160], P=0.04), and greater postoperative blood loss (568 [SD, 192] vs. 432 mL [168], P=0.02) compared with the 4G/4G carriers. There were no significant differences in the levels of the t-PA/PAI-1 complex comparing different genotype groups. The carriers of the 5G/5G genotype showed the lower preoperative PAI-1 levels, greater chest tube blood loss, and higher D-dimer levels indicating that the 5G/5G carriers may have enhanced fibrinolysis.

  17. Measurements of brain activity complexity for varying mental loads

    NASA Astrophysics Data System (ADS)

    Dhamala, Mukeshwar; Pagnoni, Giuseppe; Wiesenfeld, Kurt; Berns, Gregory S.

    2002-04-01

    Using functional magnetic resonance imaging, we investigate the variation in dynamical complexity of human brain activity for different mental loads. Our experiments measured the activity of ten subjects under three experimental conditions: a rest condition, a periodic task of finger opposition, and a task of finger opposition alternated with mathematical serial calculation. We used the correlation dimension to gauge the spatiotemporal complexity of brain activity. The experiments show a direct relationship between this complexity and the difficulty of the task. A natural interpretation is that higher levels of mental load recruit a larger number of independent neural processes that contribute to complex brain dynamics. These results suggest the possibility that the relative change in correlation dimension can be a useful global measure of brain dynamics, e.g., in determining the levels of mental activity, even if little is known about the underlying neurological processes.

  18. Effects of FCGRIIIa-158V/F polymorphism on antibody-dependent cellular cytotoxicity activity of adalimumab.

    PubMed

    Kimura, Koji; Kobayashi, Daigo; Hatoyama, Saori; Yamamoto, Mizuki; Takayanagi, Risa; Yamada, Yasuhiko

    2017-09-15

    The associations between the efficacy of IgG reagents and the FCGRIIIa-158V/F polymorphism (rs396991) have been investigated. Although the genotype frequencies in healthy Japanese have been reported, those have varied, as one study reported that the proportions of V/V, V/F, and F/F were 59.1%, 38.6%, and 2.3%, respectively, while another study found that they were 4%, 44%, and 52%, respectively. However, there are no known investigations of the association between the antibody-dependent cellular cytotoxicity (ADCC) activity of adalimumab (ADA), an IgG reagent, in combination with FcγRIIIa and the polymorphism. In this study, we analyzed healthy Japanese to clarify genotype frequency using a direct sequence method. In addition, we examined the association between the ADA-mediated ADCC activity and the polymorphism. Our results showed that the frequencies of the V/V, V/F, and F/F genotypes in healthy Japanese were 9.2%, 39.8%, and 51.0%, respectively. The average activity of ADA-mediated ADCC was 25.0%, 19.0%, and 13.3% in the V/V, V/F, and F/F genotypes, respectively. Then, the ADCC activity of V/V was significantly higher than that of F/F (p < 0.05) in therapeutic concentration. The differences in therapeutic effect of ADA among individuals can be explained, in part, by ADCC activity via the FCGRIIIa-158V/F polymorphism. © 2017 APMIS. Published by John Wiley & Sons Ltd.

  19. Low physical activity accentuates the effect of the FTO rs9939609 polymorphism on body fat accumulation.

    PubMed

    Andreasen, Camilla H; Stender-Petersen, Kirstine L; Mogensen, Mette S; Torekov, Signe S; Wegner, Lise; Andersen, Gitte; Nielsen, Arne L; Albrechtsen, Anders; Borch-Johnsen, Knut; Rasmussen, Signe S; Clausen, Jesper O; Sandbaek, Annelli; Lauritzen, Torsten; Hansen, Lars; Jørgensen, Torben; Pedersen, Oluf; Hansen, Torben

    2008-01-01

    Three independent studies have shown that variation in the fat mass and obesity-associated (FTO) gene associates with BMI and obesity. In the present study, the effect of FTO variation on metabolic traits including obesity, type 2 diabetes, and related quantitative phenotypes was examined. The FTO rs9939609 polymorphism was genotyped in a total of 17,508 Danes from five different study groups. In studies of 3,856 type 2 diabetic case subjects and 4,861 normal glucose-tolerant control subjects, the minor A-allele of rs9939609 associated with type 2 diabetes (odds ratio 1.13 [95% CI 1.06-1.20], P = 9 x 10(-5)). This association was abolished when adjusting for BMI (1.06 [0.97-1.16], P = 0.2). Among 17,162 middle-aged Danes, the A-allele associated with overweight (1.19 [1.13-1.24], P = 1 x 10(-12)) and obesity (1.27 [1.20-1.34], P = 2 x 10(-16)). Furthermore, obesity-related quantitative traits such as body weight, waist circumference, fat mass, and fasting serum leptin levels were significantly elevated in A-allele carriers. An interaction between the FTO rs9939609 genotype and physical activity (P = 0.007) was found, where physically inactive homozygous risk A-allele carriers had a 1.95 +/- 0.3 kg/m(2) increase in BMI compared with homozygous T-allele carriers. We validate that variation in FTO is associated with type 2 diabetes when not adjusted for BMI and with an overall increase in body fat mass. Furthermore, low physical activity seems to accentuate the effect of FTO rs9939609 on body fat accumulation.

  20. The Fc Receptor Polymorphisms and Expression of Neutrophil Activation Markers in Patients with Sickle Cell Disease from Western India

    PubMed Central

    Kangne, Harshada K.; Jijina, Farah F.; Italia, Yazdi M.; Jain, Dipti L.; Nadkarni, Anita H.; Gupta, Maya; Pradhan, Vandana; Mukesh, Rati D.; Ghosh, Kanjaksha K.; Colah, Roshan B.

    2013-01-01

    Objective. Sickle cell disease has variable clinical manifestations. Activation of neutrophils plays an important role in the initiation and propagation of vaso occlusive crises which can be analysed by determining the expression of neutrophil antigens such as CD16, CD32, and CD62L. The common FcγR polymorphisms (FcγRIIA and FcγRIIIB) are considered to influence clinical presentation. This study focuses on distribution of FcγR polymorphisms and their association with neutrophil activity among the patients from western India. Methods. In this paper 127 sickle cell anemia patients and 58 patients with sickle-β-thalassemia (median age 12 ± 8.58 years) with variable clinical phenotypes along with 175 normals were investigated. FcγRs polymorphisms were analysed by RFLP and AS-PCR. Activation of neutrophils was measured by flow cytometry. Results. The genotypic frequency of the H/R genotype of FcγRIIA and the NA1/NA1 genotype of FcγRIIIB was significantly decreased in patients compared to normals (P-0.0074, P-0.0471, resp.). We found a significant difference in the expression of CD32 and CD62L among the patients as against normals. A significantly higher expression of CD32 was seen in the milder patients with the H/H genotype (P-0.0231), whereas the expression of CD16 was higher in severe patients with the NA2/NA2 genotype (P-0.0312). Conclusion. The two FcγR polymorphisms had significant association with variable phenotypes of sickle cell disease. The expression of CD62L decreased in our patients indicating activation of neutrophils. PMID:24191245

  1. Mcm subunits can assemble into two different active unwinding complexes.

    PubMed

    Kanter, Diane M; Bruck, Irina; Kaplan, Daniel L

    2008-11-07

    The replication fork helicase in eukaryotes is a large complex that is composed of Mcm2-7, Cdc45, and GINS. The Mcm2-7 proteins form a heterohexameric ring that hydrolyzes ATP and provide the motor function for this unwinding complex. A comprehensive study of how individual Mcm subunit biochemical activities relate to unwinding function has not been accomplished. We studied the mechanism of the Mcm4-Mcm6-Mcm7 complex, a useful model system because this complex has helicase activity in vitro. We separately purified each of three Mcm subunits until they were each nuclease-free, and we then examined the biochemical properties of different combinations of Mcm subunits. We found that Mcm4 and Mcm7 form an active unwinding assembly. The addition of Mcm6 to Mcm4/Mcm7 results in the formation of an active Mcm4/Mcm6/Mcm7 helicase assembly. The Mcm4-Mcm7 complex forms a ringed-shaped hexamer that unwinds DNA with 3' to 5' polarity by a steric exclusion mechanism, similar to Mcm4/Mcm6/Mcm7. The Mcm4-Mcm7 complex has a high level of ATPase activity that is further stimulated by DNA. The ability of different Mcm mixtures to form rings or exhibit DNA stimulation of ATPase activity correlates with the ability of these complexes to unwind DNA. The Mcm4/Mcm7 and Mcm4/Mcm6/Mcm7 assemblies can open to load onto circular DNA to initiate unwinding. We conclude that the Mcm subunits are surprisingly flexible and dynamic in their ability to interact with one another to form active unwinding complexes.

  2. Assessment of the EEG complexity during activations from sleep.

    PubMed

    Chouvarda, I; Rosso, V; Mendez, M O; Bianchi, A M; Parrino, L; Grassi, A; Terzano, M; Cerutti, S

    2011-12-01

    The present study quantitatively analyzes the EEG characteristics during activations (Act) that occur during NREM sleep, and constitute elements of sleep microstructure (i.e. the Cyclic Alternating Pattern). The fractal dimension (FD) and the sample entropy (SampEn) measures were used to study the different sleep stages and the Act that build up the sleep structure. Polysomnographic recordings from 10 good sleepers were analyzed. The complexity indexes of the Act were compared with the non-activation (NAct) periods during non-REM sleep. In addition, complexity measures among the different Act subtypes (A1, A2 and A3) were analyzed. A3 presented a quite similar complexity independently of the sleep stage, while A1 and A2 showed higher complexity in light sleep than during deep sleep. The current results suggest that Act present a hierarchic complexity between subtypes A3 (higher), A2 (intermediate) and A1 (lower) in all sleep stages.

  3. Immune complexes inhibit interleukin-1 secretion and inflammasome activation

    PubMed Central

    Janczy, John R.; Ciraci, Ceren; Haasken, Stefanie; Iwakura, Yoichiro; Olivier, Alicia K.; Cassel, Suzanne L.; Sutterwala, Fayyaz S.

    2014-01-01

    Immunoglobulin G (IgG) immune complexes have been shown to modify immune responses driven by antigen presenting cells in either a pro- or anti-inflammatory direction depending upon the context of stimulation. However, the ability of immune complexes to modulate the inflammasome-dependent innate immune response is unknown. Here we show that IgG immune complexes suppress IL-1α and IL-1β secretion through inhibition of inflammasome activation. The mechanism by which this inhibition occurs is via immune complex ligation of activating Fcγ receptors (FcγR), resulting in prevention of both activation and assembly of the inflammasome complex in response to NLRP3, NLRC4, or AIM2 agonists. In vivo, administration of antigen in the form of an immune complex during priming of the immune response inhibited resultant adaptive immune responses in a NLRP3 dependent model of allergic airway disease. Our data reveal an unexpected mechanism regulating CD4+ T cell differentiation, whereby immune complexes suppress inflammasome activation and the generation of IL-1α and IL-1β from antigen presenting cells, which are critical for the antigen-driven differentiation of CD4+ T cells. PMID:25320279

  4. Immune complexes inhibit IL-1 secretion and inflammasome activation.

    PubMed

    Janczy, John R; Ciraci, Ceren; Haasken, Stefanie; Iwakura, Yoichiro; Olivier, Alicia K; Cassel, Suzanne L; Sutterwala, Fayyaz S

    2014-11-15

    IgG immune complexes have been shown to modify immune responses driven by APCs in either a pro- or anti-inflammatory direction depending upon the context of stimulation. However, the ability of immune complexes to modulate the inflammasome-dependent innate immune response is unknown. In this study, we show that IgG immune complexes suppress IL-1α and IL-1β secretion through inhibition of inflammasome activation. The mechanism by which this inhibition occurs is via immune complex ligation of activating FcγRs, resulting in prevention of both activation and assembly of the inflammasome complex in response to nucleotide-binding domain leucine-rich repeat (NLR) P3, NLRC4, or AIM2 agonists. In vivo, administration of Ag in the form of an immune complex during priming of the immune response inhibited resultant adaptive immune responses in an NLRP3-dependent model of allergic airway disease. Our data reveal an unexpected mechanism regulating CD4(+) T cell differentiation, by which immune complexes suppress inflammasome activation and the generation of IL-1α and IL-1β from APCs, which are critical for the Ag-driven differentiation of CD4(+) T cells.

  5. Repression and activation by multiprotein complexes that alter chromatin structure.

    PubMed

    Kingston, R E; Bunker, C A; Imbalzano, A N

    1996-04-15

    Recent studies have provided strong evidence that macromolecular complexes are used in the cell to remodel chromatin structure during activation and to create an inaccessible structure during repression, Although there is not yet any rigorous demonstration that modification of chromatin structure plays a direct, causal role in either activation or repression, there is sufficient smoke to indicate the presence of a blazing inferno nearby. It is clear that complexes that remodel chromatin are tractable in vitro; hopefully this will allow the establishment of systems that provide a direct analysis of the role that remodeling might play in activation. These studies indicate that establishment of functional systems to corroborate the elegant genetic studies on repression might also be tractable. As the mechanistic effects of these complexes are sorted out, it will become important to understand how the complexes are regulated. In many of the instances discussed above, the genes whose products make up these complexes were identified in genetic screens for effects on developmental processes. This implies a regulation of the activity of these complexes in response to developmental cues and further implies that the work to fully understand these complexes will occupy a generation of scientists.

  6. Two functional polymorphisms of ROCK2 enhance arterial stiffening through inhibiting its activity and expression.

    PubMed

    Liao, Yi-Chu; Liu, Ping-Yen; Lin, Hsiu-Fen; Lin, Wen-Yi; Liao, James K; Juo, Suh-Hang H

    2015-02-01

    Derangement of Rho-associated kinases (ROCKs) has been related to coronary artery disease and stroke. ROCK2, rather than ROCK1, plays a predominant role in vascular contractility. The present study aims to test (1) the associations between ROCK2 single nucleotide polymorphisms (SNPs) and arterial stiffness, and (2) the molecular mechanism accounting for their effects. Stiffness parameters including beta (β), elasticity modulus (Ep) and pulse wave velocity (PWV) were obtained by carotid ultrasonography. Seven tagging SNPs of ROCK2 were initially genotyped in 856 subjects and significant SNPs were replicated in another group of 527 subjects. Two SNPs in complete linkage disequilibrium were found to be significantly associated with arterial stiffness. The major alleles of rs978906 (A allele) and rs9808232 (C allele) were associated with stiffer arteries. SNP rs978906 was predicted to influence microRNA(miR)-1183 binding to ROCK2, while rs9808232 causes amino acid substitution. To determine their functional impact, plasmid constructs carrying different alleles of the significant SNPs were created. Compared to rs978906G-allele constructs, cells transfected with rs978906A-allele constructs had higher baseline luciferase activities and were less responsive to miR-1183 changes. Oxidized-low density lipoprotein (Ox-LDL) suppressed miR-1183 levels and increased ROCK2 protein amounts. For rs9808232, cells transfected with C-allele constructs had significantly higher ROCK activities than those with A-allele constructs. Leukocyte ROCK activities were further measured in 52 healthy subjects. The average ROCK activity was highest in human subjects with CC genotype at rs9808232, followed by those with AC and lowest in AA. Taken together, the present study showed that two functional SNPs of ROCK2 increase susceptibility of arterial stiffness in the Chinese population. Non-synonymous SNP rs9808232 influences ROCK2 activity, while 3' UTR SNP rs978906 affects the ROCK2 protein

  7. Peroxisome Proliferator–Activated Receptor γ Polymorphism Pro12Ala Is Associated With Nephropathy in Type 2 Diabetes

    PubMed Central

    Zhang, Hui; Zhu, Shimiao; Chen, Jing; Tang, Yang; Hu, Hailong; Mohan, Viswanathan; Venkatesan, Radha; Wang, Jianmin; Chen, Haiping

    2012-01-01

    OBJECTIVE Insulin resistance plays a part in diabetic nephropathy (DN). The association between the peroxisome proliferator–activated receptor γ Pro to Ala alteration at codon 12 (Pro12Ala) polymorphism and the risk of insulin resistance has been confirmed. The association between the polymorphism and DN risk has also been widely studied recently, but no consensus was available up to now. RESEARCH DESIGN AND METHODS A systematic search of electronic databases (MEDLINE, Embase, and China National Knowledge Infrastructure) and reference lists of relevant articles was carried out, and then 18 case-control studies involving 3,361 DN cases and 5,825 control subjects were identified. RESULTS In the overall analysis, the Ala12 variant was observed to be significantly associated with decreased DN risk (odds ratio 0.76 [95% CI 0.61–0.93]). Some evidence of heterogeneity among the included studies was detected, which could be explained by the difference of ethnicity and stage of DN. Subgroup analyses stratified by ethnicity and stage of DN were performed, and results indicated the Pro12Ala polymorphism was associated with the risk of DN in Caucasians but no similar association was observed in Asians. Additionally, we observed that Ala12 was associated with decreased risk of albuminuria. With only a few of subjects were available, we failed to detect statistically significant association between the polymorphism and end-stage renal disease (ESRD). CONCLUSIONS Our results indicated that the Ala12 variant is a significantly protective factor for DN. Future research should focus on the effect of Pro12Ala polymorphism on ESRD and gathering data of Africans. PMID:22619290

  8. Blunted insula activation reflects increased risk and reward seeking as an interaction of testosterone administration and the MAOA polymorphism.

    PubMed

    Wagels, Lisa; Votinov, Mikhail; Radke, Sina; Clemens, Benjamin; Montag, Christian; Jung, Sonja; Habel, Ute

    2017-09-01

    Testosterone, a male sex hormone, has been suggested to partly explain mixed findings in males and females when investigating behavioral tendencies associated with the MAOA polymorphism. Prior studies indicated that the MAOA polymorphism represents a vulnerability factor for financial risk-taking and harm avoidance and that testosterone increases human risk-taking. We therefore assumed an interactive influence of the MAOA polymorphism and testosterone application on decision making and corresponding neural correlates in a risk and reward context. Stratified for the MAOA polymorphism (S =short, L =long), 103 healthy males were assigned to a placebo or testosterone group (double blind, randomized) receiving a topical gel containing 50 mg testosterone. During a functional MRI scan, the participants performed a sequential decision making task. Our results indicate that testosterone and the MAOA polymorphism jointly influence sequential decision making. The MAOA-S variant was associated with less automatic harm avoidance as reflected in response times on safe decisions. Moreover, after testosterone administration, MAOA-S carriers were more risk-taking. Overall activity in the anterior cingulate cortex, anterior insula and inferior frontal gyrus increased with growing risk for losses. In the anterior insula, testosterone administration mitigated this effect solely in MAOA-S carriers. This might be a reflection of an improved coping during risk-reward conflicts subsequently modulating risky decision making. While the molecular basis is not well defined so far, our results support the assumption of testosterone as a modulatory factor for previously reported sex differences of behavioral associations with the MAOA-S variant. Hum Brain Mapp 38:4574-4593, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  9. Meta-analysis reveals an association between signal transducer and activator of transcription-4 polymorphism and hepatocellular carcinoma risk.

    PubMed

    Zhang, Li; Xu, Kuihua; Liu, Chuanmiao; Chen, Jiasheng

    2017-03-01

    Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related mortality worldwide. Signal transducer and activator of transcription (STAT) proteins play a multitude of important functions in liver pathophysiology. Recent studies have indicated associations of rs7574865 single nucleotide polymorphism (SNP) in the STAT4 gene with various autoimmune diseases. The association between STAT4 polymorphism and the risk of HCC has been analyzed in several studies, but results remain inconsistent. This study used a meta-analysis approach to comprehensively investigate the correlation between STAT4 polymorphism and HCC risk based on previously published reports. Studies were searched from the databases of PubMed, EMBase, Web of Science, and the Chinese National Knowledge Infrastructure up to 31 December 2015. The meta-analysis was carried out based on the statement of Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Eight published studies, consisting of 7503 HCC patients (cases) and 13 831 individuals without HCC (controls), were included in the present study. Meta-analysis of the included studies revealed that STAT4 rs7574865 polymorphism contributed to the risk of HCC under all four genetic models, consisting of the allelic model (G vs. T: odds ratio [OR], 1.25; 95% confidence interval [CI], 1.19-1.30), the dominant effect model (GG + GT vs. TT: OR, 1.52; 95% CI, 1.26-1.84), the recessive effect model (GG vs. GT + TT: OR, 1.35; 95% CI, 1.21-1.50), and the co-dominant effect model (GG vs.. TT: OR, 1.72; 95% CI, 1.42-2.10) comparisons. No publication bias was indicated from either visualization of the funnel plot or Egger's test. A significantly increased risk of HCC associated with the rs7574865 G was found. The rs7574865 polymorphism might be used as one risk factor for HCC. © 2016 The Japan Society of Hepatology.

  10. Plasminogen activator inhibitor-1 gene 4G/5G polymorphism in Turkish children with asthma and allergic rhinitis.

    PubMed

    Ozbek, Ozlem Yilmaz; Ataç, F Belgin; Ogus, Ersin; Ozbek, Namik

    2009-01-01

    Plasminogen activator inhibitor (PAI-1) has an essential role in tissue remodeling after inflammation. Recent literature revealed only one study evaluating PAI-1 4G/5G gene polymorphism in children with asthma and none in children with allergic rhinitis. We aimed to investigate distribution of PAI-1 4G/5G polymorphism in a group of Turkish children with asthma and allergic rhinitis and compare these findings with those obtained in normal peers. Patients with physician-diagnosed asthma (n = 106) and allergic rhinitis (n = 99) and 83 healthy peers were included in this study. We evaluated PAI-1 4G/5G polymorphism genotype as well as the possible association between PAI-1 4G/5G polymorphism and pulmonary function tests, serum total immunoglobulin E (IgE), total eosinophil count, and skin-prick test positivity in our study. The prevalence of the 4G allele significantly exceeded the values found in the controls both in patients with asthma (p = 0.001) and in patients with allergic rhinitis (p = 0.002). Interestingly, comparison of asthmatic patients revealed that mean baseline percent forced expiratory volume in 1 second and forced vital capacity were significantly higher in patients who bear 5G/5G genotype than in those who have 4G/4G or 4G/5G genotypes. No statistically significant relationship were found between PAI-1 polymorphism and total serum IgE levels, total eosinophil count, or selected skin test responses to aeroallergens. Our study suggests that Turkish children with asthma or allergic rhinitis have a higher prevalence of PAI-1 4G allele compared with their healthy peers.

  11. The 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene is not associated with HELLP syndrome.

    PubMed

    Muetze, Sabine; Eggermann, Thomas; Leeners, Brigitte; Birke, Cornelia; Kuse, Sabine; Ortlepp, Jan Rudolf; Rudnik-Schoeneborn, Sabine; Zerres, Klaus; Rath, Werner

    2009-02-01

    Plasminogen activator inhibitor-1 (PAI-1) is a major inhibitor of fibrinolysis, and a single nucleotide insertion/deletion (4G/5G) polymorphism in the promoter region of the PAI-1 gene has been identified. Subjects homozygous for the 4G allele have the highest PAI-levels due to increased PAI-1 gene transcription. Pre-eclampsia, and one of its most severe forms, the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, are characterized by increased placental thrombosis based on a procoagulatory state in the mother. Several studies have investigated the role of the PAI-1 4G/5G polymorphism in pre-eclampsia, but no study has focused especially on HELLP syndrome. Therefore we aimed to assess the association between HELLP syndrome and the 4G/5G polymorphism in the PAI-1 gene. Genotyping of the PAI-1 4G/5G promoter polymorphism was performed in 102 Caucasian women with HELLP syndrome and 102 Caucasian women with uncomplicated pregnancies. The 4G/4G genotype was more frequent in women with HELLP syndrome than in controls (35.3% vs. 22.5%, respectively) but this difference was not significantly different (P = 0.129). The frequency of the 4G allele was 0.588 in patients and 0.515 in controls. These data suggest that women carrying a 4G/4G genotype of the PAI-1 gene are not at increased risk for developing HELLP syndrome and are thus in line with the majority of previous studies on the association between the PAI-1 4G/5G polymorphism and pre-eclampsia.

  12. Using activity theory to study cultural complexity in medical education.

    PubMed

    Frambach, Janneke M; Driessen, Erik W; van der Vleuten, Cees P M

    2014-06-01

    There is a growing need for research on culture, cultural differences and cultural effects of globalization in medical education, but these are complex phenomena to investigate. Socio-cultural activity theory seems a useful framework to study cultural complexity, because it matches current views on culture as a dynamic process situated in a social context, and has been valued in diverse fields for yielding rich understandings of complex issues and key factors involved. This paper explains how activity theory can be used in (cross-)cultural medical education research. We discuss activity theory's theoretical background and principles, and we show how these can be applied to the cultural research practice by discussing the steps involved in a cross-cultural study that we conducted, from formulating research questions to drawing conclusions. We describe how the activity system, the unit of analysis in activity theory, can serve as an organizing principle to grasp cultural complexity. We end with reflections on the theoretical and practical use of activity theory for cultural research and note that it is not a shortcut to capture cultural complexity: it is a challenge for researchers to determine the boundaries of their study and to analyze and interpret the dynamics of the activity system.

  13. The role of genetic (PON1 polymorphism) and environmental factors, especially physical activity, in antioxidant function of paraoxonase.

    PubMed

    Otocka-Kmiecik, Aneta; Orłowska-Majdak, Monika

    2009-12-30

    Paraoxonase 1 (PON1) is a member of a three-gene family (PON1, PON2, and PON3). PON1 activity dominates in human plasma. It is secreted from hepatic cells and is found in the circulation bound to high-density lipoproteins (HDLs). For many years it has been known only for its ability to hydrolyze organophosphate derivatives. More recently, PON1's antioxidant activity draws attention as the enzyme was described to prevent oxidation of lipoproteins by reactive oxygen species formed during oxidative stress. PON1 was also shown to hydrolyze atherogenic products of oxidative lipid modification such as phospholipid peroxides and cholesterol ester hydroperoxides. Some studies indicate that the enzyme presents a lipolactonase activity and hydrolyzes homocysteine thiolactone (HCTL). There is growing evidence as to PON1's protective role in atherosclerosis. Genetic (PON1 polymorphism) and environmental factors and lifestyle may influence PON1 blood concentration and biological activity. Among the many recognized factors accounting for lifestyle, physical activity plays an important role. Various, often opposite, effects on PON1 status are observed in regular training and single physical activities. The results of different studies are often contradictory. It may depend on the time, intensity, and frequency of physical activity. Additionally, it seems that the effects of physical activity on PON1 blood concentration and activity are modified by environmental and lifestyle factors as well as PON1 polymorphism.

  14. The -383A>C TNFRI polymorphism is associated with soluble levels and clinical activity in rheumatoid arthritis.

    PubMed

    Valle, Y; Padilla-Gutiérrez, J R; Torres-Carrillo, N M; Ledezma-Lozano, I Y; Corona-Sánchez, E G; Vázquez-Del Mercado, M; Rangel-Villalobos, H; Gámez-Nava, J I; González-López, L; Muñoz-Valle, José Francisco

    2010-03-01

    Tumor necrosis factor-alpha (TNF-alpha) plays a central role in inflammation, and it has been directly implicated in the pathogenesis of rheumatoid arthritis (RA). TNF-alpha activity is mediated through TNFRI and TNFRII cell surface receptors, which act as physiological attenuators of TNF-alpha activity. We recruited 190 RA patients and 190 healthy subjects (HS) in order to associate the -383A>C TNFRI polymorphism with sTNFRI levels and DAS28 score in RA. In results, sTNFRI levels were higher in RA patients than HS (P = 0.04). The -383A>C TNFRI polymorphism did not show significant differences in both studied groups. However, in the RA group the sTNFRI levels were significantly elevated (P = 0.004) in A/A genotype carriers. In addition, the A/A genotype carriers had the higher DAS28 score than A/C genotype (P = 0.02). These data suggest that -383A>C TNFRI polymorphism is not a susceptibility marker in RA, whereas the increased levels of sTNFRI could reflect the clinical activity in RA patients.

  15. The Brain-Derived Neurotrophic Factor Val66Met Polymorphism Moderates an Effect of Physical Activity on Working Memory Performance

    PubMed Central

    Erickson, Kirk I.; Banducci, Sarah E.; Weinstein, Andrea M.; MacDonald, Angus W.; Ferrell, Robert E.; Halder, Indrani; Flory, Janine D.; Manuck, Stephen B.

    2014-01-01

    Physical activity enhances cognitive performance, yet individual variability in its effectiveness limits its widespread therapeutic application. Genetic differences might be one source of this variation. For example, carriers of the methionine-specifying (Met) allele of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism have reduced secretion of BDNF and poorer memory, yet physical activity increases BDNF levels. To determine whether the BDNF polymorphism moderated an association of physical activity with cognitive functioning among 1,032 midlife volunteers (mean age = 44.59 years), we evaluated participants’ performance on a battery of tests assessing memory, learning, and executive processes, and evaluated their physical activity with the Paffenbarger Physical Activity Questionnaire. BDNF genotype interacted robustly with physical activity to affect working memory, but not other areas of cognitive functioning. In particular, greater levels of physical activity offset a deleterious effect of the Met allele on working memory performance. These findings suggest that physical activity can modulate domain-specific genetic (BDNF) effects on cognition. PMID:23907543

  16. Antiparasitic activities of novel ruthenium/lapachol complexes.

    PubMed

    Barbosa, Marília I F; Corrêa, Rodrigo S; de Oliveira, Katia Mara; Rodrigues, Claudia; Ellena, Javier; Nascimento, Otaciro R; Rocha, Vinícius P C; Nonato, Fabiana R; Macedo, Taís S; Barbosa-Filho, José Maria; Soares, Milena B P; Batista, Alzir A

    2014-07-01

    The present study describes the synthesis, characterization, antileishmanial and antiplasmodial activities of novel diimine/(2,2'-bipyridine (bipy), 1,10-phenanthroline (phen), 4,4'-methylbipyridine (Me-bipy) and 4,4'-methoxybipyridine (MeO-bipy)/phosphine/ruthenium(II) complexes containing lapachol (Lap, 2-hydroxy-3-(3-33 methyl-2-buthenyl)-1,4-naphthoquinone) as bidentate ligand. The [Ru(Lap)(PPh3)2(bipy)]PF6 (1), [Ru(Lap)(PPh3)2(Me-bipy)]PF6 (2), [Ru(Lap)(PPh3)2(MeO-bipy)]PF6(3) and[Ru(Lap)(PPh3)2(phen)]PF6 (4) complexes, PPh3=triphenylphospine, were synthesized from the reactions of cis-[RuCl2(PPh3)2(X-bipy)] or cis-[RuCl2(PPh3)2(phen)], with lapachol. The [RuCl2(Lap)(dppb)] (5) [dppb=1,4-bis(diphenylphosphine)butane] was synthesized from the mer-[RuCl3(dppb)(H2O)] complex. The complexes were characterized by elemental analysis, molar conductivity, infrared and UV-vis spectroscopy, (31)P{(1)H} and (1)H NMR, and cyclic voltammetry. The Ru(III) complex, [RuCl2(Lap)(dppb)], was also characterized by the EPR technique. The structure of the complexes [Ru(Lap)(PPh3)2(bipy)]PF6 and [RuCl2(Lap)(dppb)] was elucidated by X-ray diffraction. The evaluation of the antiparasitic activities of the complexes against Leishmania amazonensis and Plasmodium falciparum demonstrated that lapachol-ruthenium complexes are more potent than the free lapachol. The [RuCl2(Lap)(dppb)] complex is the most potent and selective antiparasitic compound among the five new ruthenium complexes studied in this work, exhibiting an activity comparable to the reference drugs.

  17. Towards multilocus sequence typing of the Leishmania donovani complex: resolving genotypes and haplotypes for five polymorphic metabolic enzymes (ASAT, GPI, NH1, NH2, PGD).

    PubMed

    Mauricio, Isabel L; Yeo, Matthew; Baghaei, Mehdi; Doto, Daniela; Pratlong, Francine; Zemanova, Eva; Dedet, Jean-Pierre; Lukes, Julius; Miles, Michael A

    2006-06-01

    Multilocus enzyme electrophoresis is the gold standard for identification of Leishmania species and strains. Drawbacks include: only amino acid polymorphisms affecting electrophoretic mobility are detected; distinct allozymes can have coincident mobilities; few characters are available; and parasites must be cultured in bulk. So far, thousands of Leishmania strains have been phenotyped by multilocus enzyme electrophoresis. Here, we sequence enzyme-coding genes to provide a PCR-based higher resolution equivalent of multilocus enzyme electrophoresis, particularly for Leishmania infantum. Of 15 enzymes used for multilocus enzyme electrophoresis (MON typing) we have sequenced aspartate aminotransferase, glucose-6-phosphate isomerase, nucleoside hydrolase 1, nucleoside hydrolase 2 and 6-phosphogluconate dehydrogenase. Heterozygous alleles were common, with multiple heterozygous sites within a single locus for several of the genes. Haplotypes were resolved by allele-specific PCR and allele-specific sequencing. Heterozygous haplotypes conformed to the haplotypes of putative parents. One strain appeared to be hybrid across two genetic groups of the Leishmania donovani complex. In most cases, a single amino acid polymorphism was responsible for change in enzyme mobility. Some indistinguishable phenotypes were produced by distinct genotypes. Silent genetic polymorphisms provided enhanced discrimination over multilocus enzyme electrophoresis, for example, by subdividing the zymodeme MON-1. The PCR-based genotyping that we describe could be applied directly to clinical samples or to small volume cultures and in a multilocus sequence typing format. Furthermore, it can be used to detect recombination indirectly and for population genetics studies.

  18. Peroxisome proliferator-activated receptor gamma polymorphism is related to peak bone mass: the JPOS study.

    PubMed

    Tamaki, J; Iki, M; Morita, A; Ikeda, Y; Sato, Y; Kajita, E; Kagamimori, S; Kagawa, Y; Yoneshima, H

    2010-02-01

    We analyzed 1,217 women to examine the effect of peroxisome proliferator-activated receptors gamma (PPARgamma) C161 --> T on bone status. Among 664 premenopausal women, the C161 --> T is associated with low bone mineral density (BMD) at the total hip and femoral neck. Moreover, the odds ratio for osteopenia or osteoporosis at the femoral neck was 1.98 for premenopausal CT/TT genotypes. The impact of PPARgamma on BMD has not been conclusively established. We examined if PPARgamma C161T polymorphism is associated with BMD and its change. We conducted a baseline survey in 1996 and a 10-year follow-up survey, Japanese Population-based Osteoporosis Study, with a sample population representative of Japanese women. Of these, 1,217 participants in the 1996 survey were analyzed cross-sectionally, while longitudinal analysis was performed on 563 women. A P value < 0.0042 (=0.05/12 for three menstrual statuses and four skeletal sites) was considered statistically significant after Bonferroni correction in multiple testing for cross-sectional analysis. The total hip and femoral neck BMDs were significantly higher for CC genotype than for CT/TT genotypes among 664 premenopausal women (P = 0.0020, P = 0.0022, respectively). Compared to the CC genotype, the odds ratio for osteopenia or osteoporosis (T-scores below -1) at the femoral neck was 1.98 for premenopausal CT/TT genotypes with statistical significance (P = 0.0041). Change of BMD at either skeletal site during the follow-up period was not significantly different for either menstrual status. We conclude that the PPARgamma C161T is associated with low peak bone mass.

  19. Distribution of PTPN22 polymorphisms in SLE from western Mexico: correlation with mRNA expression and disease activity.

    PubMed

    Machado-Contreras, Jesús René; Muñoz-Valle, José Francisco; Cruz, Alvaro; Salazar-Camarena, Diana Celeste; Marín-Rosales, Miguel; Palafox-Sánchez, Claudia Azucena

    2016-08-01

    Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune inflammatory disease characterized by loss of self-tolerance with hyperactivation of autoreactive T and B cells. Protein tyrosine phosphatase non-receptor type 22 (PTPN22) encodes for lymphoid-specific phosphatase (Lyp), which is a key negative regulator of T lymphocyte activation. The aim of this study was to evaluate the genetic contribution of PTPN22 -1123G>C and +1858C>T polymorphisms and their haplotypes in SLE patients, as well as mRNA expression according to -1123G>C promoter polymorphism and disease activity. One hundred and fifty SLE patients and 150 unrelated healthy controls (HC), both Mexican mestizos, were genotyped by PCR-RFLP technique for the PTPN22 -1123G>C and +1858C>T polymorphisms. PTPN22 mRNA expression levels were determined by real-time PCR from PBMCs of thirty patients with SLE and fifteen HC carrying different genotypes. Distributions of genotype and allelic frequencies were similar between SLE and HC. The most frequent alleles were -1123 G and +1858 C in both groups (69 vs. 66 % and 97 vs. 98 %, in SLE and HC, respectively). However, the recessive model of inheritance analysis showed a lower frequency of -1123 CC genotype in SLE patients (7 vs. 15 %), suggesting a protection effect to develop SLE (OR 0.41, CI 1.10-5.28, p = 0.02). Haplotype analysis showed strong linkage disequilibrium D' = 0.98 for PTPN22 -1123G>C and +1858C>T polymorphisms, but haplotypes were not associated with SLE. The PTPN22 mRNA expression did not show differences among -1123G>C genotypes; nevertheless, a significant negative correlation with disease activity was found (r = -0.64, p < 0.01). SLE inactive patients showed similar PTPN22 mRNA expression levels to healthy controls, whereas in patients with severe flare, the expression was nearly depleted. In conclusion, we found a lack of association of PTPN22 -1123G>C and +1858C>T polymorphisms with the risk of developing SLE in a Mexican

  20. Changes in complex spike activity during classical conditioning

    PubMed Central

    Rasmussen, Anders; Jirenhed, Dan-Anders; Wetmore, Daniel Z.; Hesslow, Germund

    2014-01-01

    The cerebellar cortex is necessary for adaptively timed conditioned responses (CRs) in eyeblink conditioning. During conditioning, Purkinje cells acquire pause responses or “Purkinje cell CRs” to the conditioned stimuli (CS), resulting in disinhibition of the cerebellar nuclei (CN), allowing them to activate motor nuclei that control eyeblinks. This disinhibition also causes inhibition of the inferior olive (IO), via the nucleo-olivary pathway (N-O). Activation of the IO, which relays the unconditional stimulus (US) to the cortex, elicits characteristic complex spikes in Purkinje cells. Although Purkinje cell activity, as well as stimulation of the CN, is known to influence IO activity, much remains to be learned about the way that learned changes in simple spike firing affects the IO. In the present study, we analyzed changes in simple and complex spike firing, in extracellular Purkinje cell records, from the C3 zone, in decerebrate ferrets undergoing training in a conditioning paradigm. In agreement with the N-O feedback hypothesis, acquisition resulted in a gradual decrease in complex spike activity during the conditioned stimulus, with a delay that is consistent with the long N-O latency. Also supporting the feedback hypothesis, training with a short interstimulus interval (ISI), which does not lead to acquisition of a Purkinje cell CR, did not cause a suppression of complex spike activity. In contrast, observations that extinction did not lead to a recovery in complex spike activity and the irregular patterns of simple and complex spike activity after the conditioned stimulus are less conclusive. PMID:25140129

  1. Lack of association between plasminogen activator inhibitor type-1 (PAI-1) gene 4G/5G polymorphism and osteoarthritis.

    PubMed

    Bayram, Banu; Sayin, Emrah; Erkasap, Nilüfer; Onlü, Harun; Ozkurt, Mete; Sahin, Fezan; Türkoğlu, Züleyha

    2012-01-01

    This study was conducted in Turkish osteoarthritis patients to determine the frequency of 4G/5G polymorphism genotypes of plasminogen activator inhibitor type-1 gene and to examine the role of this polymorphism in osteoarthritis development. Genomic DNA obtained from 200 persons (140 patients with osteoarthritis and 60 healthy controls) was used in the study. DNA was amplified by polymerase chain reaction using 4G allele- and 5G allele-specific primers. Polymerase chain reaction products were assessed with CCD camera by being exposed to 2% agarose gel electrophoresis. No statistically significant difference between the groups with respect to genotype distribution was found (P > 0.05) in the study. The 4G allele frequency was indicated as 44% and 5G allele was as 56% in patients, whereas this was 45-55% in the control group. This study has established that 4G/5G polymorphism genotypes of plasminogen activator inhibitor type-1 gene do not play a role in the development of osteoarthritis in the Turkish population.

  2. PERMANENT GENETIC RESOURCES: Isolation of 60 polymorphic microsatellite loci in EST libraries of four sibling species of the phytopathogenic fungal complex Microbotryum.

    PubMed

    Giraud, T; Yockteng, R; Marthey, S; Chiapello, H; Jonot, O; Lopez-Villavicencio, M; DE Vienne, D M; Hood, M E; Refregier, G; Gendrault-Jacquemard, A; Wincker, P; Dossat, C

    2008-03-01

    We report the development of 60 microsatellite markers on four species of the fungal complex Microbotryum, causing anther smut of the Caryophyllaceae. Microsatellites were found in four expressed sequence tag (EST) libraries, built from isolates of M. lychnis-dioicae, M. violaceum sensus stricto, M. lagerheimii and M. dianthorum, collected, respectively, from the plants Silene latifolia, S. nutans, S. vulgaris and Dianthus carthusianorum. Intrapopulation polymorphism was investigated using 24 isolates, and cross-amplification was explored using 23 isolates belonging to at least 10 different Microbotryum species. This study provides numerous microsatellite markers for population genetics and mapping studies.

  3. PON1 polymorphisms are associated with polycystic ovary syndrome susceptibility, related traits, and PON1 activity in Indian women with the syndrome.

    PubMed

    Dadachanji, Roshan; Shaikh, Nuzhat; Khavale, Sushma; Patil, Anushree; Shah, Nalini; Mukherjee, Srabani

    2015-07-01

    To investigate the association of paraoxonase 1 (PON1) polymorphisms (L55M and Q192R) with polycystic ovary syndrome (PCOS) susceptibility and its related traits in Indian women. Case-control study. Academic research institute, infertility, and endocrinology clinics. Controls (n = 326), women with PCOS (n = 482). None. Genotypic and allelic frequency distribution, genotype-phenotype association, different PON1 activities (lactonase, arylesterase, and paraoxonase). The genotypic and allelic frequency distributions of the L55M polymorphism were significantly different between lean controls and lean women with PCOS, and this polymorphism reduced the risk of PCOS development in lean but not in obese Indian women. Furthermore, this polymorphism was significantly associated with decreased 2-hour glucose, apolipoprotein B, free and bioavailable T, and free androgen index concurrent with increased sex hormone-binding globulin (SHBG) and FSH levels only in lean women with PCOS. However, Q192R polymorphism showed comparable genotypic frequency distribution between controls and women with PCOS. PON1 lactonase and arylesterase activities were significantly decreased in women with PCOS compared with controls. PON1 polymorphisms were shown to influence its activities. Our study showed that L55M, but not Q192R, polymorphism is significantly associated with reduced PCOS susceptibility only in lean women and also impacts glucose metabolism, lipid parameters, and hyperandrogenemia in them. Our study therefore suggests the possibility of differential genetic pathophysiology of PCOS between lean and obese women. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  4. Selective and strain-specific NFAT4 activation by the Toxoplasma gondii polymorphic dense granule protein GRA6

    PubMed Central

    Sasai, Miwa; Ohshima, Jun; Lee, Youngae; Bando, Hironori; Takeda, Kiyoshi

    2014-01-01

    Toxoplasma gondii infection results in co-option and subversion of host cellular signaling pathways. This process involves discharge of T. gondii effector molecules from parasite secretory organelles such as rhoptries and dense granules. We report that the T. gondii polymorphic dense granule protein GRA6 regulates activation of the host transcription factor nuclear factor of activated T cells 4 (NFAT4). GRA6 overexpression robustly and selectively activated NFAT4 via calcium modulating ligand (CAMLG). Infection with wild-type (WT) but not GRA6-deficient parasites induced NFAT4 activation. Moreover, GRA6-deficient parasites failed to exhibit full virulence in local infection, and the treatment of WT mice with an NFAT inhibitor mitigated virulence of WT parasites. Notably, NFAT4-deficient mice displayed prolonged survival, decreased recruitment of CD11b+ Ly6G+ cells to the site of infection, and impaired expression of chemokines such as Cxcl2 and Ccl2. In addition, infection with type I parasites culminated in significantly higher NFAT4 activation than type II parasites due to a polymorphism in the C terminus of GRA6. Collectively, our data suggest that GRA6-dependent NFAT4 activation is required for T. gondii manipulation of host immune responses to maximize the parasite virulence in a strain-dependent manner. PMID:25225460

  5. Controlled Orientation of Active Sites in a Nanostructured Multienzyme Complex

    PubMed Central

    Lim, Sung In; Yang, Byungseop; Jung, Younghan; Cha, Jaehyun; Cho, Jinhwan; Choi, Eun-Sil; Kim, Yong Hwan; Kwon, Inchan

    2016-01-01

    Multistep cascade reactions in nature maximize reaction efficiency by co-assembling related enzymes. Such organization facilitates the processing of intermediates by downstream enzymes. Previously, the studies on multienzyme nanocomplexes assembled on DNA scaffolds demonstrated that closer interenzyme distance enhances the overall reaction efficiency. However, it remains unknown how the active site orientation controlled at nanoscale can have an effect on multienzyme reaction. Here, we show that controlled alignment of active sites promotes the multienzyme reaction efficiency. By genetic incorporation of a non-natural amino acid and two compatible bioorthogonal chemistries, we conjugated mannitol dehydrogenase to formate dehydrogenase with the defined active site arrangement with the residue-level accuracy. The study revealed that the multienzyme complex with the active sites directed towards each other exhibits four-fold higher relative efficiency enhancement in the cascade reaction and produces 60% more D-mannitol than the other complex with active sites directed away from each other. PMID:28004799

  6. Prognostic quality of activating TERT promoter mutations in glioblastoma: interaction with the rs2853669 polymorphism and patient age at diagnosis.

    PubMed

    Spiegl-Kreinecker, Sabine; Lötsch, Daniela; Ghanim, Bahil; Pirker, Christine; Mohr, Thomas; Laaber, Magdalena; Weis, Serge; Olschowski, Alfred; Webersinke, Gerald; Pichler, Josef; Berger, Walter

    2015-09-01

    Expression of the telomerase reverse transcriptase (TERT) might be altered by activating mutations of the rs2853669 polymorphism within the promoter region. Here we investigate the impact of these genomic alterations on telomerase activation and dissect their prognostic potential in glioblastoma (GBM). The respective TERT promoter region was sequenced in 126 GBM tissues and compared with clinical parameters and glioma biomarkers MGMT promoter methylation and IDH1 mutation. TERT mRNA expression, telomerase activity, and telomere lengths were determined by reverse transcriptase PCR, TRAP assay, and real-time PCR, respectively. Seventy-three percent of GBM patients harbored TERT promoter mutations associated with enhanced telomerase activity and TERT mRNA expression but reduced telomere lengths (P < .001 for all). Patients with mutated tumors exhibited significantly shorter overall survival in the entire cohort (11.5 vs 23.1 months; P < .0001) and in the primary GBM patient subgroup lacking IDH1 mutations (n = 120; P = .0084). This prognostic impact was confined to younger patients (aged <65 years), while the negative prognostic power of enhanced age at diagnosis was limited to those patients lacking TERT promoter mutations. Presence of the common single nucleotide polymorphism rs2853669, disrupting an endogenous Ets2 transcription factor-binding site, was associated with improved survival exclusively in patients with a wild-type TERT promoter. On the contrary, the shortest mean overall survival was detected in those patients harboring both an activating TERT promoter mutation and homozygous rs2853669 alleles. In summary, TERT promoter mutations are powerful prognosticators for worse course of disease in human GBM patients but their prognostic value is influenced by the rs2853669 polymorphism and age at diagnosis. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e

  7. Prognostic quality of activating TERT promoter mutations in glioblastoma: interaction with the rs2853669 polymorphism and patient age at diagnosis

    PubMed Central

    Spiegl-Kreinecker, Sabine; Lötsch, Daniela; Ghanim, Bahil; Pirker, Christine; Mohr, Thomas; Laaber, Magdalena; Weis, Serge; Olschowski, Alfred; Webersinke, Gerald; Pichler, Josef; Berger, Walter

    2015-01-01

    Background Expression of the telomerase reverse transcriptase (TERT) might be altered by activating mutations of the rs2853669 polymorphism within the promoter region. Here we investigate the impact of these genomic alterations on telomerase activation and dissect their prognostic potential in glioblastoma (GBM). Methods The respective TERT promoter region was sequenced in 126 GBM tissues and compared with clinical parameters and glioma biomarkers MGMT promoter methylation and IDH1 mutation. TERT mRNA expression, telomerase activity, and telomere lengths were determined by reverse transcriptase PCR, TRAP assay, and real-time PCR, respectively. Results Seventy-three percent of GBM patients harbored TERT promoter mutations associated with enhanced telomerase activity and TERT mRNA expression but reduced telomere lengths (P < .001 for all). Patients with mutated tumors exhibited significantly shorter overall survival in the entire cohort (11.5 vs 23.1 months; P < .0001) and in the primary GBM patient subgroup lacking IDH1 mutations (n = 120; P = .0084). This prognostic impact was confined to younger patients (aged <65 years), while the negative prognostic power of enhanced age at diagnosis was limited to those patients lacking TERT promoter mutations. Presence of the common single nucleotide polymorphism rs2853669, disrupting an endogenous Ets2 transcription factor-binding site, was associated with improved survival exclusively in patients with a wild-type TERT promoter. On the contrary, the shortest mean overall survival was detected in those patients harboring both an activating TERT promoter mutation and homozygous rs2853669 alleles. Conclusion In summary, TERT promoter mutations are powerful prognosticators for worse course of disease in human GBM patients but their prognostic value is influenced by the rs2853669 polymorphism and age at diagnosis. PMID:25681309

  8. GPX1 Pro(198)Leu polymorphism, erythrocyte GPX activity, interaction with alcohol consumption and smoking, and risk of colorectal cancer.

    PubMed

    Hansen, Rikke Dalgaard; Krath, Britta Naimi; Frederiksen, Kirsten; Tjønneland, Anne; Overvad, Kim; Roswall, Nina; Loft, Steffen; Dragsted, Lars Ove; Vogel, Ulla; Raaschou-Nielsen, Ole

    2009-05-12

    GPX1 encoding the enzyme glutathione peroxidase 1 (GPX1) and hOGG1 encoding the 8-oxoguanine glycosylase 1 (OGG1) may counteract oxidative stress and resulting DNA damage associated with lifestyle-related exposures. We examined whether the polymorphisms GPX1 Pro(198)Leu and OGG1 Ser(326)Cys or low erythrocyte GPX enzyme activity in pre-diagnostic blood samples are associated with colorectal cancer risk, and assessed possible interactions between the polymorphisms or enzyme activity and various lifestyle factors in relation to colorectal cancer risk. Additionally, we studied whether the GPX1 Pro(198)Leu polymorphism and several lifestyle factors predict GPX activity in erythrocytes. The present study was nested within the prospective "Diet, Cancer and Health" study of 57,053 Danes including 375 colorectal cancer cases and a comparison group of 779 individuals matched on gender. Biomaterial was sampled and information on lifestyle factors was obtained from questionnaires filled in at enrolment in 1993-1997. GPX1 Pro(198)Leu, hOGG1 Ser(326)Cys and erythrocyte GPX enzyme activity were not associated with risk of colorectal cancer. We observed a higher risk associated with alcohol consumption and smoking among homozygous GPX1(198)Leu carriers, with incidence rate ratios for colorectal cancer of 1.45 (95% CI: 1.17-1.81, P=0.02) per 10g alcohol intake per day and 2.56 (95% CI: 0.99-6.61, P=0.02) among ever smokers compared with never smokers at enrolment. Erythrocyte GPX activity was influenced by the GPX1 Pro(198)Leu genotype, gender, smoking intensity, and intake of fruits and vegetables. Our results indicate that lifestyle-related oxidative stress may be a risk factor for colorectal cancer among subjects with a lowered defence.

  9. Hydrolytic Activity of Esterase-Antibody Complexes Retained Within Gel Capsules After Complex Isolation.

    PubMed

    Shimazaki, Youji; Miyatsuka, Rino

    2017-07-01

    Delipidation in biological samples is important for some diagnostic tests and protein analyses. Lipids in the samples can be hydrolyzed by native esterases (ESs) within gel capsules after ES, and ES-antibody complexes are specifically trapped, extracted, and separated. Acrylamide and agarose gel capsules containing complexes of ES antibody were produced after the complexes were extracted using protein A-immobilized membranes, separated by non-denaturing electrophoresis, and stained by colloidal silver using glucose as a reductant. ES activity of ES-antibody complexes within the gel capsule was significantly higher than that in the complexes with the control antibodies upon isolation, separation, and detection of the complex. In addition, lipids bound to human serum albumin decreased after human plasma was treated with gel capsules containing ES-antibody complexes. We demonstrate that the gel capsule containing ES-antibody complexes can be successfully isolated using techniques described in this study. Furthermore, delipidation of human plasma is obtained by incubation with the gel capsule. These results indicate that surplus materials such as lipids in biological samples can be removed or reduced by gel capsule containing enzymes.

  10. Mitochondrial network complexity and pathological decrease in complex I activity are tightly correlated in isolated human complex I deficiency.

    PubMed

    Koopman, Werner J H; Visch, Henk-Jan; Verkaart, Sjoerd; van den Heuvel, Lambertus W P J; Smeitink, Jan A M; Willems, Peter H G M

    2005-10-01

    Complex I (NADH:ubiquinone oxidoreductase) is the largest multisubunit assembly of the oxidative phosphorylation system, and its malfunction is associated with a wide variety of clinical syndromes ranging from highly progressive, often early lethal, encephalopathies to neurodegenerative disorders in adult life. The changes in mitochondrial structure and function that are at the basis of the clinical symptoms are poorly understood. Video-rate confocal microscopy of cells pulse-loaded with mitochondria-specific rhodamine 123 followed by automated analysis of form factor (combined measure of length and degree of branching), aspect ratio (measure of length), and number of revealed marked differences between primary cultures of skin fibroblasts from 13 patients with an isolated complex I deficiency. These differences were independent of the affected subunit, but plotting of the activity of complex I, normalized to that of complex IV, against the ratio of either form factor or aspect ratio to number revealed a linear relationship. Relatively small reductions in activity appeared to be associated with an increase in form factor and never with a decrease in number, whereas relatively large reductions occurred in association with a decrease in form factor and/or an increase in number. These results demonstrate that complex I activity and mitochondrial structure are tightly coupled in human isolated complex I deficiency. To further prove the relationship between aberrations in mitochondrial morphology and pathological condition, fibroblasts from two patients with a different mutation but a highly fragmented mitochondrial phenotype were fused. Full restoration of the mitochondrial network demonstrated that this change in mitochondrial morphology was indeed associated with human complex I deficiency.

  11. Peroxisome proliferator-activated receptor alpha L162V polymorphism in nonalcoholic steatohepatitis and genotype 1 hepatitis C virus-related liver steatosis.

    PubMed

    Verdi, Hasibe; Koytak, Elif Sare; Onder, Oğuz; Ergül, Ayça Arslan; Cinar, Kubilay; Idilman, Ramazan; Erden, Esra; Bozdayi, Abdurrahman Mithat; Yurdaydin, Cihan; Uzunalimoglu, Ozden; Bozkaya, Hakan

    2005-11-01

    Peroxisome proliferator-activated receptor alpha (PPARalpha) plays important roles in lipid metabolism. A recently discovered L162V polymorphism of the PPARalpha gene is associated with enhanced transcriptional activity. In this study, the frequency of L162V was investigated in nonalcoholic steatohepatitis (NASH) and genotype 1 hepatitis C virus (HCV)-related liver steatosis. Seventy-two NASH and 141 HCV-infected patients (54 with steatosis, 87 without steatosis) and 119 healthy controls were included. L162V polymorphism of the PPARalpha gene was analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). PCR and RFLP analysis of the related gene segment was successful in 93%, 96%, and 100% of NASH and HCV-infected patients and controls, respectively. The frequency of the L162V polymorphism was similar in the NASH and HCV-infected patients and controls (5.9%, 3.6%, and 2.5%, respectively). No difference in the frequency of this polymorphism was observed in HCV-infected patients with or without significant liver steatosis. L162V was not associated with obesity, type 2 diabetes mellitus, hypercholesterolemia, or hypertriglyceridemia. Neither NASH nor genotype 1 HCV-related liver steatosis seems to be associated with the PPARalpha L162V polymorphism. This polymorphism may have no association with the presence of type 2 diabetes mellitus, obesity, or various blood lipid alterations in NASH and HCV-infected patients.

  12. Active mixing of complex fluids at the microscale

    SciTech Connect

    Ober, Thomas J.; Foresti, Daniele; Lewis, Jennifer A.

    2015-09-22

    Mixing of complex fluids at low Reynolds number is fundamental for a broad range of applications, including materials assembly, microfluidics, and biomedical devices. Of these materials, yield stress fluids (and gels) pose the most significant challenges, especially when they must be mixed in low volumes over short timescales. New scaling relationships between mixer dimensions and operating conditions are derived and experimentally verified to create a framework for designing active microfluidic mixers that can efficiently homogenize a wide range of complex fluids. As a result, active mixing printheads are then designed and implemented for multimaterial 3D printing of viscoelastic inks with programmable control of local composition.

  13. Active mixing of complex fluids at the microscale

    PubMed Central

    Ober, Thomas J.; Foresti, Daniele; Lewis, Jennifer A.

    2015-01-01

    Mixing of complex fluids at low Reynolds number is fundamental for a broad range of applications, including materials assembly, microfluidics, and biomedical devices. Of these materials, yield stress fluids (and gels) pose the most significant challenges, especially when they must be mixed in low volumes over short timescales. New scaling relationships between mixer dimensions and operating conditions are derived and experimentally verified to create a framework for designing active microfluidic mixers that can efficiently homogenize a wide range of complex fluids. Active mixing printheads are then designed and implemented for multimaterial 3D printing of viscoelastic inks with programmable control of local composition. PMID:26396254

  14. Active mixing of complex fluids at the microscale

    DOE PAGES

    Ober, Thomas J.; Foresti, Daniele; Lewis, Jennifer A.

    2015-09-22

    Mixing of complex fluids at low Reynolds number is fundamental for a broad range of applications, including materials assembly, microfluidics, and biomedical devices. Of these materials, yield stress fluids (and gels) pose the most significant challenges, especially when they must be mixed in low volumes over short timescales. New scaling relationships between mixer dimensions and operating conditions are derived and experimentally verified to create a framework for designing active microfluidic mixers that can efficiently homogenize a wide range of complex fluids. As a result, active mixing printheads are then designed and implemented for multimaterial 3D printing of viscoelastic inks withmore » programmable control of local composition.« less

  15. Development of a complex of activity in the solar corona

    NASA Technical Reports Server (NTRS)

    Howard, R.; Svestka, Z.

    1977-01-01

    Using Skylab observations of soft solar X-rays, the development of a complex of activity in the solar corona during its whole lifetime of seven solar rotations is studied. The basic components of the activity complex were determined to be permanently interconnected through sets of magnetic field lines, which suggests similar connections also below the photosphere. The visibility of individual loops in these connections, however, was greatly variable and typically shorter than one day. Each brightening of a coronal loop in X-rays seems to be related to a variation in the photospheric magnetic field near its footprint.

  16. Complex interaction between serum folate levels and genetic polymorphisms in folate pathway genes: biomarkers of prostate cancer aggressiveness.

    PubMed

    Jackson, Maria D; Tulloch-Reid, Marshall K; McFarlane-Anderson, Norma; Watson, Alexis; Seers, Vestra; Bennett, Franklyn I; Egleston, Brian; Ragin, Camille

    2013-03-01

    Little is known about the role of folate and polymorphisms associated with folate metabolism on prostate cancer risk in populations of African origin. We examined the relationship between serum folate and prostate cancer and whether any association was modified by genetic polymorphisms for folate metabolism. The study was case-control in design and consisted of 218 men 40-80 years old with newly diagnosed, histologically confirmed prostate cancer and 236 cancer-free men attending the same urology clinics in Jamaica, March 2005-July 2007. Serum folate was measured by an immunoassay method and genomic DNA evaluated for MTHR (C677T and A1298C), MTRR A66G, and MTR A2756G polymorphisms. Mean serum folate concentration was higher among cases (12.3 ± 4.1 nmol/L) than controls (9.7 ± 4.2 nmol/L). Serum folate concentration showed a positive association with prostate cancer (OR, 4.41; CI, 2.52-7.72 per 10 nmol/L) regardless of grade. No interactions were observed between genotype and folate concentration, but a weak gene effect was observed for MTHFR A1298C and low-grade prostate cancer. Larger studies to investigate the role of gene-gene/gene-diet interactions in Black men are needed.

  17. Polymorphisms and Interspecies Differences of the Activating and Inhibitory FcγRII of Macaca nemestrina Influence the Binding of Human IgG Subclasses1

    PubMed Central

    Trist, Halina M.; Tan, Peck Szee; Wines, Bruce D.; Ramsland, Paul A.; Orlowski, Eva; Stubbs, Janine; Gardiner, Elizabeth E.; Pietersz, Geoffrey A.; Kent, Stephen J.; Stratov, Ivan; Burton, Dennis R.; Hogarth, P. Mark

    2014-01-01

    Little is known of the impact of Fc receptor polymorphism in macaques on the binding of human IgG (huIgG) and nothing is known of this interaction in the pigtail macaque (M. nemestrina) which is used in preclinical evaluation of vaccines and therapeutic antibodies. We defined the sequence and huIgG binding characteristics of the M. nemestrina activating FcγRIIa (mnFcγRIIa) and inhibitory FcγRIIb (mnFcγRIIb) and predicted their structures using the huIgGFc:huFcγRIIa crystal structure. Large differences were observed in the binding of huIgG by mnFcγRIIa and mnFcγRIIb compared to their human FcR counterparts. MnFcγRIIa has markedly impaired binding of huIgG1 and huIgG2 immune complexes compared to huFcγRIIa (His131). In contrast, mnFcγRIIb has enhanced binding of huIgG1 and broader specificity as, unlike huFcγRIIb, it avidly binds IgG2. Mutagenesis and molecular modelling of mnFcγRIIa showed that Pro159 and Tyr160 impair the critical FG loop interaction with huIgG. The enhanced binding of huIgG1 and huIgG2 by mnFcγRIIb was shown to be dependent on His131 and Met132. Significantly, both His131 and Met132 are conserved across FcγRIIb of rhesus and cynomolgus macaques. We identified functionally significant polymorphism of mnFcγRIIa, wherein Pro at position 131, also an important polymorphic site in huFcγRIIa, almost abolished binding of huIgG2 and huIgG1 and reduced binding of huIgG3 compared to mnFcγRIIa His131. These marked interspecies differences in IgG-binding between human and macaque FcRs and polymorphisms within species have implications for pre-clinical evaluation of antibodies and vaccines in macaques. PMID:24342805

  18. Polymorphisms and interspecies differences of the activating and inhibitory FcγRII of Macaca nemestrina influence the binding of human IgG subclasses.

    PubMed

    Trist, Halina M; Tan, Peck Szee; Wines, Bruce D; Ramsland, Paul A; Orlowski, Eva; Stubbs, Janine; Gardiner, Elizabeth E; Pietersz, Geoffrey A; Kent, Stephen J; Stratov, Ivan; Burton, Dennis R; Hogarth, P Mark

    2014-01-15

    Little is known of the impact of Fc receptor (FcR) polymorphism in macaques on the binding of human (hu)IgG, and nothing is known of this interaction in the pig-tailed macaque (Macaca nemestrina), which is used in preclinical evaluation of vaccines and therapeutic Abs. We defined the sequence and huIgG binding characteristics of the M. nemestrina activating FcγRIIa (mnFcγRIIa) and inhibitory FcγRIIb (mnFcγRIIb) and predicted their structures using the huIgGFc/huFcγRIIa crystal structure. Large differences were observed in the binding of huIgG by mnFcγRIIa and mnFcγRIIb compared with their human FcR counterparts. MnFcγRIIa has markedly impaired binding of huIgG1 and huIgG2 immune complexes compared with huFcγRIIa (His(131)). In contrast, mnFcγRIIb has enhanced binding of huIgG1 and broader specificity, as, unlike huFcγRIIb, it avidly binds IgG2. Mutagenesis and molecular modeling of mnFcγRIIa showed that Pro(159) and Tyr(160) impair the critical FG loop interaction with huIgG. The enhanced binding of huIgG1 and huIgG2 by mnFcγRIIb was shown to be dependent on His(131) and Met(132). Significantly, both His(131) and Met(132) are conserved across FcγRIIb of rhesus and cynomolgus macaques. We identified functionally significant polymorphism of mnFcγRIIa wherein proline at position 131, also an important polymorphic site in huFcγRIIa, almost abolished binding of huIgG2 and huIgG1 and reduced binding of huIgG3 compared with mnFcγRIIa His(131). These marked interspecies differences in IgG binding between human and macaque FcRs and polymorphisms within species have implications for preclinical evaluation of Abs and vaccines in macaques.

  19. Prothrombin polymorphism A19911G, factor V HR2 haplotype A4070G, and plasminogen activator-inhibitor-1 polymorphism 4G/5G and the risk of retinal vein occlusion.

    PubMed

    Kuhli-Hattenbach, Claudia; Hellstern, Peter; Nägler, Dorit Karin; Kohnen, Thomas; Hattenbach, Lars-Olof

    2017-01-13

    Thus far, no data has become available to evaluate systematically the prevalences of prothrombin polymorphism A19911G (PT A19911G), factor V HR2 haplotype A4070G (FV A4070G), or plasminogen activator-inhibitor-1 polymorphism 4G/5G (PAI-1 4G/5G) in patients who develop retinal vein occlusion (RVO) without cardiovascular risk factors. We retrospectively evaluated comprehensive thrombophilia data from 42 preselected RVO patients without cardiovascular risk factors. The prevalences of different gene mutations and polymorphisms including factor V Leiden mutation G1691A (FVL), FV A4070G, prothrombin mutation G20210A, PT A19911G, and PAI-1 4G/5G were compared with 241 healthy controls matched for age and sex. A total of 20 patients (47.7%) were found to carry thrombophilic gene polymorphisms including FVL, FV A4070G, and homozygous PT A19911G compared with 72 of 241 controls (29.9%; p = 0.03). Subgroup analysis of patients with a significant personal or family history of thromboembolism revealed a high prevalence of FVL, FV A4070G, and homozygous PT A19911G (p = 0.005). FV A4070G was found to be significantly associated with at least two other heterozygous or one homozygous gene polymorphisms (p = 0.02). Multivariate analysis revealed the presence of FVL (p = 0.0017) and homozygous PT A19911G (p = 0.03) polymorphism as independent risk factors for the development of RVO. Our results indicate that in selected RVO patients screening for thrombophilic gene polymorphisms including FVL, FV A4070G and homozygous PT G19911A may be helpful in a high percentage of cases. Our findings suggest that hereditary thrombophilia associated with RVO is more likely to be multigenic than caused by any single risk factor.

  20. Recurrent pregnancy loss, plasminogen activator inhibitor-1 (-675) 4G/5G polymorphism and antiphospholipid antibodies in Czech women.

    PubMed

    Subrt, Ivan; Ulcova-Gallova, Zdenka; Cerna, Monika; Hejnalova, Marketa; Slovanova, Jitka; Bibkova, Katarina; Micanova, Zdenka

    2013-07-01

    This study compares the frequencies of plasminogen activator inhibitor-1 (-675) 4G/5G polymorphism and its relationship with eight antiphospholipid antibodies (aPLs) in serum of 157 patients with repeated pregnancy loss (RPL). PAI-1 (-675) 4G/5G polymorphism was determined using standard PCR-RFLP method. Enzyme-linked immunosorbent assay was used for the detection of aPLs against ph-serine, ph-ethanolamine, ph-inositol, ph-DL-glycerol, phosphatidic acid, annexin V, cardiolipin, and beta2-GPI. Allelic frequency and distribution of genotypes were calculated. The prevalence of the risk conferring 4G allele and 4G/4G homozygous genotype in patients and controls was compared, and the correlation between aPLs positivity and PAI-1 4G/4G genotype was tested by chi-square test. Statistically highly significant correlation between RPL and PAI-1 (-675) 4G/4G genotype was found. No correlation between PAI-1 (-675) 4G/5G polymorphism and the presence of antiphospholipid antibodies in RPL patients was observed. PAI-1 (-675) 4G/4G homozygous genotype increases the risk of RPL independently from the aPLs positivity. © 2013 John Wiley & Sons Ltd.

  1. CURRENT AND KINETIC HELICITY OF LONG-LIVED ACTIVITY COMPLEXES

    SciTech Connect

    Komm, Rudolf; Gosain, Sanjay

    2015-01-01

    We study long-lived activity complexes and their current helicity at the solar surface and their kinetic helicity below the surface. The current helicity has been determined from synoptic vector magnetograms from the NSO/SOLIS facility, and the kinetic helicity of subsurface flows has been determined with ring-diagram analysis applied to full-disk Dopplergrams from NSO/GONG and SDO/HMI. Current and kinetic helicity of activity complexes follow the hemispheric helicity rule with mainly positive values (78%; 78%, respectively, with a 95% confidence level of 31%) in the southern hemisphere and negative ones (80%; 93%, respectively, with a 95% confidence level of 22% and 14%, respectively) in the northern hemisphere. The locations with the dominant sign of kinetic helicity derived from Global Oscillation Network Group (GONG) and SDO/HMI data are more organized than those of the secondary sign even if they are not part of an activity complex, while locations with the secondary sign are more fragmented. This is the case for both hemispheres even for the northern one where it is not as obvious visually due to the large amount of magnetic activity present as compared to the southern hemisphere. The current helicity shows a similar behavior. The dominant sign of current helicity is the same as that of kinetic helicity for the majority of the activity complexes (83% with a 95% confidence level of 15%). During the 24 Carrington rotations analyzed here, there is at least one longitude in each hemisphere where activity complexes occur repeatedly throughout the epoch. These ''active'' longitudes are identifiable as locations of strong current and kinetic helicity of the same sign.

  2. 5-lipoxygenase and 5-lipoxygenase-activating protein gene polymorphisms, dietary linoleic acid, and risk for breast cancer.

    PubMed

    Wang, Jun; John, Esther M; Ingles, Sue Ann

    2008-10-01

    The n-6 polyunsaturated fatty acid 5-lipoxygenase pathway has been shown to play a role in the carcinogenesis of breast cancer. We conducted a population-based case-control study among Latina, African-American, and White women from the San Francisco Bay area to examine the association of the 5-lipoxygenase gene (ALOX5) and 5-lipoxygenase-activating protein gene (ALOX5AP) with breast cancer risk. Three ALOX5AP polymorphisms [poly(A) microsatellite, -4900 A>G (rs4076128), and -3472 A>G (rs4073259)] and three ALOX5 polymorphisms [Sp1-binding site (-GGGCGG-) variable number of tandem repeat polymorphism, -1279 G>T (rs6593482), and 760 G>A (rs2228065)] were genotyped in 802 cases and 888 controls. We did not find significant main effects of ALOX5 and ALOX5AP genotypes on breast cancer risk that were consistent across race or ethnicity; however, there was a significant interaction between the ALOX5AP -4900 A>G polymorphism and dietary linoleic acid intake (P=0.03). Among women consuming a diet high in linoleic acid (top quartile of intake, >17.4 g/d), carrying the AA genotype was associated with higher breast cancer risk (age- and race-adjusted odds ratio, 1.8; 95% confidence interval, 1.2-2.9) compared with carrying genotypes AG or GG. Among women consuming

  3. Peroxisome proliferator-activated receptor-γ (PPARγ) Pro12Ala polymorphism and colorectal cancer (CRC) risk.

    PubMed

    Wang, Wei; Shao, Yan; Tang, Shenhua; Cheng, Xianyong; Lian, Haifeng; Qin, Chengyong

    2015-01-01

    The association between the peroxisome proliferator-activated receptor-γ (PPARγ) Pro12Ala polymorphism and colorectal cancer (CRC) risk was inconclusive. We conducted a meta-analysis to evaluate the association between PPARγ Pro12Ala polymorphism and CRC risk. We searched Pubmed, EMBASE, and China National Knowledge Infrastructure databases. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. A total of 17 case-control studies with 12635 and 15803 controls were included in this meta-analysis. Overall, PPARγ Pro12Ala polymorphism was associated with CRC risk (OR = 0.84, 95% CI 0.75-0.94, P = 0.003, I(2) = 35%). In the subgroup analysis by ethnicity, a significant association was found among Caucasians (OR = 0.85, 95% CI 0.75-0.96, P = 0.007, I(2) = 38%) but not among Asians (OR = 0.76, 95% CI 0.51-1.12, P = 0.17, I(2) = 28%). In the subgroup analysis by CRC site, a significant association was found among colon cancer (OR = 0.81, 95% CI 0.66-0.98, P = 0.03, I(2) = 16%) but not among rectal cancer (OR = 0.83, 95% CI 0.57-1.21, P = 0.34, I(2) = 63%). The sensitivity analysis did not influence the result by omitting low-quality studies (OR = 0.76, 95% CI 0.63-0.93, P = 0.006, I(2) = 51%). In conclusion, this meta-analysis suggested that PPARγ Pro12Ala polymorphism was significant associated with CRC risk.

  4. Peroxisome proliferator-activated receptor-γ (PPARγ) Pro12Ala polymorphism and colorectal cancer (CRC) risk

    PubMed Central

    Wang, Wei; Shao, Yan; Tang, Shenhua; Cheng, Xianyong; Lian, Haifeng; Qin, Chengyong

    2015-01-01

    Background: The association between the peroxisome proliferator-activated receptor-γ (PPARγ) Pro12Ala polymorphism and colorectal cancer (CRC) risk was inconclusive. We conducted a meta-analysis to evaluate the association between PPARγ Pro12Ala polymorphism and CRC risk. Material and Method: We searched Pubmed, EMBASE, and China National Knowledge Infrastructure databases. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. Results: A total of 17 case-control studies with 12635 and 15803 controls were included in this meta-analysis. Overall, PPARγ Pro12Ala polymorphism was associated with CRC risk (OR = 0.84, 95% CI 0.75-0.94, P = 0.003, I2 = 35%). In the subgroup analysis by ethnicity, a significant association was found among Caucasians (OR = 0.85, 95% CI 0.75-0.96, P = 0.007, I2 = 38%) but not among Asians (OR = 0.76, 95% CI 0.51-1.12, P = 0.17, I2 = 28%). In the subgroup analysis by CRC site, a significant association was found among colon cancer (OR = 0.81, 95% CI 0.66-0.98, P = 0.03, I2 = 16%) but not among rectal cancer (OR = 0.83, 95% CI 0.57-1.21, P = 0.34, I2 = 63%). The sensitivity analysis did not influence the result by omitting low-quality studies (OR = 0.76, 95% CI 0.63-0.93, P = 0.006, I2 = 51%). Conclusions: In conclusion, this meta-analysis suggested that PPARγ Pro12Ala polymorphism was significant associated with CRC risk. PMID:26064311

  5. Receptor activator of nuclear factor kappa-B gene polymorphisms in Iranian periodontitis and peri-implantitis patients.

    PubMed

    Kadkhodazadeh, Mahdi; Baghani, Zahra; Ebadian, Ahmad Reza; Kaghazchi, Zahra; Amid, Reza

    2014-06-01

    Peri-implantitis and periodontitis are inflammatory and infectious diseases of implant and tooth-supporting tissues. Recently, the role of gene polymorphisms of immune response components in the relevant pathogenesis has been investigated. The present study was the first to evaluate the relationship between two known single nucleotide polymorphisms (SNPs) of the receptor activator of nuclear factor kappa-β (RANK) gene (rs3018362 and rs35211496) in chronic periodontitis and peri-implantitis patients in an Iranian population. Eighty-one periodontally healthy patients, 38 patients with peri-implantitis, and 74 patients with chronic periodontitis were enrolled in this study. DNA was extracted from blood arm vein samples by using Miller's salting out technique according to the manufacturer's instructions given in the extraction kit. The concentration of DNA samples was measured using a spectrophotometer. The genetic polymorphisms of the RANK gene were evaluated using a competitive allele specific polymerase chain reaction (KBioscience allele specific PCR) technique. Differences in the frequencies of genotypes and alleles in the diseased and healthy groups were analyzed using chi-squared statistical tests (P<0.05). Analysis of rs35211496 revealed statistically significant differences in the expression of the TT, TC, and CC genotypes among the three groups (P=0.00). No statistically significant difference was detected in this respect between the control group and the chronic periodontitis group. The expression of the GG, GA, and AA genotypes and allele frequencies (rs3018362) showed no statistically significant difference among the three groups (P=0.21). The results of this study indicate that the CC genotype of the rs35211496 RANK gene polymorphism was significantly associated with peri-implantitis and may be considered a genetic determinant for peri-implantitis, but this needs to be confirmed by further studies in other populations.

  6. Plasminogen activator inhibitor-1 4G/5G polymorphism, factor V Leiden, prothrombin mutations and the risk of VTE recurrence.

    PubMed

    Sundquist, Kristina; Wang, Xiao; Svensson, Peter J; Sundquist, Jan; Hedelius, Anna; Larsson Lönn, Sara; Zöller, Bengt; Memon, Ashfaque A

    2015-11-25

    Plasminogen-activator inhibitor (PAI)-1 is an important inhibitor of the plasminogen/plasmin system. PAI-1 levels are influenced by the 4G/5G polymorphism in the PAI-1 promoter. We investigated the relationship between the PAI-1 polymorphism and VTE recurrence, and its possible modification by factor V Leiden (FVL) and prothrombin (PTM) mutations. Patients (n=1,069) from the Malmö Thrombophilia Study were followed from discontinuation of anticoagulant treatment until diagnosis of VTE recurrence or the end of the study (maximum follow-up 9.8 years). One hundred twenty-seven patients (11.9 %) had VTE recurrence. PAI-1 was genotyped by TaqMan PCR. Cox regression analysis adjusted for age, sex and acquired risk factors of VTE showed no evidence of an association between PAI-1 genotype and risk of VTE recurrence in the study population as a whole. However, by including an interaction term in the analysis we showed that FVL but not PTM modified the effect of PAI-1 genotype: patients with the 4G allele plus FVL had a higher risk of VTE recurrence [hazard ratio (HR) =2.3, 95 % confidence interval (CI) =1.5-3.3] compared to patients with the 4G allele but no FVL (reference group) or FVL irrespective of PAI-1 genotype (HR=1.8, 95 % CI=1.3-2.5). Compared to reference group, 5G allele irrespective of FVL was associated with lower risk of VTE recurrence only when compared with 4G allele together with FVL. In conclusion, FVL has a modifying effect on PAI-1 polymorphism in relation to risk of VTE recurrence. The role of PAI-1 polymorphism as a risk factor of recurrent VTE may be FVL dependent.

  7. Interferon gamma +874T/A polymorphism is associated with susceptibility to active pulmonary tuberculosis development in Tunisian patients.

    PubMed

    Ben Selma, Walid; Harizi, Hedi; Bougmiza, Iheb; Hannachi, Naila; Ben Kahla, Imen; Zaieni, Radhia; Boukadida, Jalel

    2011-06-01

    Interferon gamma (IFN-γ) is a key cytokine involved mainly in the defense against intracellular pathogens such as Mycobacterium tuberculosis. Given its key role in the control of tuberculosis (TB), in the present article we have investigated a possible association between IFN-γ gene single-nucleotide polymorphism linked to high and low producer phenotypes (IFN-γ [+874T(high) → A(low)]) (rs2430561) and risk development of active TB in Tunisian patients. Genomic DNA samples were obtained from 223 patients with active TB (168 pulmonary and 55 extrapulmonary cases) and 150 healthy blood donors. Genotypes were analyzed using polymerase chain reaction-restriction fragment length polymorphism method. The +874 AA genotype (low IFN-γ producer) was significantly associated with increased risk of developing of active pulmonary TB (odds ratio [OR] = 2.18; 95% confidence intervals [CI], 1.33-3.57; P corrected for the number of genotypes [Pc] = 0.003). By contrast, the AT genotype was found to be significantly associated with resistance to pulmonary TB (OR = 0.46; 95% CI, 0.28-0.74; Pc = 0.0018) and extrapulmonary TB development (OR = 0.46; 95% CI, 0.23-0.91; Pc = 0.045). Collectively, our data showed that the IFN-γ +874T/A polymorphism is a determinant in the resistance or susceptibility to the development of active TB in the studied population.

  8. Manganese superoxide dismutase and catalase genetic polymorphisms, activity levels, and lung cancer risk in Chinese in Hong Kong.

    PubMed

    Ho, James C; Mak, Judith C W; Ho, S P; Ip, Mary S M; Tsang, Kenneth W; Lam, W K; Chan-Yeung, Moira

    2006-09-01

    Antioxidants play an important role in counteracting the effects of potential carcinogens. We investigated the risk of lung cancer development with respect to manganese superoxide dismutase (MnSOD) and catalase genetic polymorphisms and their association with erythrocyte antioxidant activities. This was a case-control study involving patients with confirmed lung cancer and age-matched healthy controls. Genotyping of MnSOD and catalase in DNA extracted from peripheral white cells was performed by polymerase chain reaction-based restriction fragment length polymorphism. Erythrocyte superoxide dismutase and catalase activities were measured spectrophotometrically using chemical kinetic reactions. We recruited 240 patients with lung cancer (63% male, aged 55.6 +/- 11.9 years, 58% adenocarcinoma, 85% clinical stage III or IV) and 240 age-matched healthy controls. The frequencies of the Val allele of MnSOD gene and the C allele of catalase gene were common (>86% and 90%, respectively), with similar distribution, in both patients with lung cancer and controls. The homozygous variant genotypes of MnSOD and catalase were not associated with increased lung cancer risk. The erythrocyte SOD and catalase activity was significantly lower among all patients with lung cancer as a whole compared with controls, irrespective of genotypes. However, patients with adenocarcinoma and non-adenocarcinoma showed differences in SOD and catalase activity among different genotypes in comparison with controls. The common Val16Ala MnSOD polymorphism and C-T substitution in the promoter region of the catalase gene do not confer increased or reduced risk of lung cancer in Chinese in Hong Kong.

  9. Antigen genes for molecular epidemiology of leishmaniasis: polymorphism of cysteine proteinase B and surface metalloprotease glycoprotein 63 in the Leishmania donovani complex.

    PubMed

    Quispe Tintaya, Kelly Wilber; Ying, Xu; Dedet, Jean-Pierre; Rijal, Suman; De Bolle, Xavier; Dujardin, Jean-Claude

    2004-03-15

    Efficient monitoring of endemic and resurgent visceral leishmaniasis (VL) requires discriminatory molecular tools that allow direct characterization of etiological agents (i.e., the Leishmania donovani complex) in host tissues. This characterization is possible through restriction fragment-length polymorphism (RFLP) analysis of polymerase chain reaction (PCR)-amplified sequences (PCR-RFLP). We present 2 new PCR-RFLP assays that target the gene locus of cysteine proteinase B (cpb), an important Leishmania antigen. The assays were applied to the characterization of 15 reference strains of the L. donovani complex, and their discriminatory power was compared with that of PCR-RFLP analysis of the gp63 gene, another Leishmania antigen, and with that of multilocus enzyme electrophoresis (MLEE), which is the reference standard for parasite typing. Restriction patterns of the cpb locus were polymorphic, but less so than gp63 patterns. When data for both loci were combined, differences between PCR-RFLP and MLEE results were encountered. Antigen gene analysis was more discriminatory and supported a different classification of parasites, one that fitted with their geographic origin. PCR-RFLP analysis of cpb also allowed direct genotyping of parasites in bone marrow aspirate and venous blood samples obtained from patients with VL. Antigen genes constitute valid targets for PCR-based Leishmania typing without the need for isolation of parasites.

  10. Comparison of Solar Active Region Complexity Andgeomagnetic Activity from 1996 TO 2014

    NASA Astrophysics Data System (ADS)

    Tanskanen, E. I.; Nikbakhsh, S.; Perez-Suarez, D.; Hackman, T.

    2015-12-01

    We have studied the influence of magnetic complexity of solar Active Regions (ARs)on geomagnetic activity from 1996 to 2014. Sunspots are visual indicators of ARswhere the solar magnetic field is disturbed. We have used International, American,Space Environment Service Center (SESC) and Space Weather Prediction Center(SWPC) sunspot numbers to examine ARs. Major manifestations of solar magneticactivity, such as flares and Coronal Mass Ejections (CMEs), are associated withARs. For this study we chose the Mount Wilson scheme. It classifies ARs in terms oftheir magnetic topology from the least complex (?) to the most complex one ( ?).Several cases have been found where the more complex structures produce strongerflares and CMEs than the less complex ones. We have a list of identified substormsavailable with different phases and their durations. This will be compared to ourmagnetic complexity data to analyse the effects of active region magnetic complexityto the magnetic activity on the vicinity of the Earth.

  11. Efficient Management of Complex Striped Files in Active Storage

    SciTech Connect

    Piernas Canovas, Juan; Nieplocha, Jaroslaw

    2008-08-25

    Active Storage provides an opportunity for reducing the band- width requirements between the storage and compute elements of cur- rent supercomputing systems, and leveraging the processing power of the storage nodes used by some modern file systems. To achieve both objec- tives, Active Storage allows certain processing tasks to be performed directly on the storage nodes, near the data they manage. However, Active Storage must also support key requirements of scientific applications. In particular, Active Storage must be able to support striped files and files with complex formats (e.g., netCDF). In this paper, we describe how these important requirements can be addressed. The experimental results on a Lustre file system not only show that our proposal can re- duce the network traffic to near zero and scale the performance with the number of storage nodes, but also that it provides an efficient treatment of striped files and can manage files with complex data structures.

  12. Effect of cyclodextrin complexation on phenylpropanoids' solubility and antioxidant activity.

    PubMed

    Kfoury, Miriana; Landy, David; Auezova, Lizette; Greige-Gerges, Hélène; Fourmentin, Sophie

    2014-01-01

    The complexation abilities of five cyclodextrins (CDs) with seven phenylpropanoids (PPs) were evaluated by UV-visible spectroscopy, phase solubility studies and molecular modeling. Formation constants (K f), complexation efficiency (CE), PP:CD molar ratio, increase in formulation bulk and complexation energy were assessed. All complexes exhibited a 1:1 stoichiometry but their stability was influenced by the nature and the position of the phenyl ring substituents. A relationship between the intrinsic solubility of guests (S 0) and the solubilizing potential of CD was proposed. Molecular modeling was used to investigate the complementarities between host and guest. Finally, the antioxidant activity of encapsulated PPs was evaluated by scavenging of the stable DPPH radical.

  13. Effect of cyclodextrin complexation on phenylpropanoids’ solubility and antioxidant activity

    PubMed Central

    Kfoury, Miriana; Landy, David; Auezova, Lizette; Greige-Gerges, Hélène

    2014-01-01

    Summary The complexation abilities of five cyclodextrins (CDs) with seven phenylpropanoids (PPs) were evaluated by UV–visible spectroscopy, phase solubility studies and molecular modeling. Formation constants (K f), complexation efficiency (CE), PP:CD molar ratio, increase in formulation bulk and complexation energy were assessed. All complexes exhibited a 1:1 stoichiometry but their stability was influenced by the nature and the position of the phenyl ring substituents. A relationship between the intrinsic solubility of guests (S 0) and the solubilizing potential of CD was proposed. Molecular modeling was used to investigate the complementarities between host and guest. Finally, the antioxidant activity of encapsulated PPs was evaluated by scavenging of the stable DPPH radical. PMID:25298799

  14. C-H bond activation by f-block complexes.

    PubMed

    Arnold, Polly L; McMullon, Max W; Rieb, Julia; Kühn, Fritz E

    2015-01-02

    Most homogeneous catalysis relies on the design of metal complexes to trap and convert substrates or small molecules to value-added products. Organometallic lanthanide compounds first gave a tantalizing glimpse of their potential for catalytic C-H bond transformations with the selective cleavage of one C-H bond in methane by bis(permethylcyclopentadienyl)lanthanide methyl [(η(5) -C5 Me5 )2 Ln(CH3 )] complexes some 25 years ago. Since then, numerous metal complexes from across the periodic table have been shown to selectively activate hydrocarbon C-H bonds, but the challenges of closing catalytic cycles still remain; many f-block complexes show great potential in this important area of chemistry. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Theoretical, spectral characterization and antineoplastic activity of new lanthanide complexes.

    PubMed

    Kostova, Irena; Trendafilova, Natasha; Momekov, Georgi

    2008-01-01

    The new cerium(III), lanthanum(III) and neodymium(III) complexes were synthesized in view of their application as cytotoxic agents. The complexes were characterized by different physicochemical methods: elemental analysis, mass spectrometry, (1)H NMR, (13)C NMR and IR spectroscopy. The spectra of the complexes were interpreted on the basis of comparison with the spectrum of the free ligand. The vibrational analysis showed that in the complexes the ligand coordinates to the metal ion through both deprotonated hydroxyl groups, however participation of the carbonyl groups in the coordination to the metal ion was also suggested. Geometry optimization of 3,3'-(ortho-pyridinomethylene)di-[4-hydroxycoumarin] H(2)(o-pyhc), (H(2)L) and its dianionic forms, o-pyhc(2-), (L(2-)) were carried out at AM1 and PM3 levels as well as using density functional theory with Becke's three parameter hybrid method and correlation functional of Lee, Yang and Parr (B3LYP) with 6-31G(d) basis set. The optimized geometries of the neutral ligand isomers were stabilized by two asymmetrical intramolecular O-H...O hydrogen bonds (HBs). The conformational search showed four low-energy dianionic species (o-pyhc(2-)) on the potential energy surface. Molecular electrostatic potential calculations showed that the most preferred sites for electrophilic attack in H(2)(o-pyhc) and o-pyhc(2-) are the carbonyl oxygen atoms. The evaluation of the cytotoxic activity of the novel lantanide complexes on HL-60 myeloid cells revealed, that they are potent cytotoxic agents. The cerium complex was found to exhibit superior activity in comparison to the lanthanum, and neodymium species, the latter being the least active. Taken together our data give us a reason to conclude that the newly synthesized lanthanide complexes should be a subset to further more detailed pharmacological and toxicological evaluation.

  16. Activation of CO2 by phosphinoamide hafnium complexes.

    PubMed

    Sgro, Michael J; Stephan, Douglas W

    2013-04-04

    Hf-phosphinoamide cation complexes behave as metal-based frustrated Lewis pairs and bind one or two equivalent of CO2 and in as well can activate CO2 in a bimetallic fashion to give a pseudo-tetrahedral P2CO2 fragment linking two Hf centres.

  17. Local Activity Principle:. the Cause of Complexity and Symmetry Breaking

    NASA Astrophysics Data System (ADS)

    Mainzer, Klaus

    2013-01-01

    The principle of local activity is precisely the missing concept to explain the emergence of complex patterns in a homogeneous medium. Leon O. Chua discovered and defined this principle in the theory of nonlinear electronic circuits in a mathematically rigorous way. The local principle can be generalized and proven at least for the class of nonlinear reaction-diffusion systems in physics, chemistry, biology and brain research. Recently, it was realized by memristors for nanoelectronic device applications in technical brains. In general, the emergence of complex patterns and structures is explained by symmetry breaking in homogeneous media. The principle of local activity is the cause of symmetry breaking in homogeneous media. We argue that the principle of local activity is really fundamental in science and can even be identified in quantum cosmology as symmetry breaking of local gauge symmetries generating the complexity of matter and forces in our universe. Finally, we consider applications in economic, financial, and social systems with the emergence of equilibrium states, symmetry breaking at critical points of phase transitions and risky acting at the edge of chaos. In any case, the driving causes of symmetry breaking and the emergence of complexity are locally active elements, cells, units, or agents.

  18. [The investigation of angiotensin converting enzyme I/D and plasminogen activator inhibitor-1 4G/5G polymorphisms in venous thromboembolism patients].

    PubMed

    Kaya, Halide; Karkucak, Mutlu; Salifoğlu, Hatice; Torun, Deniz; Kozan, Salih; Tunca, Yusuf

    2013-01-01

    Deep venous thrombosis and pulmonary embolism, known as venous thromboembolism and seen as a fairly common multifactorial diseases. Differ between populations due to genetic factors, several polymorphisms associated with venous thromboembolism was conducted. As a result of these studies the relationship between disease development and polymorphism is not clear yet. In this study we aimed to investigate the role of angiotensin converting enzyme insersion/deletion (ACE I/D) and plasminogen activator inhibitor-1 4G/5G (PAI-1 4G/5G) polymorphism in the development of disease. In our study, DNA isolated from 80 venous thromboembolism patients and 79 control groups was used. While the classical polymerase chain reaction method used to investigate the ACE I/D polymorphism, the polymerase chain reaction based on allele-specific amplification was used for the detection of PAI-1 4G/5G polymorphism. As a result, there were no significant statistical differences for ACE I/D and PAI-1 4G/5G polymorphism among patient and control groups (p> 0.05). These findings revealed that there is no relationship between these polymorphisms and the development of venous thromboembolism, but large-scale studies are need to be done.

  19. Plasminogen activator inhibitor-1 4G/5G polymorphism in infertile women with and without endometriosis.

    PubMed

    Gonçalves-Filho, Rubens P; Brandes, Ariel; Christofolini, Denise M; Lerner, Tatiana G; Bianco, Bianca; Barbosa, Caio P

    2011-05-01

    To evaluate PAI-1 genotypes in a group of infertile women with or without endometriosis and control subjects. Case-control study. Human Reproduction Center of Medicina do ABC Faculty. One hundred and forty infertile women with endometriosis, 64 women with idiopathic infertility and 148 fertile women as control subjects. The PAI-1 4G/5G polymorphism was identified by restriction fragment length polymorphism-polymerase chain reaction. Genotype distribution and allele frequency of the 4G/5G polymorphism of the PAI-1 gene. The frequencies of genotypes 4G/4G, 4G/5G and 5G/5G of the PAI-1 gene in the infertile women with endometriosis were 38.6, 37.1 and 24.3%, respectively, and in the control group 24.3, 33.8 and 41.9%, respectively (p=0.003). When the infertile women with endometriosis were divided according to their endometriosis stage, genotypes 4G/4G, 4G/5G and 5G/5G were identified, respectively, in 36.7, 32.9 and 30.4% of the patients with minimal/mild endometriosis (p=0.102) and in 41.0, 42.6 and 16.4% of the patients with moderate/severe endometriosis (p=0.001); in the women with idiopathic infertility, these genotypes were found at a frequency of 29.7, 34.3 and 36%, respectively (p=0.637). The data suggest that, in Brazilian women, the PAI-1 4G/5G polymorphism may be associated with a risk of endometriosis-associated infertility. © 2011 The Authors Acta Obstetricia et Gynecologica Scandinavica© 2011 Nordic Federation of Societies of Obstetrics and Gynecology.

  20. Circulating immune complexes and disease activity in Crohn's disease.

    PubMed Central

    Fiasse, R; Lurhuma, A Z; Cambiaso, C L; Masson, P L; Dive, C

    1978-01-01

    Circulating immune complexes were determined in 59 consecutive patients with Crohn's disease and 100 blood donors by a double method based on the inhibition of the agglutinating activity of CIq and/or rheumatoid factor on the IgG-coated polystyrene particles. In patients, the incidence of positive immune complexes was 63% and 61% at first testing, 85% and 78% at subsequent determinations; there was a good correlation between the inhibition titres of CIq and those of rheumatoid factor (p less than 0.001). In blood donors, the incidence was 22% and 14% at low titre. The incidence of immune complexes was the lowest (36%) in the group of resected patients without signs of relapse; repeat determinations showed absence of immune complexes three months postoperatively. In patients medically treated for primary disease or relapse, rheumatoid factor titre higher than 1/1 was less frequent than in medically untreated patients with active disease (p less than 0.01). A significantly higher concentration of serum alpha-1-antitrypsin and orosomucoid, and a significantly lower level of serum iron were found in patients with an IC titre exceeding 1/1; longitudinal studies showed in most cases a concordance between the evolution of immune complex titres, inflammatory parameters and clinical status. PMID:308030

  1. Superoxide scavenging activity of pirfenidone-iron complex

    SciTech Connect

    Mitani, Yoshihiro; Sato, Keizo Muramoto, Yosuke; Karakawa, Tomohiro; Kitamado, Masataka; Iwanaga, Tatsuya; Nabeshima, Tetsuji; Maruyama, Kumiko; Nakagawa, Kazuko; Ishida, Kazuhiko; Sasamoto, Kazumi

    2008-07-18

    Pirfenidone (PFD) is focused on a new anti-fibrotic drug, which can minimize lung fibrosis etc. We evaluated the superoxide (O{sub 2}{sup {center_dot}}{sup -}) scavenging activities of PFD and the PFD-iron complex by electron spin resonance (ESR) spectroscopy, luminol-dependent chemiluminescence assay, and cytochrome c reduction assay. Firstly, we confirmed that the PFD-iron complex was formed by mixing iron chloride with threefold molar PFD, and the complex was stable in distillated water and ethanol. Secondary, the PFD-iron complex reduced the amount of O{sub 2}{sup {center_dot}}{sup -} produced by xanthine oxidase/hypoxanthine without inhibiting the enzyme activity. Thirdly, it also reduced the amount of O{sub 2}{sup {center_dot}}{sup -} released from phorbor ester-stimulated human neutrophils. PFD alone showed few such effects. These results suggest the possibility that the O{sub 2}{sup {center_dot}}{sup -} scavenging effect of the PFD-iron complex contributes to the anti-fibrotic action of PFD used for treating idiopathic pulmonary fibrosis.

  2. Informational Complexity and Functional Activity of RNA Structures

    PubMed Central

    Carothers, James M.; Oestreich, Stephanie C.; Davis, Jonathan H.

    2004-01-01

    Very little is known about the distribution of functional DNA, RNA, and protein molecules in sequence space. The question of how the number and complexity of distinct solutions to a particular biochemical problem varies with activity is an important aspect of this general problem. Here we present a comparison of the structures and activities of eleven distinct GTP-binding RNAs (aptamers). By experimentally measuring the amount of information required to specify each optimal binding structure, we show that defining a structure capable of 10-fold tighter binding requires approximately 10 additional bits of information. This increase in information content is equivalent to specifying the identity of five additional nucleotide positions and corresponds to an ∼1000-fold decrease in abundance in a sample of random sequences. We observe a similar relationship between structural complexity and activity in a comparison of two catalytic RNAs (ribozyme ligases), raising the possibility of a general relationship between the complexity of RNA structures and their functional activity. Describing how information varies with activity in other heteropolymers, both biological and synthetic, may lead to an objective means of comparing their functional properties. This approach could be useful in predicting the functional utility of novel heteropolymers. PMID:15099096

  3. Association of MAOA, 5-HTT, and NET promoter polymorphisms with gene expression and protein activity in human placentas.

    PubMed

    Zhang, Huiping; Smith, Graeme N; Liu, Xudong; Holden, Jeanette J A

    2010-06-01

    Monoamine oxidase A (MAOA) and the transporters for serotonin (5-HTT) and norepinephrine (NET) may play important roles in regulating maternal monoamine neurotransmitters transferred across the placenta to the fetus. We investigated whether promoter polymorphisms in MAOA (uVNTR), 5-HTT (5-HTTLPR), and NET (NETpPR AAGG(4)) could influence gene expression and protein activity in human placentas. Normal term human placentas (n = 73) were collected, and placental MAOA, 5-HTT, and NET mRNA levels and protein activity were determined. The mRNA levels or protein activities were compared between different genotype groups. Placentas hemizygous (male fetus) or homozygous (female fetus) for MAOA uVNTR 4-repeat allele had significantly higher MAOA mRNA levels than those hemizygous or homozygous for the 3-repeat allele (P = 0.001). However, no significant difference in MAOA enzyme activity was found for these two groups of genotypes (P = 0.161). Placentas with the 5-HTTLPR short (S)-allele (S/S+S/L) had significantly lower 5-HTT mRNA levels and serotonin uptake rate than those homozygous for the long (L)-allele (L/L) (mRNA: P < 0.001; serotonin transporting activity: P < 0.001). Placentas homozygous for the NET AAGG(4) L(4) allele had significantly higher NET mRNA levels, as well as dopamine and norepinephrine uptake rates, than those with the S(4)/L(4) genotype (mRNA: P < 0.001; dopamine transporting activity: P = 0.012; norepinephrine transporting activity: P = 0.011). These findings suggest that the three promoter polymorphisms of MAOA, 5-HTT, and NET influence gene expression levels and protein activity of these genes in human placentas, potentially leading to different fetal levels of maternal monoamine neurotransmitters, which may have an impact on fetal neurodevelopment.

  4. Association of MAOA, 5-HTT, and NET promoter polymorphisms with gene expression and protein activity in human placentas

    PubMed Central

    Zhang, Huiping; Smith, Graeme N.; Liu, Xudong

    2010-01-01

    Monoamine oxidase A (MAOA) and the transporters for serotonin (5-HTT) and norepinephrine (NET) may play important roles in regulating maternal monoamine neurotransmitters transferred across the placenta to the fetus. We investigated whether promoter polymorphisms in MAOA (uVNTR), 5-HTT (5-HTTLPR), and NET (NETpPR AAGG4) could influence gene expression and protein activity in human placentas. Normal term human placentas (n = 73) were collected, and placental MAOA, 5-HTT, and NET mRNA levels and protein activity were determined. The mRNA levels or protein activities were compared between different genotype groups. Placentas hemizygous (male fetus) or homozygous (female fetus) for MAOA uVNTR 4-repeat allele had significantly higher MAOA mRNA levels than those hemizygous or homozygous for the 3-repeat allele (P = 0.001). However, no significant difference in MAOA enzyme activity was found for these two groups of genotypes (P = 0.161). Placentas with the 5-HTTLPR short (S)-allele (S/S+S/L) had significantly lower 5-HTT mRNA levels and serotonin uptake rate than those homozygous for the long (L)-allele (L/L) (mRNA: P < 0.001; serotonin transporting activity: P < 0.001). Placentas homozygous for the NET AAGG4 L4 allele had significantly higher NET mRNA levels, as well as dopamine and norepinephrine uptake rates, than those with the S4/L4 genotype (mRNA: P < 0.001; dopamine transporting activity: P = 0.012; norepinephrine transporting activity: P = 0.011). These findings suggest that the three promoter polymorphisms of MAOA, 5-HTT, and NET influence gene expression levels and protein activity of these genes in human placentas, potentially leading to different fetal levels of maternal monoamine neurotransmitters, which may have an impact on fetal neurodevelopment. PMID:20332182

  5. Higher activity of polymorphic NAD(P)H:quinone oxidoreductase in liver cytosols from blacks compared to whites.

    PubMed

    Covarrubias, Vanessa Gonzalez; Lakhman, Sukhwinder S; Forrest, Alan; Relling, Mary V; Blanco, Javier G

    2006-07-14

    In human liver, the two-electron reduction of quinone compounds, such as menadione is catalyzed by cytosolic carbonyl reductase (CBR) and NAD(P)H:quinone oxidoreductase (NQO1) activities. We assessed the relative contributions of CBR and NQO1 activities to the total menadione reducing capacity in liver cytosols from black (n=31) and white donors (n=63). Maximal menadione reductase activities did not differ between black (13.0+/-5.0 nmol/min mg), and white donors (11.4+/-6.6 nmol/min mg; p=0.208). In addition, both groups presented similar levels of CBR activities (CBR(blacks)=10.9+/-4.1 nmol/min mg) versus CBR(whites)=10.5+/-5.8 nmol/min mg; p=0.708). In contrast, blacks showed higher NQO1 activities (two-fold) than whites (NQO1(blacks)=2.1+/-3.0 nmol/min mg versus NQO1(whites)=0.9+/-1.6 nmol/min mg, p<0.01). To further explore this disparity, we tested whether NQO1 activity was associated with the common NQO1(*)2 genetic polymorphism by using paired DNA samples for genotyping. Cytosolic NQO1 activities differed significantly by NQO1 genotype status in whites (NQO1(whites[NQO1*1/*1])=1.3+/-1.7 nmol/min mg versus NQO1(whites[NQO1*1/*2+NQO1*2/*2])=0.5+/-0.7 nmol/min mg, p<0.01), but not in blacks (NQO1(blacks[NQO1*1/*1])=2.6+/-3.4 nmol/min mg versus NQO1(blacks[NQO1*1/*2])=1.1+/-1.2 nmol/min mg, p=0.134). Our findings pinpoint the presence of significant interethnic differences in polymorphic hepatic NQO1 activity.

  6. Similar Biological Activities of Two Isostructural Ruthenium and Osmium Complexes

    SciTech Connect

    Maksimoska,J.; Williams, D.; Atilla-Gokcumen, G.; Smalley, K.; Carroll, P.; Webster, R.; Filippakopoulos, P.; Knapp, S.; Herlyn, M.; Meggers, E.

    2008-01-01

    In this study, we probe and verify the concept of designing unreactive bioactive metal complexes, in which the metal possesses a purely structural function, by investigating the consequences of replacing ruthenium in a bioactive half-sandwich kinase inhibitor scaffold by its heavier congener osmium. The two isostructural complexes are compared with respect to their anticancer properties in 1205?Lu melanoma cells, activation of the Wnt signaling pathway, IC50 values against the protein kinases GSK-3? and Pim-1, and binding modes to the protein kinase Pim-1 by protein crystallography. It was found that the two congeners display almost indistinguishable biological activities, which can be explained by their nearly identical three-dimensional structures and their identical mode of action as protein kinase inhibitors. This is a unique example in which the replacement of a metal in an anticancer scaffold by its heavier homologue does not alter its biological activity.

  7. Anticancer activity of structurally related ruthenium(II) cyclopentadienyl complexes.

    PubMed

    Côrte-Real, Leonor; Mendes, Filipa; Coimbra, Joana; Morais, Tânia S; Tomaz, Ana Isabel; Valente, Andreia; Garcia, M Helena; Santos, Isabel; Bicho, Manuel; Marques, Fernanda

    2014-08-01

    A set of structurally related Ru(η(5)-C5H5) complexes with bidentate N,N'-heteroaromatic ligands have been evaluated as prospective metallodrugs, with focus on exploring the uptake and cell death mechanisms and potential cellular targets. We have extended these studies to examine the potential of these complexes to target cancer cell metabolism, the energetic-related phenotype of cancer cells. The observations that these complexes can enter cells, probably facilitated by binding to plasma transferrin, and can be retained preferentially at the membranes prompted us to explore possible membrane targets involved in cancer cell metabolism. Most malignant tumors present the Warburg effect, which consists in increasing glycolytic rates with production of lactate, even in the presence of oxygen. The reliance of glycolytic cancer cells on trans-plasma-membrane electron transport (TPMET) systems for their continued survival raises the question of their appropriateness as a target for anticancer drug development strategies. Considering the interesting findings that some anticancer drugs in clinical use are cytotoxic even without entering cells and can inhibit TPMET activity, we investigated whether redox enzyme modulation could be a potential mechanism of action of antitumor ruthenium complexes. The results from this study indicated that ruthenium complexes can inhibit lactate production and TPMET activity in a way dependent on the cancer cell aggressiveness and the concentration of the complex. Combination approaches that target cell metabolism (glycolytic inhibitors) as well as proliferation are needed to successfully cure cancer. This study supports the potential use of some of these ruthenium complexes as adjuvants of glycolytic inhibitors in the treatment of aggressive cancers.

  8. Experimental and Theoretical Studies on Biologically Active Lanthanide (III) Complexes

    NASA Astrophysics Data System (ADS)

    Kostova, I.; Trendafilova, N.; Georgieva, I.; Rastogi, V. K.; Kiefer, W.

    2008-11-01

    The complexation ability and the binding mode of the ligand coumarin-3-carboxylic acid (HCCA) to La(III), Ce(III), Nd(III), Sm(III), Gd(III) and Dy(III) lanthanide ions (Ln(III)) are elucidated at experimental and theoretical level. The complexes were characterized using elemental analysis, DTA and TGA data as well as 1H NMR and 13C NMR spectra. FTIR and Raman spectroscopic techniques as well as DFT quantum chemical calculations were used for characterization of the binding mode and the structures of lanthanide(III) complexes of HCCA. The metal—ligand binding mode is predicted through molecular modeling and energy estimation of different Ln—CCA structures using B3LYP/6-31G(d) method combined with a large quasi-relativistic effective core potential for lanthanide ion. The energies obtained predict bidentate coordination of CCA- to Ln(III) ions through the carbonylic oxygen and the carboxylic oxygen. Detailed vibrational analysis of HCCA, CCA- and Ln(III) complexes based on both calculated and experimental frequencies confirms the suggested metal—ligand binding mode. The natural bonding analysis predicts strongly ionic character of the Ln(III)-CCA bonding in the- complexes studied. With the relatively resistant tumor cell line K-562 we obtained very interesting in-vitro results which are in accordance with our previously published data concerning the activity of lanthanide(III) complexes with other coumarin derivatives.

  9. Platinum(II)-Acyclovir Complexes: Synthesis, Antiviral and Antitumour Activity

    PubMed Central

    Coluccia, M.; Boccarelli, A.; Cermelli, C.; Portolani, M.; Natile, G.

    1995-01-01

    A platinum(II) complex with the antiviral drug acyclovir was synthesized and its antiviral and anticancer properties were investigated in comparison to those of acyclovir and cisplatin. The platinum-acyclovir complex maintained the antiviral activity of the parent drug acyclovir, though showing a minor efficacy on a molar basis (ID50  =   7.85 and 1.02 μΜ for platinum-acyclovir and cisplatin, respectively). As anticancer agent, the platinum-acyclovir complex was markedly less potent than cisplatin on a mole-equivalent basis, but it was as effective as cisplatin when equitoxic dosages were administered in vivo to P388 leukaemia-bearing mice (%T/C = 209 and 211 for platinum-acyclovir and cisplatin, respectively). The platinum-acyclovir complex was also active against a cisplatin-resistant subline of the P388 leukaemia (%T/C = 140), thus suggesting a different mechanism of action. The DNA interaction properties (sequence specificity and interstrand cross-linking ability) of platinum-acyclovir were also investigated in comparison to those of cisplatin and [Pt(dien)Cl]+, an antitumour-inactive platinum-triamine compound. The results of this study point to a potential new drug endowed, at the same time, with antiviral and anticancer activity and characterized by DNA interaction properties different from those of cisplatin. PMID:18472776

  10. Synthesis of Optically Active Polystyrene Catalyzed by Monophosphine Pd Complexes.

    PubMed

    Jouffroy, Matthieu; Armspach, Dominique; Matt, Dominique; Osakada, Kohtaro; Takeuchi, Daisuke

    2016-07-11

    Cationic Pd(II) monophosphine complexes derived from α- and β-cyclodextrins (CDs) promote the homopolymerization of styrene under carbon monoxide pressure. Although reversible CO coordination takes place under catalytic conditions according to (13) C NMR studies with (13) C-enriched CO, both complexes catalyze the formation of CO-free styrene polymers. These macromolecules display optical activity as a result of the presence of stereoregular sequences within the overall atactic polymer. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Role of rs13117307 single nuclear polymorphism in the risk of uterine cervical cancer from Polish population and its impact on exocyst complex component 1 expression.

    PubMed

    Łaźniak, Sebastian; Roszak, Andrzej; Balcerek, Adam; Wareńczak-Florczak, Żaneta; Prokop, Edyta; Sowińska, Anna; Sotiri, Emianka; Tsibulski, Alexander; Sajdak, Stefan; Jagodziński, Pawel P

    2017-09-05

    We evaluated the role of NM_001024924.1:c.1330+1646C>T (rs13117307) single nucleotide polymorphism (SNP), situated in the intronic region of exocyst complex component 1 (EXCO1), in the development and spreading of cervical squamous cell carcinoma (SCC). Utilizing high resolution melting curve analysis, we analyzed this polymorphism in patients with cervical SCC (n=485) and controls (n=509) in the Polish Caucasian population. Logistic regression analysis was used to adjust for age, parity, oral contraceptive use, tobacco smoking, and menopausal status. The influence of this polymorphism on the expression of EXCO1 was assessed by reverse transcription and real-time quantitative PCR analysis. For all patients with SCC, the p trend value calculated for rs13117307 was statistically significant (ptrend=0.0158). The adjusted odds ratio (OR) for T/T vs. C/C was 1.434 (95 % CI 1.105-1.861, p=0.007). We also found a significant contribution of rs13117307 to tumor stages III, IV and grade of differentiation G3. Other contributors are parity, oral contraceptive use, smoking, and women of postmenopausal age. We observed significant upregulation of EXCO1 transcript levels in the non-cancerous cervical tissues in carriers of the T/T vs. C/C (p=0.016), as well as an increase in the EXCO1 transcript levels in the cervical SCC tissue in carriers of the T/T vs. C/C (p=0.029) and for T/T vs C/T (p=0.0032). The rs13117307 SNP variants may upregulate the transcription of EXCO1, as well as the risk of development and spreading of cervical SCC. Copyright © 2017. Published by Elsevier B.V.

  12. The Associations between RNA Splicing Complex Gene SF3A1 Polymorphisms and Colorectal Cancer Risk in a Chinese Population.

    PubMed

    Chen, Xiaohua; Du, Hua; Liu, Binjian; Zou, Li; Chen, Wei; Yang, Yang; Zhu, Ying; Gong, Yajie; Tian, Jianbo; Li, Feng; Zhong, Shan

    2015-01-01

    Aberrant alternative splicing included alterations in components of the mRNA splicing machinery often occurred in colon cancer. However, the role of SF3A1, one key component of the mRNA splicing machinery, on colorectal cancer (CRC) risk was still not elucidated. We performed a hospital-based case-control study containing 801 CRC patients and 817 cancer-free controls to examine the association between SF3A1 polymorphisms and CRC risk in a Chinese population. Four candidate SNPs (rs10376, rs5753073, rs2839998 and rs2074733) were selected based on bioinformatics analysis and previous findings. The results showed no significant associations between these SNPs and CRC risk (P > 0.05). Besides, the stratified analysis based on the smoking and alcohol use status obtained no statistically significant results. Our study was the first one to investigate the association between SF3A1 polymorphisms and CRC risk. The results suggested these four SNPs in SF3A1 were not associated with CRC risk in a Chinese population, however, further more studies are needed to confirm our findings.

  13. Plasminogen activator inhibitor-1 gene polymorphism in Iranian Azeri Turkish patients with FMF disease and its association with amyloidosis.

    PubMed

    Bonyadi, M; Shaghaghi, Z; Haghi, M; Dastgiri, S

    2013-01-01

    Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by intermittent episodes of fever with serositis, arthritis, or eriseplemya. Plasminogen activator inhibitor 1 (PAI-1) is a key element in the inhibition of fibrinolysis by inactivating tissue-type and urokinase-type plasminogen activators. We evaluated the association of PAI-1 -675 4G/5G polymorphism with the severity of FMF disease. For this purpose, 89 FMF patients with M694V homozygous mutation and 95 healthy controls from Iranian Azeri Turks were selected. Detection of this polymorphism was performed by polymerase chain reaction using allele-specific primers. No significant association was found between patients and control group. However, these data showed that FMF patients with M694V homozygous mutation carrying 4G/4G genotype have a reduced risk for development of pleuritis (odds ratios (OR) 0.36; 95 % confidence intervals (CI) 0.5-0.85; P value = 0.007) compared with 5G/5G homozygotes who have increased risk for development of amyloidosis (OR = 2.46; 95 %CI = 1.29-4.72; P value = 0.001), pleuritis (OR = 2.55; 95 %CI = 1.31-4.99; P value = 0.001), and fever (OR = 4.68; 95 %CI = 2.04-10.96; P value = 0.000). Furthermore, the allelic frequency of the 4G among the patients with pleuritis was significantly low (OR = 0.5, 95 % CI = 0.27-0.92, P value = 0.008). Our data suggest a protective role for the 4G allele against pleuritis in FMF patients with M694V homozygous mutation in this cohort. More evaluation of this polymorphism may be important and require further studies.

  14. Impact of the 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene on primary nephrotic syndrome.

    PubMed

    Luo, Yuezhong; Wang, Chao; Tu, Haitao

    2014-03-01

    The aim of the present study was to investigate whether the four guanosines (4G)/five guanosines (5G) polymorphism in the gene coding for plasminogen activator inhibitor-1 (PAI-1) affects the clinical features of primary nephrotic syndrome (PNS). A cohort of 200 biopsy-diagnosed PNS patients was studied, with 40 healthy subjects as controls. The PAI-1 gene polymorphism was detected by polymerase chain reaction and DNA sequencing. Associations between the PAI-1 4G/5G polymorphism and clinical features and pathological types of PNS were analyzed. The results indicated that the PAI-1 genotype distribution is significantly different between patients with PNS and healthy controls, with significantly higher numbers of the 4G/4G genotype and lower numbers of the 5G5G genotype detected in PNS patients compared to controls (both P<0.05). The frequency of the 4G allele was also significantly higher in PNS patients compared to healthy controls (P<0.01). Among the different pathological types of PNS, IgA nephropathy (IgAN) and membranous nephropathy (MN) were associated with significantly increased frequencies of the 4G/4G and 4G/5G genotypes, as well as of the 4G allele. The increased 4G frequency was also detected in patients with minimal change disease (MCD). Significantly increased international normalized ratio (INR) and prolonged activated partial thromboplastin time (APTT) were observed in 4G/4G compared to 5G/5G PNS subjects. The response to steroids was not significantly different among the three genotypes. In conclusion, the 4G allele of the PAI-1 gene appears to be associated with PNS, especially in MN and IgAN patients. These findings suggest that specific targeting may be required for the treatment of PNS patients with the 4G/4G genotype.

  15. Signal transducers and activators of transcription (STATs) gene polymorphisms related with susceptibility to rheumatic heart disease in north Indian population.

    PubMed

    Gupta, Usha; Mir, Snober S; Srivastava, Apurva; Garg, Naveen; Agarwal, Surendra K; Pande, Shantanu; Mittal, Balraj

    2014-09-01

    Rheumatic heart disease (RHD) is the most serious complication of heart that comprises inflammatory reactions in heart valves. Cytokines play a critical role in triggering inflammatory reactions and they activate the Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signaling pathway. Altered signals of STATs play important roles in the balance between proinflammatory and anti-inflammatory cytokines in inflammatory diseases. The aim of the present study was to investigate for the association of polymorphisms related with STAT genes, i.e. STAT3 (rs4796793 C/G) and STAT5b (rs6503691 C/T) with the pathogenesis of RHD. This case-control association study involved 300 healthy controls and 400 RHD patients from North Indian Population. We categorized RHD patients into two subgroups based on involvement of heart valves, mitral valve lesion alone (MVL), and combined valve lesions including mitral valve (CVL). Genotyping was done by RFLP/Taqman probes. We observed that STAT3 CG and GG genotypes were significantly associated with RHD (p=0.030 and p=0.014 respectively), STAT5b CT and TT genotypes were also significantly associated with RHD (p≤0.001). Haplotype analysis revealed that minor alleles of both the variants (Grs4796793Trs6503691) were significantly associated (p<0.0001) with increased risk of the disease susceptibility irrespective of gender or age of onset of the disease. However, the polymorphisms were not involved in severity of RHD as both MVL and CVL patients were equally affected. STAT Grs4796793Trs6503691 carriers may have reduced production of STAT3 leading to damage of heart valves. Thus, STAT genes polymorphisms may be useful markers for the identification of individuals with high risk of RHD in the susceptible population. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Peroxisome proliferator-activated receptor gamma (PPARG) rs1801282 C>G polymorphism is associated with cancer susceptibility in asians: an updated meta-analysis

    PubMed Central

    Wang, Yafeng; Chen, Yu; Jiang, Heping; Tang, Weifeng; Kang, Mingqiang; Liu, Tianyun; Guo, Zengqing; Ma, Zhiqiang

    2015-01-01

    Peroxisome proliferator-activated receptor gamma (PPARG) is related to inflammation and plays an important role in the development of cancer. PPARG rs1801282 C>G polymorphism might influence the risk of cancer by regulating production of PPARG gene. Hence, a comprehensive meta-analysis was conducted to explore the association of PPARG rs1801282 C>G polymorphism with cancer susceptibility. An extensive search of PubMed and Embase databases for all relevant publications was carried out. A total of 38 publications with 16,844 cancer cases and 23,736 controls for PPARG rs1801282 C>G polymorphism were recruited in our study. Our results indicated that PPARG rs1801282 C>G variants were associated with an increased cancer risk in Asian populations and gastric cancer. In summary, the findings suggest that PPARG rs1801282 C>G polymorphism may play a crucial role in malignant transformation and the development of cancer. PMID:26550180

  17. A Fractal Dimension Survey of Active Region Complexity

    NASA Technical Reports Server (NTRS)

    McAteer, R. T. James; Gallagher, Peter; Ireland, Jack

    2005-01-01

    A new approach to quantifying the magnetic complexity of active regions using a fractal dimension measure is presented. This fully-automated approach uses full disc MDI magnetograms of active regions from a large data set (2742 days of the SoHO mission; 9342 active regions) to compare the calculated fractal dimension to both Mount Wilson classification and flare rate. The main Mount Wilson classes exhibit no distinct fractal dimension distribution, suggesting a self-similar nature of all active regions. Solar flare productivity exhibits an increase in both the frequency and GOES X-ray magnitude of flares from regions with higher fractal dimensions. Specifically a lower threshold fractal dimension of 1.2 and 1.25 exists as a necessary, but not sufficient, requirement for an active region to produce M- and X-class flares respectively .

  18. A Fractal Dimension Survey of Active Region Complexity

    NASA Technical Reports Server (NTRS)

    McAteer, R. T. James; Gallagher, Peter; Ireland, Jack

    2005-01-01

    A new approach to quantifying the magnetic complexity of active regions using a fractal dimension measure is presented. This fully-automated approach uses full disc MDI magnetograms of active regions from a large data set (2742 days of the SoHO mission; 9342 active regions) to compare the calculated fractal dimension to both Mount Wilson classification and flare rate. The main Mount Wilson classes exhibit no distinct fractal dimension distribution, suggesting a self-similar nature of all active regions. Solar flare productivity exhibits an increase in both the frequency and GOES X-ray magnitude of flares from regions with higher fractal dimensions. Specifically a lower threshold fractal dimension of 1.2 and 1.25 exists as a necessary, but not sufficient, requirement for an active region to produce M- and X-class flares respectively .

  19. [Association between peroxisome proliferator-activated receptors gene polymorphism and essential hypertension].

    PubMed

    Lin, Yao; Gu, Shu-jun; Wu, Ming; Chen, Qiu; Zhou, Zheng-yuan; Yu, Hao; Zhang, Li-jun; Luo, Wen-shu; Guo, Zhi-rong

    2012-06-01

    To investigate the association between ten single nucleotide polymorphism (SNP) in the peroxisome proliferator-activated receptor (PPAR) α/δ/γ and essential hypertension (EH). Participants were recruited within the framework of a cohort populations survey from the PMMJS (Prevention of Multiple Metabolic Disorders and MS in Jiangsu Province) which was conducted in the urban community of Jiangsu province from 1999 to 2007. Eight hundred and twenty subjects (551 non-hypertensive subjects, 269 hypertensive subjects) were randomly selected but were not related to each other. Ten SNP (rs135539, rs1800206, rs4253778 of PPARα; rs2016520, rs9794 of PPARδ; rs10865710, rs1805192, rs4684847, rs709158 and rs3856806 of PPARγ) were selected from the HapMap database. χ(2) test was used to determine whether the whole population was in H-W genetic equilibrium. SHEsis software was used to examine the relations of SNP and linkage equilibrium. Logistic regression model was used to examine the association between ten SNP in the PPAR and EH. Difference on the distribution of four SNP genotypes including rs1800206, rs9794, rs10865710 and rs4684847 between high blood pressure and non-high blood pressure group, high systolic blood pressure (SBP) and normal SBP group, high diastolic blood pressure (DBP) and normal DBP group was significant (P < 0.05). After adjusting factors as age, sex, body mass index, fasting plasma glucose, high density lipoprotein cholesterol-C, high-fat diet and compared with wild-type gene carriers, the OR (95%CI) of objects with rs1800206 V allele appeared in high blood pressure, high SBP and high DBP were 0.60 (0.41 - 0.89), 0.57 (0.37 - 0.88) and 0.61 (0.39 - 0.96), respectively. The OR (95%CI) of objects with G allele of rs9794 were 0.63 (0.46 - 0.87), 0.51 (0.36 - 0.73) and 0.68 (0.47 - 1.01). The OR (95%CI) of objects with G allele of rs10865710 were 1.62 (1.19 - 2.20), 1.59 (1.14 - 2.22) and 1.53 (1.07 - 2.18), respectively. While the OR (95%CI) of

  20. Evidence of gene orthology and trans-species polymorphism, but not of parallel evolution, despite high levels of concerted evolution in the major histocompatibility complex of flamingo species.

    PubMed

    Gillingham, M A F; Courtiol, A; Teixeira, M; Galan, M; Bechet, A; Cezilly, F

    2016-02-01

    The major histocompatibility complex (MHC) is a cornerstone in the study of adaptive genetic diversity. Intriguingly, highly polymorphic MHC sequences are often not more similar within species than between closely related species. Divergent selection of gene duplicates, balancing selection maintaining trans-species polymorphism (TSP) that predate speciation and parallel evolution of species sharing similar selection pressures can all lead to higher sequence similarity between species. In contrast, high rates of concerted evolution increase sequence similarity of duplicated loci within species. Assessing these evolutionary models remains difficult as relatedness and ecological similarities are often confounded. As sympatric species of flamingos are more distantly related than allopatric species, flamingos represent an ideal model to disentangle these evolutionary models. We characterized MHC Class I exon 3, Class IIB exon 2 and exon 3 of the six extant flamingo species. We found up to six MHC Class I loci and two MHC Class IIB loci. As all six species shared the same number of MHC Class IIB loci, duplication appears to predate flamingo speciation. However, the high rate of concerted evolution has prevented the divergence of duplicated loci. We found high sequence similarity between all species regardless of codon position. The latter is consistent with balancing selection maintaining TSP, as under this mechanism amino acid sites under pathogen-mediated selection should be characterized by fewer synonymous codons (due to their common ancestry) than under parallel evolution. Overall, balancing selection maintaining TSP appears to result in high MHC similarity between species regardless of species relatedness and geographical distribution.

  1. Association between peroxisome proliferator-activated receptor-alpha, delta, and gamma polymorphisms and risk of coronary heart disease: A case-control study and meta-analysis.

    PubMed

    Qian, Yufeng; Li, Peiwei; Zhang, Jinjie; Shi, Yu; Chen, Kun; Yang, Jun; Wu, Yihua; Ye, Xianhua

    2016-08-01

    Risk of coronary heart disease (CHD) has been suggested to be associated with polymorphisms of peroxisome proliferator-activated receptors (PPARs), while the results were controversial. We aimed to systematically assess the association between PPAR polymorphisms and CHD risk. A case-control study with 446 subjects was conducted to evaluate the association between CHD risk and C161T polymorphism, which was of our special interest as this polymorphism showed different effects on risks of CHD and acute coronary syndrome (ACS). Meta-analyses were conducted to assess all PPAR polymorphisms. Either a fixed- or a random-effects model was adopted to estimate overall odds ratios (ORs). In the case-control study, T allele carriers of C161T polymorphism were not significantly associated with CHD risk (Odds ratio (OR) = 0.74, 95% confidence interval (CI) 0.47-1.15, P = 0.19), while T allele carriers showed higher risk of ACS (OR = 1.63, 95% CI 1.00-2.65, P = 0.048). The meta-analysis indicated that compared with CC homozygous, T allele carriers had lower CHD risk (OR = 0.69, 95% CI 0.59-0.82, P < 0.001) but higher ACS risk (OR = 1.43, 95% CI 1.09-1.87, P = 0.010). Three other polymorphisms were also found to be significantly associated with CHD risk under dominant model: PPAR-alpha intron 7G/C polymorphism (CC+GC vs GG, OR 1.42, 95% CI 1.13-1.78, P = 0.003), L162V polymorphism (VV+LV vs LL, OR 0.74, 95% CI 0.56-0.97, P = 0.031), and PPAR-delta +294T/C polymorphism (CC+TC vs TT, OR 1.51, 95% CI 1.12-2.05, P = 0.007). The results suggested that PPAR-alpha intron 7G/C and L162V, PPAR-delta +294T/C and PPAR-gamma C161T polymorphisms could affect CHD susceptibility, and C161T polymorphism might have different effects on CHD and ACS.

  2. Common polymorphisms in C3, factor B, and factor H collaborate to determine systemic complement activity and disease risk

    PubMed Central

    Heurich, Meike; Martínez-Barricarte, Ruben; Francis, Nigel J.; Roberts, Dawn L.; Rodríguez de Córdoba, Santiago; Morgan, B. Paul; Harris, Claire L.

    2011-01-01

    Common polymorphisms in complement alternative pathway (AP) proteins C3 (C3R102G), factor B (fBR32Q), and factor H (fHV62I) are associated with age-related macular degeneration (AMD) and other pathologies. Our published work showed that fBR32Q influences C3 convertase formation, whereas fHV62I affects factor I cofactor activity. Here we show how C3R102G (C3S/F) influences AP activity. In hemolysis assays, C3102G activated AP more efficiently (EC50 C3102G: 157 nM; C3102R: 191 nM; P < 0.0001). fB binding kinetics and convertase stability were identical, but native and recombinant fH bound more strongly to C3b102R (KD C3b102R: 1.0 μM; C3b102G: 1.4 μM; P < 0.0001). Accelerated decay was unaltered, but fH cofactor activity was reduced for C3b102G, favoring AP amplification. Combining disease “risk” variants (C3102G, fB32R, and fH62V) in add-back assays yielded sixfold higher hemolytic activity compared with “protective” variants (C3102R, fB32Q, and fH62I; P < 0.0001). These data introduce the concept of a functional complotype (combination of polymorphisms) defining complement activity in an individual, thereby influencing susceptibility to AP-driven disease. PMID:21555552

  3. The AIRE -230Y Polymorphism Affects AIRE Transcriptional Activity: Potential Influence on AIRE Function in the Thymus.

    PubMed

    Lovewell, Thomas R J; McDonagh, Andrew J; Messenger, Andrew G; Azzouz, Mimoun; Tazi-Ahnini, Rachid

    2015-01-01

    The autoimmune regulator (AIRE) is expressed in the thymus, particularly in thymic medullary epithelial cells (mTECs), and is required for the ectopic expression of a diverse range of peripheral tissue antigens by mTECs, facilitating their ability to perform negative selection of auto-reactive immature T-cells. The expression profile of peripheral tissue antigens is affected not only by AIRE deficiency but also with variation of AIRE activity in the thymus. Therefore we screened 591bp upstream of the AIRE transcription start site including AIRE minimal promoter for single nucleotide polymorphism (SNPs) and identified two SNPs -655R (rs117557896) and -230Y (rs751032) respectively. To study the effect of these variations on AIRE promoter activity we generated a Flp-In host cell line which was stably transfected with a single copy of the reporter vector. Relative promoter activity was estimated by comparing the luciferase specific activity for lysates of the different reporter AIRE promoter-reporter gene constructs including AIRE-655G AIRE-230C, AIRE-655G AIRE-230T and AIRE-655A AIRE-230C. The analysis showed that the commonest haplotype AIRE-655G AIRE-230C has the highest luciferase specific activity (p<0.001). Whereas AIRE-655G AIRE-230T has a luciferase specific activity value that approaches null. Both AIRE promoter polymorphic sites have one allele that forms a CpG methylation site which we determined can be methylated in methylation assays using the M.SssI CpG methyltransferase. AIRE-230Y is in a conserved region of the promoter and is adjacent to a predicted WT1 transcription factor binding site, suggesting that AIRE-230Y affects AIRE expression by influencing the binding of biochemical factors to this region. Our findings show that AIRE-655GAIRE-230T haplotype could dramatically alter AIRE transcription and so have an effect on the process of negative selection and affect susceptibility to autoimmune conditions.

  4. Spin crossover and polymorphism in a family of 1,2-bis(4-pyridyl)ethene-bridged binuclear iron(II) complexes. A key role of structural distortions.

    PubMed

    Matouzenko, Galina S; Jeanneau, Erwann; Verat, Alexander Yu; Bousseksou, Azzedine

    2011-10-07

    Two polymorphic modifications 1 and 3 of binuclear compound [{Fe(dpia)(NCS)(2)}(2)(bpe)] and pseudo-polymorphic modification [{Fe(dpia)(NCS)(2)}(2)(bpe)]·2CH(3)OH (2), where dpia = di-(2-picolyl)amine, bpe = 1,2-bis(4-pyridyl)ethene, were synthesized, and their structures, magnetic properties, and Mössbauer spectra were studied. Variable-temperature magnetic susceptibility measurements of three binuclear compounds show different types of magnetic behaviour. The complex 1 exhibits a gradual two-step spin crossover (SCO) suggesting the occurrence of the mixed [HS-LS] (HS: high spin, LS: low spin) pair at the plateau temperature (182 K), at which about 50% of the complexes undergoes a thermal spin conversion. The complex 2 displays an abrupt full one-step spin transition without hysteresis, centred at about 159 K. The complex 3 is paramagnetic over the temperature range 20-290 K. The single-crystal X-ray studies show that all three compounds are built up from the bpe-bridged binuclear molecules. The structure of 1 was solved for three spin isomers [HS-HS], [HS-LS], and [LS-LS] at three temperatures 300 K, 183 K, and 90 K. The crystal structures for 2 and 3 were determined for the [HS-HS] complexes at room temperature. The analysis of correlations between the structural characteristics and different types of magnetic behaviour for new 1-3 binuclear complexes, as well as for previously reported binuclear compounds, revealed that the SCO process (occurrence of full one-step, two-step, or partial (50%) SCO) is specified by the degree of distortion of the octahedral geometry of the [FeN(6)] core, caused by both packing and strain effects arising from terminal and/or bridging ligands. The comparison of the magnetic properties and the networks of intra- and inter-molecular interactions in the crystal lattice for the family of related SCO binuclear compounds suggests that the intermolecular interactions play a predominant role in the cooperativeness of the spin transition

  5. Single-nucleotide polymorphisms and activity analysis of the promoter and enhancer of the pig lactase gene.

    PubMed

    Du, Hai-Ting; Zhu, Hong-Yan; Wang, Jia-Mei; Zhao, Wei; Tao, Xiao-Li; Ba, Cai-Feng; Tian, Yu-Min; Su, Yu-Hong

    2014-07-15

    Lactose intolerance in northern Europeans is strongly associated with a single-nucleotide polymorphism (SNP) located 14 kb upstream of the human lactase gene: -13,910 C/T. We examined whether SNPs in the 5' flanking region of the pig lactase gene are similar to those in the human gene and whether these polymorphisms play a functional role in regulating pig lactase gene expression. The 5' flanking region of the lactase gene from several different breeds of pigs was cloned and analyzed for gene regulatory activity of a luciferase reporter gene. One SNP was found in the enhancer region (-797 G/A) and two were found in the promoter region (-308G/C and -301 A/G). The promoter C-308,G-301(Pro-CG) strongly promotes the expression of the lactase gene, but the promoter G-308,A-301(Pro-GA) does not. The enhancer A-797(Enh-A) genotype for Pro-GA can significantly enhance promoter activity, but has an inhibitory effect on Pro-CG. The Enhancer G-797(Enh-G) has a significant inhibitory effect on both promoters. In conclusion, the order of effectiveness on the pig lactase gene is Enh-A+Pro-GA>Enh-A/G+Pro-CG>Enh-G+Pro-GA. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. Synthesis and cytotoxic activity of metallic complexes of lawsone.

    PubMed

    Oramas-Royo, Sandra; Torrejón, Concepción; Cuadrado, Irene; Hernández-Molina, Rita; Hortelano, Sonsoles; Estévez-Braun, Ana; de Las Heras, Beatriz

    2013-05-01

    In the present study, a series of metallic complexes of the 1,4-naphthoquinone lawsone (2-6) were synthesized and evaluated for potential cytotoxicity in a mouse leukemic macrophagic RAW 264.7 cell line. Cell viability was determined by the MTT assay. Significant growth inhibition was observed for the copper complex (4) with an IC(50) value of 2.5 μM. This compound was selected for further evaluation of cytotoxic activity on several human cancer cells including HT-29 (human colorectal adenocarcinoma), HepG2 (human hepatocellular carcinoma) and HeLa, (human cervical adenocarcinoma cells). Significant cell viability decrease was also observed in HepG2 cells. The apoptotic potential of this complex was evaluated in these cells. Compound 4 induced apoptosis by a mechanism that involves the activation of caspases 3, 8 and 9 and modulation of apoptotic-related proteins such as Bax, Bad, and p53. These results indicate that metal complexes of lawsone derivatives, in particular compound 4, might be used for the design of new antitumoral agents. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Encapsulation of active ingredients in polysaccharide-protein complex coacervates.

    PubMed

    Devi, Nirmala; Sarmah, Mandip; Khatun, Bably; Maji, Tarun K

    2017-01-01

    Polysaccharide-protein complex coacervates are amongst the leading pair of biopolymer systems that has been used over the past decades for encapsulation of numerous active ingredients. Complex coacervation of polysaccharides and proteins has received increasing research interest for the practical application in encapsulation industry since the pioneering work of complex coacervation by Bungenburg de Jong and co-workers on the system of gelatin-acacia, a protein-polysaccharide system. Because of the versatility and numerous potential applications of these systems essentially in the fields of food, pharmaceutical, cosmetics and agriculture, there has been intense interest in recent years for both fundamental and applied studies. Precisely, the designing of the micronscale and nanoscale capsules for encapsulation and control over their properties for practical applications garners renewed interest. This review discusses on the overview of polysaccharide-protein complex coacervates and their use for the encapsulation of diverse active ingredients, designing and controlling of the capsules for delivery systems and developments in the area. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Task complexity modulates pilot electroencephalographic activity during real flights.

    PubMed

    Di Stasi, Leandro L; Diaz-Piedra, Carolina; Suárez, Juan; McCamy, Michael B; Martinez-Conde, Susana; Roca-Dorda, Joaquín; Catena, Andrés

    2015-07-01

    Most research connecting task performance and neural activity to date has been conducted in laboratory conditions. Thus, field studies remain scarce, especially in extreme conditions such as during real flights. Here, we investigated the effects of flight procedures of varied complexity on the in-flight EEG activity of military helicopter pilots. Flight procedural complexity modulated the EEG power spectrum: highly demanding procedures (i.e., takeoff and landing) were associated with higher EEG power in the higher frequency bands, whereas less demanding procedures (i.e., flight exercises) were associated with lower EEG power over the same frequency bands. These results suggest that EEG recordings may help to evaluate an operator's cognitive performance in challenging real-life scenarios, and thus could aid in the prevention of catastrophic events.

  9. Activity-Dependent Neuronal Model on Complex Networks

    PubMed Central

    de Arcangelis, Lucilla; Herrmann, Hans J.

    2012-01-01

    Neuronal avalanches are a novel mode of activity in neuronal networks, experimentally found in vitro and in vivo, and exhibit a robust critical behavior: these avalanches are characterized by a power law distribution for the size and duration, features found in other problems in the context of the physics of complex systems. We present a recent model inspired in self-organized criticality, which consists of an electrical network with threshold firing, refractory period, and activity-dependent synaptic plasticity. The model reproduces the critical behavior of the distribution of avalanche sizes and durations measured experimentally. Moreover, the power spectra of the electrical signal reproduce very robustly the power law behavior found in human electroencephalogram (EEG) spectra. We implement this model on a variety of complex networks, i.e., regular, small-world, and scale-free and verify the robustness of the critical behavior. PMID:22470347

  10. Pyridylphosphinate metal complexes: synthesis, structural characterisation and biological activity.

    PubMed

    Cross, Jasmine M; Gallagher, Natalie; Gill, Jason H; Jain, Mohit; McNeillis, Archibald W; Rockley, Kimberly L; Tscherny, Fiona H; Wirszycz, Natasha J; Yufit, Dmitry S; Walton, James W

    2016-08-09

    For the first time, a series of 25 pseudo-octahedral pyridylphosphinate metal complexes (Ru, Os, Rh, Ir) has been synthesised and assessed in biological systems. Each metal complex incorporates a pyridylphosphinate ligand, a monodentate halide and a capping η(6)-bound aromatic ligand. Solid- and solution-state analyses of two complexes reveal a structural preference for one of a possible two diastereomers. The metal chlorides hydrolyse rapidly in D2O to form a 1 : 1 equilibrium ratio between the aqua and chloride adducts. The pKa of the aqua adduct depends upon the pyridyl substituent and the metal but has little dependence upon the phosphinate R' group. Toxicity was measured in vitro against non-small cell lung carcinoma H460 cells, with the most potent complexes reporting IC50 values around 50 μM. Binding studies with selected amino acids and nucleobases provide a rationale for the variation in toxicity observed within the series. Finally, an investigation into the ability of the chelating amino acid l-His to displace the phosphinate O-metal bond shows the potential for phosphinate complexes to act as prodrugs that can be activated in the intracellular environment.

  11. Interactive flare sites within an active region complex

    NASA Technical Reports Server (NTRS)

    Poletto, G.; Gary, G. A.; Machado, M. E.

    1993-01-01

    We examine here a set of images of an active region complex, acquired on June 24-25, 1980, by the Hard X-ray Imaging Spectrometer on SMM, with the purpose of establishing whether there was any interplay between the frequent activity observed at different sites in the activity center and, in such a case, how the interaction was established. By analyzing both quiet and active orbits we show that, as a rule, activity originating in one region triggers the other region's activity. However, we find little unambiguous evidence for the presence of large-scale interconnecting loops. A comparison of X-ray images with magnetic field observations suggested that we interpret the active region behavior in terms of the interaction between different loop systems, in a scenario quite analogous to the interacting bipole representation of individual flares. We conclude that active region interplay provides an easily observable case to study the time-dependent topology and the mechanisms for the spreading of activity in transient events over all energy scales.

  12. Clinical medicine between science, ethics and economy: a complex activity.

    PubMed

    Federspil, Giovanni

    2004-01-01

    Until recently the common opinion was that medicine was substantially a natural science. In recent years, this has completely changed because two non-naturalistic disciplines have become part of the physician's activity; ethics and economy. These new disciplines have evidenced many problems to which doctors did not pay much attention before; however, they had an impact on the clinician's sensibility. At present, clinical medicine represents a complex knowledge as well as an activity: it is both a "historical" and a "technological" science characterized by a specific goal, the recovery or maintenance of health, and by a series of values.

  13. Superoxide production is inversely related to complex I activity in inherited complex I deficiency.

    PubMed

    Verkaart, Sjoerd; Koopman, Werner J H; van Emst-de Vries, Sjenet E; Nijtmans, Leo G J; van den Heuvel, Lambertus W P J; Smeitink, Jan A M; Willems, Peter H G M

    2007-03-01

    Deficiency of NADH:ubiquinone oxidoreductase or complex I (CI) is the most common cause of disorders of the oxidative phosphorylation system in humans. Using life cell imaging and blue-native electrophoresis we quantitatively compared superoxide production and CI amount and activity in cultured skin fibroblasts of 7 healthy control subjects and 21 children with inherited isolated CI deficiency. Thirteen children had a disease causing mutation in one of the nuclear-encoded CI subunits, whereas in the remainder the genetic cause of the disease is not yet established. Superoxide production was significantly increased in all but two of the patient cell lines. An inverse relationship with the amount and residual activity of CI was observed. In agreement with this finding, rotenone, a potent inhibitor of CI activity, dose-dependently increased superoxide production in healthy control cells. Also in this case an inverse relationship with the residual activity of CI was observed. In sharp contrast, however, rotenone did not decrease the amount of CI. The data presented show that superoxide production is increased in inherited CI deficiency and that this increase is primarily a consequence of the reduction in cellular CI activity and not of a further leakage of electrons from mutationally malformed complexes.

  14. Geometric complexity is increased in in vitro activated platelets.

    PubMed

    Bianciardi, Giorgio

    2015-06-01

    This article investigates the use of computerized fractal analysis for objective characterization of the complexity of platelets in vitro stimulated by low level thrombin (0.02 U mL(-1) ), collected from healthy individuals and observed by means of transmission electron microscopy. Platelet boundaries were extracted by means of automatically image analysis. Local fractal dimension was evaluated by the box-counting technique (measure of geometric complexity of the platelet outline). The results showed that the platelet boundary is fractal when observed by transmission electron microscopy and that, after an in vitro platelet activation test, the shape of platelets present increased geometric complexity in comparison to the no stimulated platelets (P < 0.001), with 100% correct classification. Computerized fractal analysis of platelet shape by transmission electron microscopy can provide accurate, quantitative, data to study platelet activation. The results may play important roles in the evaluation of the platelets status in pathological conditions, like as atherosclerosis and diabetes mellitus, where in in vivo activated platelets have been described.

  15. Effect of bovine ABCG2 Y581S polymorphism on concentrations in milk of enrofloxacin and its active metabolite ciprofloxacin.

    PubMed

    Otero, J A; García-Mateos, D; de la Fuente, A; Prieto, J G; Álvarez, A I; Merino, G

    2016-07-01

    The ATP-binding cassette transporter G2 (ABCG2) is involved in the secretion of several drugs into milk. The bovine Y581S ABCG2 polymorphism increases the secretion into milk of the fluoroquinolone danofloxacin in Holstein cows. Danofloxacin and enrofloxacin are the fluoroquinolones most widely used in veterinary medicine. Both enrofloxacin (ENRO) and its active metabolite ciprofloxacin (CIPRO) reach milk at relatively high concentrations. The aim of this work was to study the effect of the bovine Y581S ABCG2 polymorphism on in vitro transport as well as on concentrations in plasma and in milk of ENRO and CIPRO. Experiments using cells overexpressing bovine ABCG2 showed the effects of ABCG2 on the transport of CIPRO, demonstrating more efficient in vitro transport of this antimicrobial by the S581 variant as compared with the Y581 variant. Animal studies administering 2.5mg/kg of ENRO subcutaneously to Y/Y 581 and Y/S 581 cows revealed that concentrations in plasma of ENRO and CIPRO were significantly lower in Y/S animals. Regardless of the genotype, the antimicrobial profile in milk after the administration of ENRO was predominantly of CIPRO. With respect to the genotype effects on the amounts of drugs present in milk, AUC0-24 values were more than 1.2 times higher in Y/S cows for ENRO and 2.2 times for CIPRO, indicating a greater capacity of Y581S to transfer these drugs into milk. These results emphasize the clinical relevance of this polymorphism as a factor affecting the concentrations in plasma and in milk of drugs of importance in veterinary medicine.

  16. Association of polymorphisms of peroxisome proliferator activated receptors in early and late onset of type 2 diabetes mellitus.

    PubMed

    Raj, Resal; Bhatti, Jasvinder Singh; Bhadada, Sanjay Kumar; Ramteke, Pramod W

    2017-03-06

    Genetic variation of disease susceptible genes is different in different ethnic groups and there is an evidence of association of polymorphisms of Peroxisome Proliferator Activated Receptors (PPARs) in Type 2 Diabetes Mellitus (T2DM). This research analyses the association of PPARs in early and late onset of T2DM in North Indian Population (NIP). Total of 703 subjects were recruited from north of India and subjects were further divided into subjects of early onset (less than 25 years of onset, 26 T2DM and 26 controls) and late onset (more than 25 years of onset, 326 T2DM and 325 controls). The onset of T2DM begins from 15 years and continues further to maximum T2DM subjects to the age of 50 (76% of T2DM). High BMI and WHR, high blood pressure leading to early onset of hypertension, early mortality due to T2DM (7% of T2DM is above 75 years and 3% of T2DM has 20 years duration of onset) and high hyperglycemic NIP were the few outcomes of this research. There is a strong association of PPAR γ, PPAR α and PPAR δ genes on the susceptibility of T2DM in late onset but not with the early onset of T2DM subjects in North Indian Population: Dual association of PPAR γ was observed with its genotype G/G (Ala/Ala) favoring protection against T2DM and genotype C/C (Pro/Pro) favoring susceptibility to T2DM. Association of intron7 polymorphism of PPAR α and +T294C polymorphism of PPAR δ on the susceptibility to T2DM requires further analysis. Copyright © 2017 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  17. Gender-specific association of the plasminogen activator inhibitor-1 4G/5G polymorphism with central arterial blood pressure.

    PubMed

    Björck, Hanna M; Eriksson, Per; Alehagen, Urban; De Basso, Rachel; Ljungberg, Liza U; Persson, Karin; Dahlström, Ulf; Länne, Toste

    2011-07-01

    The functional plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism has previously been associated with hypertension. In recent years, central blood pressure, rather than brachial has been argued a better measure of cardiovascular damage and clinical outcome. The aim of this study was to investigate the possible influence of the 4G/5G polymorphism on central arterial blood pressure in a cohort of elderly individuals. We studied 410 individuals, 216 men and 194 women, aged 70-88. Central pressures and pulse waveforms were calculated from the radial artery pressure waveform by the use of the SphygmoCor system and a generalized transfer function. Brachial pressure was recorded using oscillometric technique (Dinamap, Critikon, Tampa, FL). PAI-1 antigen was determined in plasma. The results showed that central pressures were higher in women carrying the PAI-1 4G/4G genotype compared to female carriers of the 5G/5G genotype, (P = 0.025, P = 0.002, and P = 0.002 for central systolic-, diastolic-, and mean arterial pressure, respectively). The association remained after adjustment for potentially confounding factors related to hypertension. No association of the PAI-1 genotype with blood pressure was found in men. Multiple regression analysis revealed an association between PAI-1 genotype and plasma PAI-1 levels (P = 0.048). Our findings show a gender-specific association of the PAI-1 4G/5G polymorphism with central arterial blood pressure. The genotype effect was independent of other risk factors related to hypertension, suggesting that impaired fibrinolytic potential may play an important role in the development of central hypertension in women.

  18. Plasminogen activator inhibitor-1 4G/5G polymorphism and ischemic stroke risk: a meta-analysis in Chinese population.

    PubMed

    Cao, Yuezhou; Chen, Weixian; Qian, Yun; Zeng, Yanying; Liu, Wenhua

    2014-12-01

    The guanosine insertion/deletion polymorphism (4G/5G) of plasminogen activator inhibitor-1 (PAI-1) gene has been suggested as a risk factor for ischemic stroke (IS), but direct evidence from genetic association studies remains inconclusive even in Chinese population. Therefore, we performed a meta-analysis to evaluate this association. All of the relevant studies were identified from PubMed, Embase, Chinese National Knowledge Infrastructure database and Chinese Wanfang database up to September 2013. Statistical analyses were conducted with Revman 5.2 and STATA 12.0 software. Odds ratio (OR) with 95% confidence interval (CI) values were applied to evaluate the strength of the association. Heterogeneity was evaluated by Q-test and the I² statistic. The Begg's test and Egger's test were used to assess the publication bias. A significant association and a borderline association between the PAI-1 4G/5G polymorphism and IS were found under the recessive model (OR = 1.639, 95% CI = 1.136-2.364) and allelic model (OR = 1.256, 95% CI = 1.000-1.578), respectively. However, no significant association was observed under homogeneous comparison model (OR = 1.428, 95% CI = 0.914-2.233), heterogeneous comparison model (OR = 0.856, 95% CI = 0.689-1.063) and dominant model (OR = 1.036, 95% CI = 0.846-1.270). This meta-analysis suggested that 4G4G genotype of PAI-1 4G/5G polymorphism might be a risk factor for IS in the Chinese population.

  19. Peroxisome proliferator-activated receptors alpha and gamma2 polymorphisms in nonalcoholic fatty liver disease: a study in Brazilian patients.

    PubMed

    Domenici, Fernanda Aparecida; Brochado, Maria José Franco; Martinelli, Ana de Lourdes Candolo; Zucoloto, Sergio; da Cunha, Selma Freire de Carvalho; Vannucchi, Helio

    2013-10-25

    Non-alcoholic fatty liver disease (NAFLD) refers to the accumulation of hepatic steatosis in the absence of excess alcohol consumption. The pathogenesis of fatty liver disease and steatohepatitis (NASH) is not fully elucidated, but the common association with visceral obesity, hyperlipidemia, hypertension and type 2 diabetes mellitus (T2DM) suggests that it is the hepatic manifestation of metabolic syndrome. Peroxisome proliferator-activated receptor PPARα and PPARγ are members of a family of nuclear receptors involved in the metabolism of lipids and carbohydrates, adipogenesis and sensitivity to insulin. The objective of this study was to analyze the polymorphisms Leu162Val of PPARα and Pro12Ala of PPARγ as genetic risk factors for the development and progression of NAFLD. One hundred and three NAFLD patients (89 NASH, 14 pure steatosis) and 103 healthy volunteers were included. Single nucleotide polymorphisms (SNPs) Leu162Val and Pro12Ala were analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). NASH patients presented higher BMI, AST and prevalence of T2DM than patients with pure steatosis. A higher prevalence of 12Ala allele was observed in the NASH Subgroup when compared to Control Group. When we grouped NASH and Steatosis Subgroups (NAFLD), we found lower serum glucose and more advanced fibrosis in the Leu162Val SNP. On the other hand, there was no statistical difference in clinical, laboratorial and histological parameters according to the Pro12Ala SNP. We documented a lower prevalence of 12Ala allele of gene PPARγ in the NASH Subgroup when compared to Control Group. In NAFLD patients, there were no associations among the occurrence of Pro12Ala SNP with clinical, laboratorial and histological parameters. We also documented more advanced fibrosis in the Leu162Val SNP. The obtained data suggest that Pro12Ala SNP may result in protection against liver injury and that Leu162Val SNP may be involved in the

  20. Influences of a DRD2 polymorphism on updating of long-term memory representations and caudate BOLD activity: magnification in aging.

    PubMed

    Persson, Jonas; Rieckmann, Anna; Kalpouzos, Grégoria; Fischer, Håkan; Bäckman, Lars

    2015-04-01

    A number of genetic polymorphisms are related to individual differences in cognitive performance. Striatal dopamine (DA) functions, associated with cognitive performance, are linked to the TaqIA polymorphism of the DRD2/ANKK1 gene. In humans, presence of an A1 allele of the DRD2/ANKK1-TaqIA polymorphism is related to reduced density of striatal DA D2 receptors. The resource-modulation hypothesis assumes that aging-related losses of neurochemical and structural brain resources modulate the extent to which genetic variations affect cognitive functioning. Here, we tested this hypothesis using functional MRI during long-term memory (LTM) updating in younger and older carriers and noncarriers of the A1-allele of the TaqIa polymorphism. We demonstrate that older A1-carriers have worse memory performance, specifically during LTM updating, compared to noncarriers. Moreover, A1-carriers exhibited less blood oxygen level-dependent (BOLD) activation in left caudate nucleus, a region critical to updating. This effect was only seen in older adults, suggesting magnification of genetic effects on functional brain activity in aging. Further, a positive relationship between caudate BOLD activation and updating performance among non-A1 carriers indicated that caudate activation was behaviorally relevant. These results demonstrate a link between the DRD2/ANKK1-TaqIA polymorphism and neurocognitive deficits related to LTM updating, and provide novel evidence that this effect is magnified in aging.

  1. Structural complexities in the active layers of organic electronics.

    PubMed

    Lee, Stephanie S; Loo, Yueh-Lin

    2010-01-01

    The field of organic electronics has progressed rapidly in recent years. However, understanding the direct structure-function relationships between the morphology in electrically active layers and the performance of devices composed of these materials has proven difficult. The morphology of active layers in organic electronics is inherently complex, with heterogeneities existing across multiple length scales, from subnanometer to micron and millimeter range. A major challenge still facing the organic electronics community is understanding how the morphology across all of the length scales in active layers collectively determines the device performance of organic electronics. In this review we highlight experiments that have contributed to the elucidation of structure-function relationships in organic electronics and also point to areas in which knowledge of such relationships is still lacking. Such knowledge will lead to the ability to select active materials on the basis of their inherent properties for the fabrication of devices with prespecified characteristics.

  2. MCP-1 -2518 A/G functional polymorphism is associated with increased susceptibility to active pulmonary tuberculosis in Tunisian patients.

    PubMed

    Ben-Selma, Walid; Harizi, Hedi; Boukadida, Jalel

    2011-11-01

    Monocyte chemoattractant protein-1 (MCP-1) plays crucial role in protective immunity against Mycobacterium tuberculosis (MT). In this study, we examined whether single nucleotide polymorphism (SNP) -2518 A/G (rs 1024611) of MCP-1 affect the susceptibility to active tuberculosis (TB) in Tunisian populations. Genomic DNA from patients with active TB (168 cases of pulmonary TB and 55 cases of extrapulmonary TB) and ethnically controls (150 cases) was genotyped for the MCP-1 -2518 A/G SNP by polymerase chain reaction fragment length polymorphism (PCR-RFLP). We observed that -2518 G allele and GG genotype (high MCP-1 producer) frequencies were significantly more elevated in active pulmonary TB group in comparison to control group [34 vs. 22%; P = 0.0007; 15 vs. 5%, P corrected for the number of genotypes (Pc) = 0.015; respectively]. Additionally, they were associated with increased risk development of this clinical form of TB [odds ratio (OR) = 1.83, 95% confidence intervals (CI) = 1.26-2.66; OR = 3.1, 95% CI = 1.28-7.76; respectively]. However, wild type allele -2518 A and AA genotype were over-represented in control group (78 and 62%) and seem to be protective factors against TB. Moreover, -2518 AA genotype was more frequent in control group and was associated with resistance against development of active pulmonary TB (OR = 0.56, 95% CI = 0.35-0.89, Pc = 0.03). Our findings confirm the key role of -2518 A/G SNP of MCP-1 and support its association with resistance/susceptibility to the development of active pulmonary TB in the Tunisian population.

  3. Polymerase chain reaction-single strand conformation polymorphism analyses of nuclear and chloroplast DNA provide evidence for recombination, multiple introductions and nascent speciation in the Caulerpa taxifolia complex.

    PubMed

    Meusnier, I; Valero, M; Destombe, C; Godé, C; Desmarais, E; Bonhomme, F; Stam, W T; Olsen, J L

    2002-11-01

    Independent lines of evidence support an Australian origin for the Mediterranean populations of the tropical alga Caulerpa taxifolia. To complement previous biogeographical studies based on nuclear rDNA internal transcribed spacer (ITS), a new chloroplast marker was developed--the cp 16S rDNA intron-2. Sequence variability for both nuclear and chloroplast markers were assessed in 110 individuals using single strand conformation polymorphism. Comparison of intrapopulation genetic diversity between invasive Mediterranean and 'native' Australian populations revealed the occurrence of two divergent and widespread clades. The first clade grouped nontropical invasive populations with inshore-mainland populations from Australia, while the second clustered all offshore-island populations studied so far. Despite our finding of nine distinct nuclear and five distinct chloroplast profiles, a single nucleocytoplasmic combination was characteristic of the invasive populations and sexual reproduction was found to be very rare. C. taxifolia is clearly a complex of genetically and ecologically differentiated sibling species or subspecies.

  4. Paraoxonase 1 (PON1) gene-108C>T and p.Q192R polymorphisms and arylesterase activity of the enzyme in patients with dementia.

    PubMed

    Bednarska-Makaruk, Małgorzata Ewa; Krzywkowski, Tomasz; Graban, Alla; Lipczyńska-Łojkowska, Wanda; Bochyńska, Anna; Rodo, Maria; Wehr, Hanna; Ryglewicz, Danuta Krystyna

    2013-01-01

    Paraoxonase 1 (PON1) activity was determined using phenylacetate as substrate (arylesterase activity) in 304 individuals with dementia--136 recognised as probable Alzheimer's disease (AD), 64 as dementia of vascular origin (VaD) and 104 as mixed dementia (MD) and in 129 persons without symptoms of dementia and in a good general health. -108C>T polymorphism in the PON1 gene promoter and p.Q192R polymorphism in the coding region were identified. PON1 activity was significantly lower in demented patients as compared with controls particularly in dementia of a neurodegenerative character (AD and MD). The prevalence of PON1-108T allele carriers was significantly higher in the AD group than in controls. The frequencies of the p.Q192R genotypes did not differ significantly between the investigated groups. An association of the rare T-R haplotype with dementia, particularly with dementia of the neurodegenerative type, was found. Multivariate regression analysis showed a significant association of PON1 activity with PON1 -108C>T and p.Q192R polymorphisms. The influence not only of promoter -108C>T, but also of p.Q192R polymorphism on PON1 arylesterase activity was observed. One has to admit that this kind of polymorphism does not preclude interference with the enzyme activity. It could be concluded that the PON1 gene promoter polymorphism plays an additional role in Alzheimer's disease development. It seems however that PON1 activity has a dominating influence on the dementia risk.

  5. Influence of decreased fibrinolytic activity and plasminogen activator inhibitor-1 4G/5G polymorphism on the risk of venous thrombosis.

    PubMed

    Vuckovic, Biljana A; Djeric, Mirjana J; Tomic, Branko V; Djordjevic, Valentina J; Bajkin, Branislav V; Mitic, Gorana P

    2017-08-01

    : Objective of our study is to determine whether decreased fibrinolytic activity or plasminogen activator inhibitor (PAI)-1 4G/5G polymorphism influence the risk of venous thrombosis.Our case-control study included 100 patients with venous thrombosis, and 100 random controls. When patients were compared with random controls, unconditional logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs).Decreased fibrinolytic activity yielded a 2.7-fold increase in risk for venous thrombosis than physiological fibrinolytic activity (OR 2.70; 95% CI 1.22-5.98), when comparing patients with random controls. Adjustment for several putative confounders did not change the estimate (OR 3.02; 95% CI 1.26-7.22). Analysis of venous thrombotic risk influenced by PAI-1 genotype, showed no influence of PAI-1 4G/5G gene variant in comparison with 5G/5G genotype (OR 0.57 95% CI; 0.27-1.20).Decreased fibrinolytic activity increased, whereas PAI-1 4G/5G polymorphism did not influence venous thrombosis risk in this study.

  6. CLYBL is a polymorphic human enzyme with malate synthase and β-methylmalate synthase activity

    PubMed Central

    Strittmatter, Laura; Li, Yang; Nakatsuka, Nathan J.; Calvo, Sarah E.; Grabarek, Zenon; Mootha, Vamsi K.

    2014-01-01

    CLYBL is a human mitochondrial enzyme of unknown function that is found in multiple eukaryotic taxa and conserved to bacteria. The protein is expressed in the mitochondria of all mammalian organs, with highest expression in brown fat and kidney. Approximately 5% of all humans harbor a premature stop polymorphism in CLYBL that has been associated with reduced levels of circulating vitamin B12. Using comparative genomics, we now show that CLYBL is strongly co-expressed with and co-evolved specifically with other components of the mitochondrial B12 pathway. We confirm that the premature stop polymorphism in CLYBL leads to a loss of protein expression. To elucidate the molecular function of CLYBL, we used comparative operon analysis, structural modeling and enzyme kinetics. We report that CLYBL encodes a malate/β-methylmalate synthase, converting glyoxylate and acetyl-CoA to malate, or glyoxylate and propionyl-CoA to β-methylmalate. Malate synthases are best known for their established role in the glyoxylate shunt of plants and lower organisms and are traditionally described as not occurring in humans. The broader role of a malate/β-methylmalate synthase in human physiology and its mechanistic link to vitamin B12 metabolism remain unknown. PMID:24334609

  7. Heredity mode of genetic polymorphism in aldehyde oxidase activity in Donryu strain rats.

    PubMed

    Adachi, M; Itoh, K; Abe, H; Tanaka, Y

    2008-01-01

    Donryu strain rats show genetic polymorphisms in the aldehyde oxidase gene, resulting in the phenotypic expression of ultrarapid metabolizers with homozygous nucleotide sequences (337G, 2604C), extensive metabolizers with heterozygous nucleotide sequences (377G/A, 2604C/T), and poor metabolizers with homozygous nucleotide sequences (377A, 2604T). In the mating experiments the ratio of the number of ultrarapid metabolizers, extensive metabolizers, and poor metabolizers rats in the F1 generation from the heterozygous F0 extensive metabolizers male and female rats was roughly 0.6 : 1.5 : 1, and the ratio converged to approximately 1 : 2 : 1 in the F2 generation from the heterozygous F1 extensive metabolizers male and female rats. On the contrary, all the F2 generation from homozygous F1 ultrarapid metabolizers male and female rats or from homozygous F1 poor metabolizers male and female rats had the ultrarapid metabolizers or the poor metabolizers genotypes and phenotypes. The genotypes completely agreed with the phenotypes in all individuals of F0, F1, and F2 generations. The results indicate that the genetic polymorphism of aldehyde oxidase in Donryu strain rats obeys Mendelian heredity. The reason for a low ratio of the ultrarapid metabolizers rats in the commercially available Donryu strain rats - not more than several per cent - compared with the ratio expected from the Mendelian rule is unknown.

  8. Distribution and genotype frequency of the C1431T and pro12ala polymorphisms of the peroxisome proliferator activator receptor gamma gene in an Iranian population.

    PubMed

    Rooki, Hassan; Haerian, Monir-Sadat; Azimzadeh, Pedram; Ebrahimi, Mahmoud; Mirhafez, Reza; Ferns, Gordon; Ghayour-Mobarhan, Majid; Zali, Mohammad-Reza

    2013-10-01

    Peroxisome proliferator activator receptor gamma (PPARγ) is a nuclear transcription factor regulating multiple genes involved in cell growth, differentiation, carbohydrate and lipid metabolism and energy production. Several genetic variations in the PPARγ gene have been identified to be associated with diabetes, obesity, dyslipidemia, insulin resistance, metabolic syndrome and coronary artery disease. The present study was designed to explore the distribution of two common single nucleotide polymorphisms of the PPARγ gene (C1431T and Pro12Ala) in an Iranian population. Genotype frequencies for these two polymorphisms were compared for 160 healthy Iranian individuals with reports from other populations. The Genotyping was performed using real-time polymerase chain reaction. The genotype distribution of the C1431T PPARγ polymorphism was 0.869 for the CC genotype, 0.119 for the CT genotype and 0.013 for uncommon TT genotype. Allelic frequencies were 0.93 for C and 0.07 for T allele respectively. For the Pro12Ala polymorphism of PPARγ gene, genotypic distributions and allelic frequencies were, 0.813 for CC, 0.181 for CG and 0.06 for GG and 0.903 for C and 0.097 for G respectively. Allelic and genotypic frequencies for both polymorphisms of PPARγ gene were in Hardy-Weinberg equilibrium. Iran is a country with an ethnically diverse population and a comparison of allelic and genotypic frequencies of PPARγ C1431T and Pro12Ala polymorphisms between our population and others showed significant differences.

  9. Characterization and biological activity of Solidago canadensis complex.

    PubMed

    Šutovská, M; Capek, P; Kocmálová, M; Fraňová, S; Pawlaczyk, I; Gancarz, R

    2013-01-01

    Polyphenolic-polysaccharide-protein complex has been isolated from flowers of Solidago canadensis L. by hot alkaline extraction procedure. Compositional analyses of S canadensis complex revealed the presence of carbohydrates (43 wt%), protein (27 wt%), phenolics (12 wt%), uronic acids (10 wt%) and inorganic material (8 wt%). The carbohydrate part was rich in neutral sugars (81 wt%) while uronids were determined in lower amount (19 wt%). Monosaccharide analysis of carbohydrate part revealed the presence of five main sugar components, i.e. rhamnose (~23 wt%), arabinose (~20 wt%), uronic acids (~19 wt%), galactose (~17 wt%) and glucose (~14 wt%), and indicated thus the presence of rhamnogalacturonan and arabinogalactan in S. canadensis complex. HPLC analysis of complex showed one single peak of molecule mass at 11.2 kDa. Antitussive activity tests, performed in three doses of Solidago complex, showed the reduction of the number of cough efforts in the dose-dependent manner. Higher doses (50 and 75 mg/kg b.w.) were shown to be by 15 and 20% more effective than that of lower one (25mg/kg b.w.). However, the antitussive effect of the highest dose (75 mg/kg b.w.) was by 10% lower in comparison with that of codeine, the strongest antitussive agent. Besides, the highest dose of the complex (75 mg/kg b.w.) significantly decreased values of specific airways resistance and their effect remained longer as that of salbutamol, a representative of classic antiasthmatic drugs. Copyright © 2012 Elsevier B.V. All rights reserved.

  10. Plasminogen activator inhibitor-1 4G/5G polymorphism and retinopathy risk in type 2 diabetes: a meta-analysis.

    PubMed

    Zhang, Tengyue; Pang, Chong; Li, Ningdong; Zhou, Elaine; Zhao, Kanxing

    2013-01-02

    Mounting evidence has suggested that plasminogen activator inhibitor-1 (PAI-1) is a candidate for increased risk of diabetic retinopathy. Studies have reported that insertion/deletion polymorphism in the PAI-1 gene may influence the risk of this disease. To comprehensively address this issue, we performed a meta-analysis to evaluate the association of PAI-1 4G/5G polymorphism with diabetic retinopathy in type 2 diabetes. Data were retrieved in a systematic manner and analyzed using Review Manager and STATA Statistical Software. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. Nine studies with 1, 217 cases and 1, 459 controls were included. Allelic and genotypic comparisons between cases and controls were evaluated. Overall analysis suggests a marginal association of the 4G/5G polymorphism with diabetic retinopathy (for 4G versus 5G: OR 1.13, 95%CI 1.01 to 1.26; for 4G/4G versus 5G/5G: OR 1.30, 95%CI 1.04 to 1.64; for 4G/4G versus 5G/5G + 4G/5G: OR 1.26, 95%CI 1.05 to 1.52). In subgroup analysis by ethnicity, we found an association among the Caucasian population (for 4G versus 5G: OR 1.14, 95% CI 1.00 to 1.30; for 4G/4G versus 5G/5G: OR 1.33, 95%CI 1.02 to 1.74; for 4G/4G versus 5G/5G + 4G/5G: OR 1.41, 95%CI 1.13 to 1.77). When stratified by the average duration of diabetes, patients with diabetes histories longer than 10 years have an elevated susceptibility to diabetic retinopathy than those with shorter histories (for 4G/4G versus 5G/5G: OR 1.47, 95%CI 1.08 to 2.00). We also detected a higher risk in hospital-based studies (for 4G/4G versus 5G/5G+4G/5G: OR 1.27, 95%CI 1.02 to 1.57). The present meta-analysis suggested that 4G/5G polymorphism in the PAI-1 gene potentially increased the risk of diabetic retinopathy in type 2 diabetes and showed a discrepancy in different ethnicities. A higher susceptibility in patients with longer duration of diabetes (more than 10 years) indicated a gene

  11. Plasminogen activator inhibitor-1 4G/5G polymorphism and retinopathy risk in type 2 diabetes: a meta-analysis

    PubMed Central

    2013-01-01

    Background Mounting evidence has suggested that plasminogen activator inhibitor-1 (PAI-1) is a candidate for increased risk of diabetic retinopathy. Studies have reported that insertion/deletion polymorphism in the PAI-1 gene may influence the risk of this disease. To comprehensively address this issue, we performed a meta-analysis to evaluate the association of PAI-1 4G/5G polymorphism with diabetic retinopathy in type 2 diabetes. Methods Data were retrieved in a systematic manner and analyzed using Review Manager and STATA Statistical Software. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. Results Nine studies with 1, 217 cases and 1, 459 controls were included. Allelic and genotypic comparisons between cases and controls were evaluated. Overall analysis suggests a marginal association of the 4G/5G polymorphism with diabetic retinopathy (for 4G versus 5G: OR 1.13, 95%CI 1.01 to 1.26; for 4G/4G versus 5G/5G: OR 1.30, 95%CI 1.04 to 1.64; for 4G/4G versus 5G/5G + 4G/5G: OR 1.26, 95%CI 1.05 to 1.52). In subgroup analysis by ethnicity, we found an association among the Caucasian population (for 4G versus 5G: OR 1.14, 95% CI 1.00 to 1.30; for 4G/4G versus 5G/5G: OR 1.33, 95%CI 1.02 to 1.74; for 4G/4G versus 5G/5G + 4G/5G: OR 1.41, 95%CI 1.13 to 1.77). When stratified by the average duration of diabetes, patients with diabetes histories longer than 10 years have an elevated susceptibility to diabetic retinopathy than those with shorter histories (for 4G/4G versus 5G/5G: OR 1.47, 95%CI 1.08 to 2.00). We also detected a higher risk in hospital-based studies (for 4G/4G versus 5G/5G+4G/5G: OR 1.27, 95%CI 1.02 to 1.57). Conclusions The present meta-analysis suggested that 4G/5G polymorphism in the PAI-1 gene potentially increased the risk of diabetic retinopathy in type 2 diabetes and showed a discrepancy in different ethnicities. A higher susceptibility in patients with longer duration of diabetes (more than 10

  12. Summary of contributions to GAW Group 15: family-based samples are useful in identifying common polymorphisms associated with complex traits.

    PubMed

    Knight, Stacey; Uh, Hae-Won; Martinez, Maria

    2009-01-01

    Traditionally, family-based samples have been used for genetic analyses of single-gene traits caused by rare but highly penetrant risk variants. The utility of family-based genetic data for analyzing common complex traits is unclear and contains numerous challenges. To assess the utility as well as to address these challenges, members of Genetic Analysis Workshop 16 Group 15 analyzed Framingham Heart Study data using family-based designs ranging from parent--offspring trios to large pedigrees. We investigated different methods including traditional linkage tests, family-based association tests, and population-based tests that correct for relatedness between subjects, and tests to detect parent-of-origin effects. The analyses presented an assortment of positive findings. One contribution found increased power to detect epistatic effects through linkage using ascertainment of sibships based on extreme quantitative values or presence of disease associated with the quantitative value. Another contribution found four single-nucleotide polymorphisms (SNPs) showing a maternal effect, two SNPs with an imprinting effect, and one SNP having both effects on a binary high blood pressure trait. Finally, three contributions illustrated the advantage of using population-based methods to detect association to complex binary or quantitative traits. Our findings highlight the contribution of family-based samples to the genetic dissection of complex traits. (c) 2009 Wiley-Liss, Inc.

  13. A phylogenetic assessment of the polyphyletic nature and intraspecific color polymorphism in the Bactrocera dorsalis complex (Diptera, Tephritidae)

    PubMed Central

    Leblanc, Luc; San Jose, Michael; Barr, Norman; Rubinoff, Daniel

    2015-01-01

    Abstract The Bactrocera dorsalis complex (Tephritidae) comprises 85 species of fruit flies, including five highly destructive polyphagous fruit pests. Despite significant work on a few key pest species within the complex, little has been published on the majority of non-economic species in the complex, other than basic descriptions and illustrations of single specimens regarded as typical representatives. To elucidate the species relationships within the Bactrocera dorsalis complex, we used 159 sequences from one mitochondrial (COI) and two nuclear (elongation factor-1α and period) genes to construct a phylogeny containing 20 described species from within the complex, four additional species that may be new to science, and 26 other species from Bactrocera and its sister genus Dacus. The resulting concatenated phylogeny revealed that most of the species placed in the complex appear to be unrelated, emerging across numerous clades. This suggests that they were placed in the Bactrocera dorsalis complex based on the similarity of convergent characters, which does not appear to be diagnostic. Variations in scutum and abdomen color patterns within each of the non-economic species are presented and demonstrate that distantly-related, cryptic species overlap greatly in traditional morphological color patterns used to separate them in keys. Some of these species may not be distinguishable with confidence by means other than DNA data. PMID:26798267

  14. A phylogenetic assessment of the polyphyletic nature and intraspecific color polymorphism in the Bactrocera dorsalis complex (Diptera, Tephritidae).

    PubMed

    Leblanc, Luc; San Jose, Michael; Barr, Norman; Rubinoff, Daniel

    2015-01-01

    The Bactrocera dorsalis complex (Tephritidae) comprises 85 species of fruit flies, including five highly destructive polyphagous fruit pests. Despite significant work on a few key pest species within the complex, little has been published on the majority of non-economic species in the complex, other than basic descriptions and illustrations of single specimens regarded as typical representatives. To elucidate the species relationships within the Bactrocera dorsalis complex, we used 159 sequences from one mitochondrial (COI) and two nuclear (elongation factor-1α and period) genes to construct a phylogeny containing 20 described species from within the complex, four additional species that may be new to science, and 26 other species from Bactrocera and its sister genus Dacus. The resulting concatenated phylogeny revealed that most of the species placed in the complex appear to be unrelated, emerging across numerous clades. This suggests that they were placed in the Bactrocera dorsalis complex based on the similarity of convergent characters, which does not appear to be diagnostic. Variations in scutum and abdomen color patterns within each of the non-economic species are presented and demonstrate that distantly-related, cryptic species overlap greatly in traditional morphological color patterns used to separate them in keys. Some of these species may not be distinguishable with confidence by means other than DNA data.

  15. The COMT Val/Met polymorphism is associated with reading-related skills and consistent patterns of functional neural activation.

    PubMed

    Landi, Nicole; Frost, Stephen J; Mencl, W Einar; Preston, Jonathan L; Jacobsen, Leslie K; Lee, Maria; Yrigollen, Carolyn; Pugh, Kenneth R; Grigorenko, Elena L

    2013-01-01

    In both children and adults there is large variability in reading skill, with approximately 5-10% of individuals characterized as having reading disability; these individuals struggle to learn to read despite adequate intelligence and opportunity. Although it is well established that a substantial portion of this variability is attributed to the genetic differences between individuals, specifics of the connections between reading and the genome are not understood. This article presents data that suggest that variation in the COMT gene, which has previously been associated with variation in higher-order cognition, is associated with reading and reading-related skills, at the level of both brain and behavior. In particular, we found that the COMT Val/Met polymorphism at rs4680, which results in the substitution of the ancestral Valine (Val) by Methionine (Met), was associated with better performance on a number of critical reading measures and with patterns of functional neural activation that have been linked to better readers. We argue that this polymorphism, known for its broad effects on cognition, may modulate (likely through frontal lobe function) reading skill. © 2012 Blackwell Publishing Ltd.

  16. A polymorphism in the norepinephrine transporter gene alters promoter activity and is associated with attention-deficit hyperactivity disorder

    PubMed Central

    Kim, Chun-Hyung; Hahn, Maureen K.; Joung, Yoosook; Anderson, Susan L.; Steele, Angela H.; Mazei-Robinson, Michelle S.; Gizer, Ian; Teicher, Martin H.; Cohen, Bruce M.; Robertson, David; Waldman, Irwin D.; Blakely, Randy D.; Kim, Kwang-Soo

    2006-01-01

    The norepinephrine transporter critically regulates both neurotransmission and homeostasis of norepinephrine in the nervous system. In this study, we report a previously uncharacterized and common A/T polymorphism at −3081 upstream of the transcription initiation site of the human norepinephrine transporter gene [solute carrier family 6, member 2 (SLC6A2)]. Using both homologous and heterologous promoter-reporter constructs, we found that the −3081(T) allele significantly decreases promoter function compared with the A allele. Interestingly, this T allele creates a new palindromic E2-box motif that interacts with Slug and Scratch, neural-expressed transcriptional repressors binding to the E2-box motif. We also found that both Slug and Scratch repress the SLC6A2 promoter activity only when it contains the T allele. Finally, we observed a significant association between the −3081(A/T) polymorphism and attention-deficit hyperactivity disorder (ADHD), suggesting that anomalous transcription factor-based repression of SLC6A2 may increase risk for the development of attention-deficit hyperactivity disorder and other neuropsychiatric diseases. PMID:17146058

  17. A promoter polymorphism in the monoamine oxidase A gene is associated with the pineal MAOA activity in Alzheimer's disease patients.

    PubMed

    Wu, Ying-Hui; Fischer, David F; Swaab, Dick F

    2007-09-05

    Monoamine oxidase A (MAOA) is involved in the pathogenesis of mood disorders and Alzheimer's disease (AD). MAOA activity and gene expression have been found to be up-regulated in different brain areas of AD patients, including the pineal gland. Increased pineal MAOA activity might contribute to the reduced pineal melatonin production in AD. A promoter polymorphism of a variable number tandem repeats (VNTR) in the MAOA gene shows to affect MAOA transcriptional activity in vitro. Here we examined in 63 aged controls and 44 AD patients the effects of the MAOA-VNTR on MAOA gene expression and activity in the pineal gland as endophenotypes, and on melatonin production. AD patients carrying long MAOA-VNTR genotype (consisting of 3.5- or 4-repeat alleles) showed higher MAOA gene expression and activity than the short-genotyped (i.e., 3-repeat allele) AD patients. Moreover, the AD-related up-regulation of MAOA showed up only among long-genotype bearing subjects. There was no significant effect of the MAOA-VNTR on MAOA activity or gene expression in controls, or on melatonin production in both controls and AD patients. Our data suggest that the MAOA-VNTR affects the activity and gene expression of MAOA in the brain of AD patients, and is involved in the changes of monoamine metabolism.

  18. Complexing Methylene Blue with Phosphorus Dendrimers to Increase Photodynamic Activity.

    PubMed

    Dabrzalska, Monika; Janaszewska, Anna; Zablocka, Maria; Mignani, Serge; Majoral, Jean Pierre; Klajnert-Maculewicz, Barbara

    2017-02-23

    The efficiency of photodynamic therapy is limited mainly due to low selectivity, unfavorable biodistribution of photosensitizers, and long-lasting skin sensitivity to light. However, drug delivery systems based on nanoparticles may overcome the limitations mentioned above. Among others, dendrimers are particularly attractive as carriers, because of their globular architecture and high loading capacity. The goal of the study was to check whether an anionic phosphorus dendrimer is suitable as a carrier of a photosensitizer-methylene blue (MB). As a biological model, basal cell carcinoma cell lines were used. We checked the influence of the MB complexation on its singlet oxygen production ability using a commercial fluorescence probe. Next, cellular uptake, phototoxicity, reactive oxygen species (ROS) generation, and cell death were investigated. The MB-anionic dendrimer complex (MB-1an) was found to generate less singlet oxygen; however, the complex showed higher cellular uptake and phototoxicity against basal cell carcinoma cell lines, which was accompanied with enhanced ROS production. Owing to the obtained results, we conclude that the photodynamic activity of MB complexed with an anionic dendrimer is higher than free MB against basal cell carcinoma cell lines.

  19. The trifunctional sulfate-activating complex (SAC) of Mycobacterium tuberculosis.

    PubMed

    Sun, Meihao; Andreassi, John L; Liu, Shuqing; Pinto, Rachel; Triccas, James A; Leyh, Thomas S

    2005-03-04

    The sulfate activation pathway is essential for the assimilation of sulfate and, in many bacteria, is comprised of three reactions: the synthesis of adenosine 5'-phosphosulfate (APS), the hydrolysis of GTP, and the 3'-phosphorylation of APS to produce 3'-phosphoadenosine 5'-phosphosulfate (PAPS), whose sulfuryl group is reduced or transferred to other metabolites. The entire sulfate activation pathway is organized into a single complex in Mycobacterium tuberculosis. Although present in many bacteria, these tripartite complexes have not been studied in detail. Initial rate characterization of the mycobacterial system reveals that it is poised for extremely efficient throughput: at saturating ATP, PAPS synthesis is 5800 times more efficient than APS synthesis. The APS kinase domain of the complex does not appear to form the covalent E.P intermediate observed in the closely related APS kinase from Escherichia coli. The stoichiometry of GTP hydrolysis and APS synthesis is 1:1, and the APS synthesis reaction is driven 1.1 x 10(6)-fold further during GTP hydrolysis; the system harnesses the full chemical potential of the hydrolysis reaction to the synthesis of APS. A key energy-coupling step in the mechanism is a ligand-induced isomerization that enhances the affinity of GTP and commits APS synthesis and GTP hydrolysis to the completion of the catalytic cycle. Ligand-induced increases in guanine nucleotide affinity observed in the mycobacterial system suggest that it too undergoes the energy-coupling isomerization.

  20. Histone Acetyltransferase Complexes Can Mediate Transcriptional Activation by the Major Glucocorticoid Receptor Activation Domain

    PubMed Central

    Wallberg, Annika E.; Neely, Kristen E.; Gustafsson, Jan-Åke; Workman, Jerry L.; Wright, Anthony P. H.; Grant, Patrick A.

    1999-01-01

    Previous studies have shown that the Ada adapter proteins are important for glucocorticoid receptor (GR)-mediated gene activation in yeast. The N-terminal transactivation domain of GR, τ1, is dependent upon Ada2, Ada3, and Gcn5 for transactivation in vitro and in vivo. Using in vitro techniques, we demonstrate that the GR-τ1 interacts directly with the native Ada containing histone acetyltransferase (HAT) complex SAGA but not the related Ada complex. Mutations in τ1 that reduce τ1 transactivation activity in vivo lead to a reduced binding of τ1 to the SAGA complex and conversely, mutations increasing the transactivation activity of τ1 lead to an increased binding of τ1 to SAGA. In addition, the Ada-independent NuA4 HAT complex also interacts with τ1. GAL4-τ1-driven transcription from chromatin templates is stimulated by SAGA and NuA4 in an acetyl coenzyme A-dependent manner. Low-activity τ1 mutants reduce SAGA- and NuA4-stimulated transcription while high-activity τ1 mutants increase transcriptional activation, specifically from chromatin templates. Our results demonstrate that the targeting of native HAT complexes by the GR-τ1 activation domain mediates transcriptional stimulation from chromatin templates. PMID:10454542

  1. Solid state characterization of azelnidipine-oxalic acid co-crystal and co-amorphous complexes: The effect of different azelnidipine polymorphs.

    PubMed

    Pan, Yahui; Pang, Wenzhe; Lv, Jie; Wang, Jing; Yang, Caiqin; Guo, Wei

    2017-05-10

    In present study, based on the two polymorphs (α and β form) of azelnidipine (AZE), 12 complexes of AZE and oxalic acid (OXA) were prepared by solvent-assisted grinding (SG) and neat powder grinding (NG) methods at the AZE/OXA molar ratios of 2:1, 1:1, and 1:2. The effect of the different polymorphs of AZE on the micro-structure of the complexes were investigated by powder X-ray diffraction (PXRD), tempreture modulated differential scanning calorimetry and thermogravimetric analysis, cryo-field emission scanning electron microscope system, fourier transform infrared (FTIR), and solid-state nuclear magnetic resonance spectroscopy. β-AZE-OXA co-crystal was produced at β-AZE/OXA molar ratio of 2:1 when SG method was used; while α-AZE was used to produce α-AZE-OXA co-crystal at same condition. However, the other 10 combinations were in co-amorphous forms, including the NG samples with α (or β)-AZE/OXA molar ratios of 2:1, 1:1 (SG and NG), and 1:2 (SG and NG). Although the XRD pattern and IR spectra of the two co-crystals showed no difference, the melting enthalpy and specific heat cp of the β-AZE-OXA co-crystal was higher than that of the α-AZE-OXA co-crystal, indicating that the numbers of solvent molecules which entered the two co-crystal lattices were different. Interestingly, obvious difference occurred in the IR spectra between the α-AZE-OXA and β-AZE-OXA co-amorphous systems. 1745cm(-1) wave-numbers, which were assigned to the free CO groups, appeared in the α-AZE-OXA co-amorphous systems even when just a small amount of OXA was introduced, thereby indicating the presence of different intermolecular forces in the two series of co-amorphous forms. The solubility in different media and the dissolution rate in 0.1molL(-1) HCl of the 12 complexes were determined. The dramatically improved dissolution rates of the α- and β-AZE-OXA 1:2 (NG) combinations in vitro showed potential in improving the physicochemical properties of AZE by co-amorphous complex

  2. Potent anticancer activity of photo-activated oxo-bridged diiron(III) complexes.

    PubMed

    Chanu, S Binita; Banerjee, Samya; Roy, Mithun

    2017-01-05

    Cancer-specific anticancer drugs are still an elusive goal. Using light as the temporal control to generate cytotoxic species from photo-activated prodrug in the presence or absence of molecular oxygen has shown potential application targeted chemotherapy as in photodynamic therapy (PDT). In the present work we explored the chemistry of several photo-active (μ-oxo)diiron(III) complexes of the following formulation [{Fe(μ-O) (L-his)(B)}2](ClO4)2 (1a-1c), [Fe2(μ-O)(H2O)2B4](ClO4)4 (2b, 2c) and [Fe2(μ-O)(μ-O2CMe)B4](ClO4)3 (3b, 3c), L-his = l-histidine, B is 2,2'-bipyridine, 1,10-phenanthroline (phen) and dipyrido[3,2-d:2',3'-f]quinoxaline (dpq) complexes for tumor-specific anticancer activity. Facile redox chemistry and photochemical aspects of the complexes prompted us to investigate the cytotoxic as well as the photo-activated cytotoxic properties of the complexes to the cancer cells. In the present investigation we explored the cancer-specific condition of excess concentration of H2O2 for our approach to targeted chemotherapy. Cytotoxic effect of the complexes to the cancer cells was found to be significantly higher than in normal cells indicating tumor-specific anticancer activity of the complexes. Cytotoxic effect was even more pronounced when the cancer cells treated with the complexes were exposed to the visible light (400-700 nm). There was >12 fold increase in cytotoxicity of the photoactivated complexes in cancer cells (MCF-7) in comparison to the normal cells (MCF-10a). We have defined a factor viz. cancer cell specificity factor (f) describing the targeted photochemotherapeutic effect of the complexes at their specific concentration. The factor (f) > 1 indicated the cancer cell specificity of the complexes, while f > 2.5 for the complexes under the visible light exposure suggested photodynamic effect. DCFDA assay indicated the presence of excess of ROS in the treated HeLa cells. ROS concentration was found to increase even more on visible

  3. A genomic assessment of species boundaries and hybridization in a group of highly polymorphic anoles (distichus species complex).

    PubMed

    MacGuigan, Daniel J; Geneva, Anthony J; Glor, Richard E

    2017-06-01

    Delimiting young species is one of the great challenges of systematic biology, particularly when the species in question exhibit little morphological divergence. Anolis distichus, a trunk anole with more than a dozen subspecies that are defined primarily by dewlap color, may actually represent several independent evolutionary lineages. To test this, we utilized amplified fragment length polymorphisms (AFLP) genome scans and genetic clustering analyses in conjunction with a coalescent-based species delimitation method. We examined a geographically widespread set of samples and two heavily sampled hybrid zones. We find that genetic divergence is associated with a major biogeographic barrier, the Hispaniolan paleo-island boundary, but not with dewlap color. Additionally, we find support for hypotheses regarding colonization of two Hispaniolan satellite islands and the Bahamas from mainland Hispaniola. Our results show that A. distichus is composed of seven distinct evolutionary lineages still experiencing a limited degree of gene flow. We suggest that A. distichus merits taxonomic revision, but that dewlap color cannot be relied upon as the primary diagnostic character.

  4. Characterization of the breakpoints of a polymorphic inversion complex detects strict and broad breakpoint reuse at the molecular level.

    PubMed

    Puerma, Eva; Orengo, Dorcas J; Salguero, David; Papaceit, Montserrat; Segarra, Carmen; Aguadé, Montserrat

    2014-09-01

    Inversions are an integral part of structural variation within species, and they play a leading role in genome reorganization across species. Work at both the cytological and genome sequence levels has revealed heterogeneity in the distribution of inversion breakpoints, with some regions being recurrently used. Breakpoint reuse at the molecular level has mostly been assessed for fixed inversions through genome sequence comparison, and therefore rather broadly. Here, we have identified and sequenced the breakpoints of two polymorphic inversions-E1 and E2 that share a breakpoint-in the extant Est and E1 + 2 chromosomal arrangements of Drosophila subobscura. The breakpoints are two medium-sized repeated motifs that mediated the inversions by two different mechanisms: E1 via staggered breaks and subsequent repair and E2 via repeat-mediated ectopic recombination. The fine delimitation of the shared breakpoint revealed its strict reuse at the molecular level regardless of which was the intermediate arrangement. The occurrence of other rearrangements in the most proximal and distal extended breakpoint regions reveals the broad reuse of these regions. This differential degree of fragility might be related to their sharing the presence outside the inverted region of snoRNA-encoding genes.

  5. Methadone dose in heroin-dependent patients: role of clinical factors, comedications, genetic polymorphisms and enzyme activity

    PubMed Central

    Mouly, Stéphane; Bloch, Vanessa; Peoc'h, Katell; Houze, Pascal; Labat, Laurence; Ksouda, Kamilia; Simoneau, Guy; Declèves, Xavier; Bergmann, Jean Francois; Scherrmann, Jean-Michel; Laplanche, Jean-Louis; Lepine, Jean-Pierre; Vorspan, Florence

    2015-01-01

    Aims Methadone is characterized by wide intersubject variability regarding the dose needed to obtain full therapeutic response. We assessed the influence of sociodemographic, ethnic, clinical, metabolic and genotypic variables on methadone maintenance dose requirement in opioid-dependent responder patients. Methods Eighty-one stable patients (60 men and 21 women, 43.7 ± 8.1 years old, 63.1 ± 50.9 mg day−1 methadone), divided into quartiles with respect to the median daily dose, were enrolled and underwent clinical examination, treatment history and determination of liver/intestinal cytochrome P450 (CYP) 3A4 activity measured by the midazolam test, R,S-methadone trough concentration and clinically significant polymorphisms of the OPRM1, DRD2, COMT, ABCB1, CYP2B6, CYP3A5, CYP2C19 and CYP2D6 genes. Results Methadone maintenance dose was correlated to the highest dose ever used (r2 = 0.57, P < 0.0001). Fractioned methadone intake (odds ratio 4.87, 95% confidence interval 1.27–18.6, P = 0.02), bodyweight (odds ratio 1.57, 95% confidence interval 1.01–2.44, P = 0.04), history of cocaine dependence (80 vs. 44 mg day−1 in never-addict patients, P = 0.005) and ethnicity (Asian > Caucasian > African, P = 0.04) were independently associated with high-dose methadone in multiple regression analysis. A modest correlation was observed between liver/intestinal CYP3A4 activity and methadone dose at steady state (Spearman rank correlation coefficient [rs] = 0.21, P = 0.06) but not with highest dose ever used (rs = 0.15, P = 0.18) or dose-normalized R,S-methadone trough concentrations (rs = −0.05, P = 0.64). Concomitant CYP3A4 inhibitors only affected the relationship between methadone dose and R,S-methadone trough concentration. None of the genetic polymorphisms explored was predictive of the methadone maintenance dose. Conclusions Methadone maintenance dose was predicted by sociodemographic and clinical variables rather than genetic polymorphisms or liver/intestinal CYP

  6. Polymorphism rs7278468 is associated with Age-related cataract through decreasing transcriptional activity of the CRYAA promoter.

    PubMed

    Ma, Xiaoyin; Jiao, Xiaodong; Ma, Zhiwei; Hejtmancik, J Fielding

    2016-03-17

    CRYAA plays critical functional roles in lens transparency and opacity, and polymorphisms near CRYAA have been associated with age-related cataract (ARC). This study examines polymorphisms in the CRYAA promoter region for association with ARC and elucidates the mechanisms of this association. Three SNPs nominally associated with ARC were identified in the promoter region of CRYAA: rs3761382 (P = 0.06, OR (Odds ratio) = 1.5), rs13053109 (P = 0.04, OR = 1.6), rs7278468 (P = 0.007, OR = 0.6). The C-G-T haplotype increased the risk for ARC overall (P = 0.005, OR = 1.8), and both alleles and haplotypes show a stronger association with cortical cataract (rs3761382, P = 0.002, OR = 2.1; rs13053109, P = 0.002, OR = 2.1; rs7278468, P = 0.0007, OR = 0.5; C-G-T haplotype, P = 0.0003, OR = 2.2). The C-G-T risk haplotype decreased transcriptional activity through rs7278468, which lies in a consensus binding site for the transcription repressor KLF10. KLF10 binding inhibited CRYAA transcription, and both binding and inhibition were greater with the T rs7278468 allele. Knockdown of KLF10 in HLE cells partially rescued the transcriptional activity of CRYAA with rs7278468 T allele, but did not affect activity with the G allele. Thus, our data suggest that the T allele of rs7278468 in the CRYAA promoter is associated with ARC through increasing binding of KLF-10 and thus decreasing CRYAA transcription.

  7. Integrin activation and focal complex formation in cardiac hypertrophy

    NASA Technical Reports Server (NTRS)

    Laser, M.; Willey, C. D.; Jiang, W.; Cooper, G. 4th; Menick, D. R.; Zile, M. R.; Kuppuswamy, D.

    2000-01-01

    Cardiac hypertrophy is characterized by both remodeling of the extracellular matrix (ECM) and hypertrophic growth of the cardiocytes. Here we show increased expression and cytoskeletal association of the ECM proteins fibronectin and vitronectin in pressure-overloaded feline myocardium. These changes are accompanied by cytoskeletal binding and phosphorylation of focal adhesion kinase (FAK) at Tyr-397 and Tyr-925, c-Src at Tyr-416, recruitment of the adapter proteins p130(Cas), Shc, and Nck, and activation of the extracellular-regulated kinases ERK1/2. A synthetic peptide containing the Arg-Gly-Asp (RGD) motif of fibronectin and vitronectin was used to stimulate adult feline cardiomyocytes cultured on laminin or within a type-I collagen matrix. Whereas cardiocytes under both conditions showed RGD-stimulated ERK1/2 activation, only collagen-embedded cells exhibited cytoskeletal assembly of FAK, c-Src, Nck, and Shc. In RGD-stimulated collagen-embedded cells, FAK was phosphorylated only at Tyr-397 and c-Src association occurred without Tyr-416 phosphorylation and p130(Cas) association. Therefore, c-Src activation is not required for its cytoskeletal binding but may be important for additional phosphorylation of FAK. Overall, our study suggests that multiple signaling pathways originate in pressure-overloaded heart following integrin engagement with ECM proteins, including focal complex formation and ERK1/2 activation, and many of these pathways can be activated in cardiomyocytes via RGD-stimulated integrin activation.

  8. Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity

    PubMed Central

    Mathias, Rommel A.; Greco, Todd M.; Oberstein, Adam; Budayeva, Hanna G.; Chakrabarti, Rumela; Rowland, Elizabeth A.; Kang, Yibin; Shenk, Thomas; Cristea, Ileana M.

    2014-01-01

    Summary Sirtuins (SIRTs) are critical enzymes that govern genome regulation, metabolism, and aging. Despite conserved deacetylase domains, mitochondrial SIRT4 and SIRT5 have little to no deacetylase activity, and a robust catalytic activity for SIRT4 has been elusive. Here, we establish SIRT4 as a cellular lipoamidase that regulates the pyruvate dehydrogenase complex (PDH). Importantly, SIRT4 catalytic efficiency for lipoyl- and biotinyl-lysine modifications is superior to its deacetylation activity. PDH, which converts pyruvate to acetyl-CoA, has been known to be primarily regulated by phosphorylation of its E1 component. We determine that SIRT4 enzymatically hydrolyzes the lipoamide cofactors from the E2 component dihydrolipoyllysine acetyltransferase (DLAT), diminishing PDH activity. We demonstrate SIRT4-mediated regulation of DLAT lipoyl levels and PDH activity in cells and in vivo, in mouse liver. Furthermore, metabolic flux switching via glutamine stimulation induces SIRT4 lipoamidase activity to inhibit PDH, highlighting SIRT4 as a guardian of cellular metabolism. PMID:25525879

  9. Integrin activation and focal complex formation in cardiac hypertrophy

    NASA Technical Reports Server (NTRS)

    Laser, M.; Willey, C. D.; Jiang, W.; Cooper, G. 4th; Menick, D. R.; Zile, M. R.; Kuppuswamy, D.

    2000-01-01

    Cardiac hypertrophy is characterized by both remodeling of the extracellular matrix (ECM) and hypertrophic growth of the cardiocytes. Here we show increased expression and cytoskeletal association of the ECM proteins fibronectin and vitronectin in pressure-overloaded feline myocardium. These changes are accompanied by cytoskeletal binding and phosphorylation of focal adhesion kinase (FAK) at Tyr-397 and Tyr-925, c-Src at Tyr-416, recruitment of the adapter proteins p130(Cas), Shc, and Nck, and activation of the extracellular-regulated kinases ERK1/2. A synthetic peptide containing the Arg-Gly-Asp (RGD) motif of fibronectin and vitronectin was used to stimulate adult feline cardiomyocytes cultured on laminin or within a type-I collagen matrix. Whereas cardiocytes under both conditions showed RGD-stimulated ERK1/2 activation, only collagen-embedded cells exhibited cytoskeletal assembly of FAK, c-Src, Nck, and Shc. In RGD-stimulated collagen-embedded cells, FAK was phosphorylated only at Tyr-397 and c-Src association occurred without Tyr-416 phosphorylation and p130(Cas) association. Therefore, c-Src activation is not required for its cytoskeletal binding but may be important for additional phosphorylation of FAK. Overall, our study suggests that multiple signaling pathways originate in pressure-overloaded heart following integrin engagement with ECM proteins, including focal complex formation and ERK1/2 activation, and many of these pathways can be activated in cardiomyocytes via RGD-stimulated integrin activation.

  10. Aluminum complexes of the redox-active [ONO] pincer ligand.

    PubMed

    Szigethy, Géza; Heyduk, Alan F

    2012-07-14

    A series of aluminum complexes containing the tridentate, redox-active ligand bis(3,5-di-tert-butyl-2-phenol)amine ([ONO]H(3)) in three different oxidation states were synthesized. The aluminum halide salts AlCl(3) and AlBr(3) were reacted with the doubly deprotonated form of the ligand to afford five-coordinate [ONHO(cat)]AlX(solv) complexes (1a, X = Cl, solv = OEt(2); 1b, X = Br, solv = THF), each having a trigonal bipyramidal coordination geometry at the aluminum and containing the [ONHO(cat)](2-) ligand with a protonated, sp(3)-hybridized nitrogen donor. The [ONO] ligand platform may also be added to aluminum through the use of the oxidized ligand salt [ONO(q)]K, which was reacted with AlCl(3) in the presence of either diphenylacetylacetonate (acacPh(2)(-)) or 8-oxyquinoline (quinO(-)) to afford [ONO(q)]Al(acacPh(2))Cl (2) or [ONO(q)]Al(quinO)Cl (3), respectively, with well-defined [ONO(q)](-) ligands. Quinonate complexes 2 and 3 were reduced by one electron to afford the corresponding complexes K{[ONO(sq)]Al(acacPh(2))(py)} (4) and K{[ONO(sq)]Al(quinO)(py)} (5), respectively, containing well-defined [ONO(sq)](2-) ligands. The addition of tetrachloro-1,2-quinone to 1a in the presence of pyridine resulted in the expulsion of HCl and the formation of an aluminum complex with two different redox active ligands, [ONO]Al(o-O(2)C(6)Cl(4))(py) (6). Similar results were obtained when 1a was reacted with 9,10-phenanthrenequinone to afford [ONO]Al(o-O(2)C(14)H(8))(py) (7) or with pyrene-4,5-dione to afford [ONO]Al(o-O(2)C(16)H(8))(py) (8). Structural, spectroscopic and preliminary magnetic measurements on 6-8 suggest ligand non-innocent redox behavior in these complexes.

  11. IMAGING BRAIN ACTIVATION: SIMPLE PICTURES OF COMPLEX BIOLOGY

    PubMed Central

    Dienel, Gerald A.; Cruz, Nancy F.

    2009-01-01

    Elucidation of biochemical, physiological, and cellular contributions to metabolic images of brain is important for interpretation of images of brain activation and disease. Discordant brain images obtained with [14C]deoxyglucose (DG) and [1- or 6-14C]glucose were previously ascribed to increased glycolysis and rapid [14C]lactate release from tissue, but direct proof of [14C]lactate release from activated brain structures is lacking. Analysis of factors contributing to images of focal metabolic activity evoked by monotonic acoustic stimulation of conscious rats reveals that labeled metabolites of [1- or 6-14C]glucose are quickly released from activated cells due to decarboxylation reactions, spreading via gap junctions, and efflux via lactate transporters. Label release from activated tissue accounts for most of the additional [14C]glucose consumed during activation compared to rest. Metabolism of [3,4-14C]glucose generates about four times more [14C]lactate compared to 14CO2 in extracellular fluid suggesting that most lactate is not locally oxidized. In brain slices, direct assays of lactate uptake from extracellular fluid demonstrate that astrocytes have faster influx and higher transport capacity than neurons. Also, lactate transfer from a single astrocyte to other gap junction-coupled astrocytes exceeds astrocyte-to-neuron lactate shuttling. Astrocytes and neurons have excess capacities for glycolysis, and oxidative metabolism in both cell types rises during sensory stimulation. The energetics of brain activation is quite complex and the proportion of glucose consumed by astrocytes and neurons, lactate generation by either cell type, and the contributions of both cell types to brain images during brain activation are likely to vary with the stimulus paradigm and activated pathways. PMID:19076439

  12. GT-CATS: Tracking Operator Activities in Complex Systems

    NASA Technical Reports Server (NTRS)

    Callantine, Todd J.; Mitchell, Christine M.; Palmer, Everett A.

    1999-01-01

    Human operators of complex dynamic systems can experience difficulties supervising advanced control automation. One remedy is to develop intelligent aiding systems that can provide operators with context-sensitive advice and reminders. The research reported herein proposes, implements, and evaluates a methodology for activity tracking, a form of intent inferencing that can supply the knowledge required for an intelligent aid by constructing and maintaining a representation of operator activities in real time. The methodology was implemented in the Georgia Tech Crew Activity Tracking System (GT-CATS), which predicts and interprets the actions performed by Boeing 757/767 pilots navigating using autopilot flight modes. This report first describes research on intent inferencing and complex modes of automation. It then provides a detailed description of the GT-CATS methodology, knowledge structures, and processing scheme. The results of an experimental evaluation using airline pilots are given. The results show that GT-CATS was effective in predicting and interpreting pilot actions in real time.

  13. Activation of CS2 and CS by ML3 complexes.

    PubMed

    Ariafard, Alireza; Brookes, Nigel J; Stranger, Robert; Yates, Brian F

    2008-09-10

    The aim of this study was to determine the best neutral ML3 metal complexes for activating and cleaving the multiple bonds in CS2 and CS. Current experimental results show that, so far, only one bond in CS2 can be cleaved, and that CS can be activated but the bond is not broken. In the work described in this paper, density functional theory calculations have been used to evaluate the effectiveness of different ML3 complexes to activate the C-S bonds in CS2 and CS, with M = Mo, Re, W, and Ta and L = NH2. These calculations show that the combination of Re and Ta in the L3Re/CS2/TaL3 complex would be the most promising system for the cleavage of both C-S bonds of CS2. The reaction to cleave both C-S bonds is predicted to be exothermic by about 700 kJ mol(-1) and to proceed in an almost barrierless fashion. In addition, we are able to rationalize why the breaking of the C-S bond in CS has not been observed experimentally with M = Mo: this reaction is strongly endothermic. There is a subtle interplay between charge transfer and pi back-donation, and it appears that the Mo-C and Mo-S bonds are not strong enough to compensate for the breaking of the C-S bond. Our results suggest that, instead, CS could be cleaved with ReL3 or, even better, with a combination of ReL3 and TaL3. Molecular orbitals and Mulliken charges have been used to help explain these trends and to make predictions about the most promising systems for future experimental exploration.

  14. Formation and activation by phosphorylation of activin receptor complexes.

    PubMed

    Willis, S A; Zimmerman, C M; Li, L I; Mathews, L S

    1996-04-01

    Activin is a protein growth and differentiation factor that initiates intracellular events through the activation of a complex of transmembrane protein serine kinases. Two subfamilies of receptor serine kinases, type I and type II, have been identified, and both receptor types may be required to generate a transmembrane signal. Investigation of the interaction between various activin receptors (ActRs) revealed that ActRs I and II could exist in a stable complex and that formation of that complex between transiently overexpressed molecules was not regulated by ligand. Analysis of phosphorylation suggested that activin induced phosphorylation of receptor I, probably at residues within a conserved glycine and serine-rich sequence in the juxtamembrane region referred to as the GS domain. Phosphorylation of the GS domain was dependent upon a functional ActRII. Introduction of an activin type I receptor, ALK4, into the mink lung epithelial cell line, L17, conferred activin responsiveness on those cells. Mutation of specific combinations of serines and threonines in the core sequence of the ALK4 GS domain to alanine rendered that receptor incompetent for signaling. Mutation of the same sets of residues to glutamic acid produced molecules that supported activin signaling but that did not display elevated basal signaling anticipated for a constitutively active receptor. However, mutation of a threonine residue in the carboxy-terminal half of the GS domain, T206, to glutamic acid yielded receptors with constitutive activity. Taken together, these results support a role for phosphorylation of type I ActRs in the generation of a biological signal.

  15. Effect of the Pro12Ala Polymorphism of the Peroxisome Proliferator-activated Receptor γ2 Gene on Lipid Profile and Adipokines Levels in Obese Subjects

    PubMed Central

    Becer, E; Çırakoğlu, A

    2017-01-01

    Abstract Peroxisome proliferator-activated receptor γ (PPARγ) is a key regulator of metabolism, adipokines production and secretion. The aim of this study was to investigate the association between the PPARγ2 gene Pro12Ala polymorphism in obesity in terms of body mass index (BMI), lipid parameters, homeostasis model assessment of insulin resistance (HOMA-IR), serum lipid, leptin, adiponectin, resistin and chemerin levels. The study included 160 obese and 140 non obese subjects. The Pro12Ala polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Serum lipid, leptin, adiponectin, resistin and chemerin levels were measured. No association was found between the Pro12Ala polymorphism and BMI. Strikingly, in the study group, obese subjects with the AA genotype had significantly higher triglycerides (p = 0.046) and resistin (p <0.001) levels than those with the wild-type PP and heterozygous PA genotypes. Serum leptin and chemerin levels were significantly associated with Pro-12Ala poymorphism in the obese and non obese groups (p <0.01). In the obese group, subjects with the homozygous AA genotype had significantly lower adiponectin (p = 0.010) activity than the PP genotype. Our results suggest that the PPARγ2 gene Pro12Ala polymorphism has no direct association with obesity but does have significant influences on lipid profiles and adipokines levels. PMID:28924543

  16. Effect of the Pro12Ala Polymorphism of the Peroxisome Proliferator-activated Receptor γ2 Gene on Lipid Profile and Adipokines Levels in Obese Subjects.

    PubMed

    Becer, E; Çırakoğlu, A

    2017-06-30

    Peroxisome proliferator-activated receptor γ (PPARγ) is a key regulator of metabolism, adipokines production and secretion. The aim of this study was to investigate the association between the PPARγ2 gene Pro12Ala polymorphism in obesity in terms of body mass index (BMI), lipid parameters, homeostasis model assessment of insulin resistance (HOMA-IR), serum lipid, leptin, adiponectin, resistin and chemerin levels. The study included 160 obese and 140 non obese subjects. The Pro12Ala polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Serum lipid, leptin, adiponectin, resistin and chemerin levels were measured. No association was found between the Pro12Ala polymorphism and BMI. Strikingly, in the study group, obese subjects with the AA genotype had significantly higher triglycerides (p = 0.046) and resistin (p <0.001) levels than those with the wild-type PP and heterozygous PA genotypes. Serum leptin and chemerin levels were significantly associated with Pro-12Ala poymorphism in the obese and non obese groups (p <0.01). In the obese group, subjects with the homozygous AA genotype had significantly lower adiponectin (p = 0.010) activity than the PP genotype. Our results suggest that the PPARγ2 gene Pro12Ala polymorphism has no direct association with obesity but does have significant influences on lipid profiles and adipokines levels.

  17. Active printed materials for complex self-evolving deformations.

    PubMed

    Raviv, Dan; Zhao, Wei; McKnelly, Carrie; Papadopoulou, Athina; Kadambi, Achuta; Shi, Boxin; Hirsch, Shai; Dikovsky, Daniel; Zyracki, Michael; Olguin, Carlos; Raskar, Ramesh; Tibbits, Skylar

    2014-12-18

    We propose a new design of complex self-evolving structures that vary over time due to environmental interaction. In conventional 3D printing systems, materials are meant to be stable rather than active and fabricated models are designed and printed as static objects. Here, we introduce a novel approach for simulating and fabricating self-evolving structures that transform into a predetermined shape, changing property and function after fabrication. The new locally coordinated bending primitives combine into a single system, allowing for a global deformation which can stretch, fold and bend given environmental stimulus.

  18. Esterase activity of BSA-ZnO nanoparticle complex

    NASA Astrophysics Data System (ADS)

    Bhogale, A.; Nair, A.; Patel, N.; Miotello, A.; Kothari, D. C.

    2014-04-01

    The effect of Zinc Oxide Nanoparticles (ZnO NPs) on functional properties of Bovine Serum Albumin (BSA) protein was studied. ZnO NPs were synthesized with average size of ˜7.5 nm as obtained from TEM analysis. The catalytic conversion of p-nitrophenylacetate (PNPA) to p-nitrophenol in the presence of BSA attached with ZnO NPs was examined by UV-Vis spectroscopy at room temperature. The result suggests that esterase activity of BSA is significantly enhanced (6 times) due to the ground state BSA-ZnO complex formation.

  19. Active Printed Materials for Complex Self-Evolving Deformations

    PubMed Central

    Raviv, Dan; Zhao, Wei; McKnelly, Carrie; Papadopoulou, Athina; Kadambi, Achuta; Shi, Boxin; Hirsch, Shai; Dikovsky, Daniel; Zyracki, Michael; Olguin, Carlos; Raskar, Ramesh; Tibbits, Skylar

    2014-01-01

    We propose a new design of complex self-evolving structures that vary over time due to environmental interaction. In conventional 3D printing systems, materials are meant to be stable rather than active and fabricated models are designed and printed as static objects. Here, we introduce a novel approach for simulating and fabricating self-evolving structures that transform into a predetermined shape, changing property and function after fabrication. The new locally coordinated bending primitives combine into a single system, allowing for a global deformation which can stretch, fold and bend given environmental stimulus. PMID:25522053

  20. Pyruvate Dehydrogenase Complex Activity in Normal and Deficient Fibroblasts

    PubMed Central

    Sheu, Kwan-Fu Rex; Hu, Chii-Whei C.; Utter, Merton F.

    1981-01-01

    Pyruvate dehydrogenase complex (PDC) activity in human skin fibroblasts appears to be regulated by a phosphorylation-dephosphorylation mechanism, as is the case with other animal cells. The enzyme can be activated by pretreating the cells with dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase, before they are disrupted for measurement of PDC activity. With such treatment, the activity reaches 5-6 nmol/min per mg of protein at 37°C with fibroblasts from infants. Such values represent an activation of about 5-20-fold over those observed with untreated cells. That this assay, based on [1-14C]pyruvate decarboxylation, represents a valid measurement of the overall PDC reaction is shown by the dependence of 14CO2 production on the presence of thiamin-PP, coenzyme A (CoA), Mg++, and NAD+. Also, it has been shown that acetyl-CoA and 14CO2 are formed in a 1:1 ratio. A similar degree of activation of PDC can also be achieved by adding purified pyruvate dehydrogenase phosphatase and high concentrations of Mg++ and Ca++, or in some cases by adding the metal ions alone to the cell homogenate after disruption. These results strongly suggest that activation is due to dephosphorylation. Addition of NaF, which inhibits dephosphorylation, leads to almost complete loss of PDC activity. Assays of completely activated PDC were performed on two cell lines originating from patients reported to be deficient in this enzyme (Blass, J. P., J. Avigan, and B. W. Ublendorf. 1970. J. Clin. Invest. 49: 423-432; Blass, J. P., J. D. Schuman, D. S. Young, and E. Ham. 1972. J. Clin. Invest. 51: 1545-1551). Even after activation with DCA, fibroblasts from the patients showed values of only 0.1 and 0.3 nmol/min per mg of protein. A familial study of one of these patients showed that both parents exhibited activity in fully activated cells about half that of normal values, whereas cells from a sibling appeared normal. These results demonstrate the inheritance nature of PDC deficiency

  1. Residual vein thrombosis and onset of post-thrombotic syndrome: influence of the 4G/5G polymorphism of plasminogen activator inhibitor-1 gene.

    PubMed

    Incalcaterra, Egle; Meli, Francesco; Muratori, Ida; Corrado, Egle; Amato, Corrado; Canino, Baldassare; Ferrara, Filippo

    2014-03-01

    Plasminogen activator inhibitor-1 (PAI-1) is the most important inhibitor of plasminogen activator. The functional 4G/5G polymorphism of the gene coding for PAI-1 may affect PAI-1 plasmatic activity, influencing the imbalance between coagulation and fibrinolysis cascades. In this prospective cohort analytic study, we investigated the role of this single nucleotide polymorphism in the persistence of thrombotic lesion and the occurrence of post-thrombotic syndrome. In a group of 168 patients with post-surgical deep vein thrombosis of the legs, we analyzed the 4G/5G polymorphism in the promoter of PAI-1 gene and plasmatic PAI-1 activity. Enrolled patients were divided in two groups: patients with 4G/5G polymorphism and increased PAI-1 activity (n=85) and patients without 4G/5G polymorphism and normal PAI-1 activity (n=83). All patients were treated according to current protocols and re-examined after 3, 12 and 36 months in order to evaluate the persistence of thrombotic lesion and the occurrence of post-thrombotic syndrome. We found a significantly increased PAI activity in carrier of the 4G allele, who experienced much more frequently a persistence of thrombosis after 3, 12 and 36 months and/or the development of post-thrombosis syndrome, in spite of the anticoagulant treatment. These data not only confirm the role played by PAI-1 activity and by the 4G/5G SNP of the PAI-1 gene, but also suggest that current therapeutic protocols, recommending the administration of low weight molecular heparin and oral anticoagulant for the treatment of deep vein thrombosis, could be non sufficient for patients genetically predisposed to a less efficient clot lysis. Copyright © 2013. Published by Elsevier Ltd.

  2. The chromosomal passenger complex activates Polo kinase at centromeres.

    PubMed

    Carmena, Mar; Pinson, Xavier; Platani, Melpi; Salloum, Zeina; Xu, Zhenjie; Clark, Anthony; Macisaac, Fiona; Ogawa, Hiromi; Eggert, Ulrike; Glover, David M; Archambault, Vincent; Earnshaw, William C

    2012-01-01

    The coordinated activities at centromeres of two key cell cycle kinases, Polo and Aurora B, are critical for ensuring that the two sister kinetochores of each chromosome are attached to microtubules from opposite spindle poles prior to chromosome segregation at anaphase. Initial attachments of chromosomes to the spindle involve random interactions between kinetochores and dynamic microtubules, and errors occur frequently during early stages of the process. The balance between microtubule binding and error correction (e.g., release of bound microtubules) requires the activities of Polo and Aurora B kinases, with Polo promoting stable attachments and Aurora B promoting detachment. Our study concerns the coordination of the activities of these two kinases in vivo. We show that INCENP, a key scaffolding subunit of the chromosomal passenger complex (CPC), which consists of Aurora B kinase, INCENP, Survivin, and Borealin/Dasra B, also interacts with Polo kinase in Drosophila cells. It was known that Aurora A/Bora activates Polo at centrosomes during late G2. However, the kinase that activates Polo on chromosomes for its critical functions at kinetochores was not known. We show here that Aurora B kinase phosphorylates Polo on its activation loop at the centromere in early mitosis. This phosphorylation requires both INCENP and Aurora B activity (but not Aurora A activity) and is critical for Polo function at kinetochores. Our results demonstrate clearly that Polo kinase is regulated differently at centrosomes and centromeres and suggest that INCENP acts as a platform for kinase crosstalk at the centromere. This crosstalk may enable Polo and Aurora B to achieve a balance wherein microtubule mis-attachments are corrected, but proper attachments are stabilized allowing proper chromosome segregation.

  3. A polymorphic dinucleotide repeat in the rat nucleolin gene forms Z-DNA and inhibits promoter activity

    PubMed Central

    Rothenburg, Stefan; Koch-Nolte, Friedrich; Rich, Alexander; Haag, Friedrich

    2001-01-01

    Many sequences in eukaryotic genomes have the potential to adopt a left-handed Z-DNA conformation. We used a previously described assay based on the binding of a mAb to Z-DNA to inquire whether Z-DNA is formed in the rat nucleolin (Ncl) gene in metabolically active, permeabilized nuclei. Using real-time PCR to measure Z-DNA formation, the potential Z-DNA sequence element Z1 [(CA)10(CG)8] in the promoter region was found to be enriched 571- to 4,040-fold in different cell lines, whereas Z2 [AC(GC)5CCGT(CG)2] in the first intron was enriched 12- to 34-fold. Ncl promoter activity was 1.5- to 16-fold stronger than that of the simian virus 40 promoter and enhancer. This activity was further increased 36–54% when Z1 was deleted. The inhibitory effect of Z1 on Ncl promoter activity was independent of location and orientation. The Ncl Z1 element is identical to the genetic marker D9Arb5. Five allelic variants of Z1 were identified by sequence analysis of genomic DNA from various rats. The two most common alleles differed significantly (up to 27%) in their capacity to inhibit Ncl promoter activity. This finding suggests that differences in Z-DNA formation by polymorphic dinucleotide repeats may be one of the factors contributing to genetic variation. PMID:11447254

  4. miR-196a-2 rs11614913 polymorphism is associated with vitiligo by affecting heterodimeric molecular complexes of Tyr and Tyrp1.

    PubMed

    Cui, T-T; Yi, X-L; Zhang, W-G; Wei, C; Zhou, F-B; Jian, Z; Wang, G; Gao, T-W; Li, C-Y; Li, K

    2015-10-01

    Tyrosinase and tyrosinase-related protein 1 (Tyr-Tyrp1) complex plays a critical role in the synthesis of melanin intermediates, which involves the production of reactive oxygen species (ROS) and contributes to the development of vitiligo. Based on our previous observation that rs11614913 single nucleotide polymorphism (SNP) in miR-196a-2 could affect the risk of vitiligo by influencing Tyrp1, we hypothesized that the same SNP could also regulate the level of Tyr in vitiligo. The aim of this study was to evaluate the potential association between rs11614913 SNP in miR-196a-2 and serum Tyr level in vitiligo and the regulatory role of miR-196a-2 in the expression of Tyr in melanocytes. The serum Tyr level was detected in 116 patients with vitiligo and 116 controls by ELISA plate assay. The expression level of Tyrp1 and Tyr in PIG1(normal melanocyte cell lines) cells was analyzed by western blotting. The ROS level and apoptosis rate in PIG1 cells transfected with si-Tyr or control siRNA were tested by flow cytometry. The results show that the individuals with TT+TC genotypes in miR-196a-2 and higher Tyr level in serum had an increased risk of vitiligo compared with those who had the CC genotype and lower Tyr level (P < 0.001). Furthermore, the rs11614913 C allele in miR-196a-2 enhanced its inhibitory regulation on the expression of Tyr, the down-regulation of which in melanocytes successfully reduced the intracellular ROS levels and the apoptosis rate. In conclusion, our findings suggest that miR-196a-2 polymorphisms can regulate the Tyr levels, which influences the susceptibility of vitiligo.

  5. Supramolecular coordination and antimicrobial activities of constructed mixed ligand complexes

    NASA Astrophysics Data System (ADS)

    El-Sonbati, A. Z.; Diab, M. A.; El-Bindary, A. A.; Abou-Dobara, M. I.; Seyam, H. A.

    2013-03-01

    A novel series of copper(II) and palladium(II) with 4-derivatives benzaldehyde pyrazolone (Ln) were synthesized. The mixed ligand complexes were prepared by using 1,10-phenanthroline (Phen) as second ligand. The structure of these complexes was identified and confirm by elemental analysis, molar conductivity, UV-Vis, IR and 1H NMR spectroscopy and magnetic moment measurements as well as thermal analysis. The ligand behaves as a neutral bidentate ligand through ON donor sites. ESR spectra show the simultaneous presence of a planar trans and a nearly planar cis isomers in the 1:2 ratio for all N,O complexes [Cu(Ln)2]Cl2ṡ2H2O. Schiff bases (Ln) were tested against bacterial species; namely two Gram positive bacteria (Staphylococcus aureus and Bacillus cereus) and two Gram negative bacteria (Escherichia coli and Klebsiella pneumoniae) and fungal species (Aspergillus niger, Fusarium oxysporium, Penicillium italicum and Alternaria alternata). The tested compounds have antibacterial activity against S. aureus, B. cereus and K. pneumoniae.

  6. Synthesis and Antimicrobial Activity of Silver Citrate Complexes

    PubMed Central

    Djokić, Stojan

    2008-01-01

    Formation of silver citrate/citric acid complexed solutions was investigated. Although, silver citrate is minimally soluble in water, it can successfully be dissolved in citric acid solutions. The maximum concentration of Ag(I) in solution is estimated at 23 to 25 g/L if the concentration of citric acid is at least 4 mol/L or higher. The dissolution of silver citrate in citric acid solutions was attributed to the formation of silver citrate complexes of a general formula [Ag3(C6H5O7)n+1]3n−. The silver citrate/citric acid solutions, containing more than about 13 g/L Ag+ ion, have exhibited a decrease in Ag(I) concentration in solution over time, due to crystallization. The crystallization product was attributed to the formation of [Ag3C6H5O7]x·nH2O. Importantly, the diluted silver citrate/citric acid complexed solutions have exhibited very strong bacteriostatic and bactericidal activities. PMID:19079586

  7. A promoter polymorphism rs2075824 within IMPA2 gene affecting the transcription activity: possible relationship with schizophrenia.

    PubMed

    Li, Jia; Huang, Sheng; Dai, Hui-Rong; Wang, Juan; Lin, Li-Hui; Xiao, Hui; Peng, Xia; Li, Fei; Wang, Yu-Ping; Yuan, Jian-Min; Li, Li

    2017-04-01

    Previous studies with biological and genetic evidence indicate that the myo-inositol monophosphatase 2 (IMPA2) gene may influence schizophrenia. We performed a genetic association study in Han Chinese cohorts. Five single nucleotide polymorphisms within IMPA2 promoter region (rs971363, rs971362, rs2075824, rs111410794 and rs111610121), as well as one (rs45442994, in intron 1) that was positively associated in another study, were selected for genotyping in 1397 patients with schizophrenia and 1285 mentally healthy controls. Genotype and allele frequencies were assessed by gender stratification. Interestingly, rs2075824 showed a strong association with schizophrenia (P = 4.1 × 10(-4) ), and the T allele was more frequent in cases than controls [P = 5.6 × 10(-5) , OR (95% CI) = 1.26 (1.13-1.41)]. In vitro promoter assay showed that the transcription activity of the T allele promoter was higher than that of the C allele promoter and the T allele of rs2075824 contributed to risk for schizophrenia. By stratifying males and females, we found a gender-specific association for IMPA2 and schizophrenia: the T allele of rs2075824 was more frequent in male cases compared with male controls [P = 1.4 × 10(-4) , OR (95% CI) = 1.33 (1.15-1.55)]. Our data suggest that a promoter polymorphism of IMPA2 possibly contributed to risk for schizophrenia by elevating transcription activity in Han Chinese individuals. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  8. Investigation and analysis of single nucleotide polymorphisms in Janus kinase/signal transducer and activator of transcription genes with leukemia.

    PubMed

    Zhong, Yuejiao; Wu, Jianzhong; Chen, Baoan; Ma, Rong; Cao, Haixia; Wang, Zhuo; Cheng, Lu; Ding, Jiahua; Feng, Jifeng

    2012-06-01

    Aberrant activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway may predispose to leukemia due to deregulation of proliferation, differentiation or apoptosis. This study was conducted to investigate whether any association exists between genetic polymorphisms in the JAK2, STAT3 and STAT5 genes and individual susceptibility to leukemia. A case-control study was carried out using a Chinese sample set with 344 cases of leukemia and 346 controls matched by age and ethnicity. Genomic DNA was assayed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) on 13 single nucleotide polymorphisms (SNPs). Genotype analyses showed that two SNPs, namely rs17886724 and rs2293157 located in STAT3 and STAT5, respectively, were significantly associated with leukemia (p < 0.05 for all). Interaction analyses of SNPs (rs17886724|rs2293157; rs11079041| rs2293157) showed that there were inferior associations in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) compared to the control group (0.1 > p > 0.05). Linkage disequilibrium existed between rs11079041 and rs2293157 in both leukemia and control groups (r(2) = 0.7). The haplotypes displayed significant association between rs11079041 and rs2293157 in both leukemia and control groups (p < 0.05). The accuracy rate of the support vector machine (SVM) classification model in making a prediction of leukemia was 97%. The results indicated that STAT3 and STAT5 gene SNPs may be prognostic of leukemia.

  9. Association of Plasminogen Activator Inhibitor-Type 1 (-675 4G/5G) Polymorphism with Pre-Eclampsia: Systematic Review

    PubMed Central

    Morgan, Jessie A.; Bombell, Sarah; McGuire, William

    2013-01-01

    Background and Aims Excessive generation of plasminogen activator inhibitor-type 1 (PAI-1) is implicated in the pathogenesis of pre-eclampsia and related conditions. The PAI-1 (−675 4G/5G) promoter polymorphism (rs1799889) affects transcriptional activity and is a putative genetic risk factor for pre-eclampsia. The aim of this study was identify, appraise and synthesise the available evidence for the association of the PAI-1 (−675 4G/5G) polymorphism with pre-eclampsia. Methods Systematic review and random effects meta-analysis of genetic association studies. Results We found 12 eligible genetic association studies in which a total of 1511 women with pre-eclampsia, eclampsia or HELLP syndrome and 3492 controls participated. The studies were generally small (median number of cases 102, range 24 to 403) and underpowered to detect plausible association sizes. Meta-analysis of all of the studies detected statistically significant gene-disease associations in the recessive [pooled odds ratio 1.28 (95% confidence interval 1.09, 1.50); population attributable risk 7.7%] and dominant [pooled odds ratio 1.21 (95% confidence interval 1.01, 1.44); population attributable risk 13.7%] models. We did not find evidence of statistical heterogeneity, funnel plot asymmetry or small study bias. Conclusions These data suggest that the fibrinolytic pathway regulated by the PAI-1 gene may contribute to the pathogenesis of pre-eclampsia and related conditions. This association, if confirmed in larger genetic association studies, may inform research efforts to develop novel interventions or help to prioritise therapeutic targets that merit evaluation in randomised clinical trials. PMID:23457639

  10. The Effect of Clade-Specific Sequence Polymorphisms on HIV-1 Protease Activity and Inhibitor Resistance Pathways

    SciTech Connect

    Bandaranayake, Rajintha M.; Kolli, Madhavi; King, Nancy M.; Nalivaika, Ellen A.; Heroux, Annie; Kakizawa, Junko; Sugiura, Wataru; Schiffer, Celia A.

    2010-09-08

    The majority of HIV-1 infections around the world result from non-B clade HIV-1 strains. The CRF01{_}AE (AE) strain is seen principally in Southeast Asia. AE protease differs by {approx}10% in amino acid sequence from clade B protease and carries several naturally occurring polymorphisms that are associated with drug resistance in clade B. AE protease has been observed to develop resistance through a nonactive-site N88S mutation in response to nelfinavir (NFV) therapy, whereas clade B protease develops both the active-site mutation D30N and the nonactive-site mutation N88D. Structural and biochemical studies were carried out with wild-type and NFV-resistant clade B and AE protease variants. The relationship between clade-specific sequence variations and pathways to inhibitor resistance was also assessed. AE protease has a lower catalytic turnover rate than clade B protease, and it also has weaker affinity for both NFV and darunavir (DRV). This weaker affinity may lead to the nonactive-site N88S variant in AE, which exhibits significantly decreased affinity for both NFV and DRV. The D30N/N88D mutations in clade B resulted in a significant loss of affinity for NFV and, to a lesser extent, for DRV. A comparison of crystal structures of AE protease shows significant structural rearrangement in the flap hinge region compared with those of clade B protease and suggests insights into the alternative pathways to NFV resistance. In combination, our studies show that sequence polymorphisms within clades can alter protease activity and inhibitor binding and are capable of altering the pathway to inhibitor resistance.

  11. Cloud-to-ground lightning activity in mesoscale convective complexes

    NASA Technical Reports Server (NTRS)

    Goodman, S. J.; Macgorman, D. R.

    1986-01-01

    An analysis of the evolution of cloud-to-ground lightning discharges attending convective storms in mesoscale convective systems was conducted in the framework of the mesoscale convective complexes (MCCs) life cycle. The lightning discharge data were acquired by a commercially available lightning detection and location system. Peak rates averaged 42/min for the MCCs analyzed; these rates are comparable to the highest observed rates within other mesoscale storm systems and are greater than 20 times the rates previously observed in isolated thunderstorms. Lightning damage occurs with half of the MCCs and is most frequent between the development and the mature phases of the MCC life cycle. The most active period is also characterized by the greatest average number of discrete strokes and largest fraction of multiple-stroke discharges. The total cloud-to-ground lightning activity and maximum flashing rate do not appear to be directly related to either the size of the cloud shield or total duration of the MCC.

  12. A nuclear single-nucleotide polymorphism (SNP) potentially useful for the separation of Rhodnius prolixus from members of the Rhodnius robustus cryptic species complex (Hemiptera: Reduviidae)

    PubMed Central

    Pavan, Márcio G.; Mesquita, Rafael D.; Lawrence, Gena G.; Lazoski, Cristiano; Dotson, Ellen M.; Abubucker, Sahar; Mitreva, Makedonka; Randall-Maher, Jennifer; Monteiro, Fernando A.

    2013-01-01

    The design and application of rational strategies that rely on accurate species identification are pivotal for effective vector control. When morphological identification of the target vector species is impractical, the use of molecular markers is required. Here we describe a non-coding, single-copy nuclear DNA fragment that contains a single-nucleotide polymorphism (SNP) with the potential to distinguish the important domestic Chagas disease vector, Rhodnius prolixus, from members of the four sylvatic Rhodnius robustus cryptic species complex. A total of 96 primer pairs obtained from whole genome shotgun sequencing of the R. prolixus genome (12,626 random reads) were tested on 43 R. prolixus and R. robustus s.l. samples. One of the seven amplicons selected (AmpG) presented a SNP, potentially diagnostic for R. prolixus, on the 280th site. The diagnostic nature of this SNP was then performed on 154 R. prolixus and R. robustus s.l. samples aimed at achieving the widest possible geographic coverage. The results of a 60% majority rule Bayesian consensus tree and a median-joining network constructed based on the genetic variability observed reveal the paraphyletic nature of the R. robustus species complex, with respect to R. prolixus. AmpG region is located in the fourth intron of the Transmembrane protein 165 gene, which seems to be in the R. prolixus X chromosome. Other possible chromosomal locations of the AmpG region in the R. prolixus genome are also presented and discussed. PMID:23219914

  13. Lovesongs and period gene polymorphisms indicate Lutzomyia cruzi (Mangabeira, 1938) as a sibling species of the Lutzomyia longipalpis (Lutz and Neiva, 1912) complex.

    PubMed

    Vigoder, Felipe M; Araki, Alejandra S; Bauzer, Luiz G S R; Souza, Nataly A; Brazil, Reginaldo P; Peixoto, Alexandre A

    2010-08-01

    The sand fly Lutzomyia cruzi (Mangabeira, 1938) is implicated as a vector of American visceral leishmaniasis (AVL) in some areas of Brazil. Lutzomyia cruzi is closely related to Lutzomyia longipalpis s.l. (Lutz and Neiva, 1912) the main Latin American vector of AVL and a species complex. Although females of the two species are identical, the males can be distinguished by differences in the genitalia. Nevertheless, pheromone analysis shows that Lu. cruzi males produce 9-methyl-germacrene-B, which has also been found in a number of Latin American populations of Lu. longipalpis s.l. In addition, analysis of microsatellite loci shows that the level of divergence between Lu. cruzi and Lu. longipalpis s.l. is similar to that observed among the Lu. longipalpis s.l. sibling species. Here we present the lovesongs of Lu. cruzi males which are similar to the Burst-type songs produced by one of the Lu. longipalpis s.l. sibling species. We also present data on the molecular polymorphisms of the period gene of Lu. cruzi that indicate this species as another sibling within the Lu. longipalpis complex. The results highlight the importance of an integrative approach to understand the patterns of genetic and phenotypic divergence among very closely related vector species. Copyright 2010. Published by Elsevier B.V.

  14. Genome-wide analysis of synonymous single nucleotide polymorphisms in Mycobacterium tuberculosis complex organisms: resolution of genetic relationships among closely related microbial strains.

    PubMed Central

    Gutacker, Michaela M; Smoot, James C; Migliaccio, Cristi A Lux; Ricklefs, Stacy M; Hua, Su; Cousins, Debby V; Graviss, Edward A; Shashkina, Elena; Kreiswirth, Barry N; Musser, James M

    2002-01-01

    Several human pathogens (e.g., Bacillus anthracis, Yersinia pestis, Bordetella pertussis, Plasmodium falciparum, and Mycobacterium tuberculosis) have very restricted unselected allelic variation in structural genes, which hinders study of the genetic relationships among strains and strain-trait correlations. To address this problem in a representative pathogen, 432 M. tuberculosis complex strains from global sources were genotyped on the basis of 230 synonymous (silent) single nucleotide polymorphisms (sSNPs) identified by comparison of four genome sequences. Eight major clusters of related genotypes were identified in M. tuberculosis sensu stricto, including a single cluster representing organisms responsible for several large outbreaks in the United States and Asia. All M. tuberculosis sensu stricto isolates of previously unknown phylogenetic position could be rapidly and unambiguously assigned to one of the eight major clusters, thus providing a facile strategy for identifying organisms that are clonally related by descent. Common clones of M. tuberculosis sensu stricto and M. bovis are distinct, deeply branching genotypic complexes whose extant members did not emerge directly from one another in the recent past. sSNP genotyping rapidly delineates relationships among closely related strains of pathogenic microbes and allows construction of genetic frameworks for examining the distribution of biomedically relevant traits such as virulence, transmissibility, and host range. PMID:12524330

  15. Attenuation of the effect of the FTO rs9939609 polymorphism on total and central body fat by physical activity in adolescents: the HELENA study.

    PubMed

    Ruiz, Jonatan R; Labayen, Idoia; Ortega, Francisco B; Legry, Vanessa; Moreno, Luis A; Dallongeville, Jean; Martínez-Gómez, David; Bokor, Szilvia; Manios, Yannis; Ciarapica, Donatella; Gottrand, Frederic; De Henauw, Stefaan; Molnár, Denes; Sjöström, Michael; Meirhaeghe, Aline

    2010-04-01

    To examine whether physical activity attenuates the effect of the FTO rs9939609 polymorphism on body fat estimates in adolescents. Cross-sectional study. Athens, Greece; Dortmund, Germany; Ghent, Belgium; Heraklion, Greece; Lille, France; Pécs, Hungary; Rome, Italy; Stockholm, Sweden; Vienna, Austria; and Zaragoza, Spain, from October 2006 to December 2007. Adolescents from the Healthy Lifestyle in Europe by Nutrition in Adolescence Cross-Sectional Study (n = 752). Physical activity. The FTO rs9939609 polymorphism was genotyped. Physical activity was assessed by accelerometry. We measured weight, height, waist circumference, and triceps and subscapular skinfolds; body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]) and body fat percentage were calculated. The A allele of the FTO polymorphism was significantly associated with higher BMI (+0.42 per risk allele), higher body fat percentage (+1.03% per risk allele), and higher waist circumference (+0.85 cm per risk allele). We detected significant or borderline gene x physical activity interactions for the studied body fat estimates (for interaction, P = .02, .06, and .10 for BMI, body fat percentage, and waist circumference, respectively). Indeed, the effect of the FTO rs9939609 polymorphism on these body fat parameters was much lower in adolescents who met the daily physical activity recommendations (ie, >/=60 min/d of moderate to vigorous physical activity) compared with those who did not: +0.17 vs +0.65 per risk allele in BMI, respectively; +0.40% vs +1.70% per risk allele in body fat percentage, respectively; and +0.60 vs +1.15 cm per risk allele in waist circumference, respectively. Adolescents meeting the daily physical activity recommendations may overcome the effect of the FTO rs9939609 polymorphism on obesity-related traits.

  16. Performance Assessment Assistance Activities in the DOE Complex - 12325

    SciTech Connect

    Seitz, Roger R.; Phifer, Mark A.; Letourneau, Martin J.

    2012-07-01

    The United States Department of Energy Office of Environmental Management (DOE-EM) has established a Performance Assessment Community of Practice (PA CoP) to foster the sharing of information among performance assessment (PA) and risk assessment practitioners, regulators and oversight personnel. The general intent is to contribute to continuous improvement in the consistency, technical adequacy and quality of implementation of PAs and risk assessments around the DOE Complex. The PA CoP activities have involved commercial disposal facilities and international participants to provide a global perspective. The PA CoP has also sponsored annual technical exchanges as a means to foster improved communication and to share lessons learned from on-going modelling activities. The PA CoP encourages activities to provide programmatic and technical assistance in the form of sharing experience and lessons learned with practitioners during the development of PAs and risk assessments. This assistance complements DOE-EM reviews through the Low-Level Waste Disposal Facility Federal Review Group (LFRG) that are conducted after modelling efforts are completed. Such up-front assistance is providing additional value in terms of improving consistency and sharing of information. There has been a substantial increase in the amount of assistance being provided. The assistance has been well received by practitioners and regulators that have been involved. The paper highlights assistance and sharing of information that has been conducted in the last two years to support activities underway in support of proposed disposal facilities at Paducah, Portsmouth, and the Idaho National Laboratory and tank closure at Hanford. DOE-EM established the PA CoP to help improve the consistency and quality of implementation of modelling activities around the DOE Complex. The PA CoP has sponsored annual technical exchanges as a means to foster improved communication and to share lessons learned from ongoing

  17. Impact of the -675 4G/5G polymorphism of the plasminogen activator inhibitor-1 gene on childhood IgA nephropathy.

    PubMed

    Han, Su-Ryun; Kim, Cheon-Jong; Lee, Byung-Cheol

    2012-04-01

    Plasminogen activator inhibitor-1 (PAI-1) is an important regulator of the fibrinolytic pathway and extracellular matrix (ECM) turnover. The -675 4G/5G polymorphism in the PAI-1 promoter is associated with altered PAI-1 transcription, suggesting that this polymorphism may be a candidate risk factor for diseases characterized by ECM accumulation, such as immunoglobulin A nephropathy (IgAN) and mesangial proliferative glomerulonephritis (MesPGN). We genotyped childhood patients with biopsy-confirmed IgAN (n=111) and MesPGN (n=47), and healthy control subjects (n=230) for the -675 4G/5G PAI-1 polymorphism by polymerase chain reaction-restriction fragment length polymorphism methods. The distribution of the 4G/4G (27.9%), 4G/5G (45.1%) and 5G/5G (27.0%) genotypes in IgAN patients was significantly different from the healthy controls (32.2, 54.3 and 13.5%, respectively) (p=0.0092). There was no significant difference in the genotype distributions of the 4G/5G polymorphism between MesPGN patients and the healthy controls. Regarding the impact of the polymorphism on IgAN, the 4G/4G genotype was markedly increased in patients with proteinuria (≥1,000 mg/day) and/or hypertension when compared to patients without proteinuria and hypertension (OR=5.23, 95% CI 1.34-20.38, P=0.0183). These findings indicate that the PAI-1 gene polymorphism may affect the susceptibility of childhood IgAN.

  18. Impact of the -675 4G/5G polymorphism of the plasminogen activator inhibitor-1 gene on childhood IgA nephropathy

    PubMed Central

    HAN, SU-RYUN; KIM, CHEON-JONG; LEE, BYUNG-CHEOL

    2012-01-01

    Plasminogen activator inhibitor-1 (PAI-1) is an important regulator of the fibrinolytic pathway and extracellular matrix (ECM) turnover. The -675 4G/5G polymorphism in the PAI-1 promoter is associated with altered PAI-1 transcription, suggesting that this polymorphism may be a candidate risk factor for diseases characterized by ECM accumulation, such as immunoglobulin A nephropathy (IgAN) and mesangial proliferative glomerulonephritis (MesPGN). We genotyped childhood patients with biopsy-confirmed IgAN (n=111) and MesPGN (n=47), and healthy control subjects (n=230) for the -675 4G/5G PAI-1 polymorphism by polymerase chain reaction-restriction fragment length polymorphism methods. The distribution of the 4G/4G (27.9%), 4G/5G (45.1%) and 5G/5G (27.0%) genotypes in IgAN patients was significantly different from the healthy controls (32.2, 54.3 and 13.5%, respectively) (p=0.0092). There was no significant difference in the genotype distributions of the 4G/5G polymorphism between MesPGN patients and the healthy controls. Regarding the impact of the polymorphism on IgAN, the 4G/4G genotype was markedly increased in patients with proteinuria (≥1,000 mg/day) and/or hypertension when compared to patients without proteinuria and hypertension (OR=5.23, 95% CI 1.34–20.38, P=0.0183). These findings indicate that the PAI-1 gene polymorphism may affect the susceptibility of childhood IgAN. PMID:22969955

  19. Visuomotor expertise and dimensional complexity of cerebral cortical activity.

    PubMed

    Hung, Tsung-Min; Haufler, Amy J; Lo, Li-Chuan; Mayer-Kress, Gottfried; Hatfield, Bradley D

    2008-04-01

    This study employed the correlation dimension (D2) to examine whether visuomotor expertise was inversely related to the complexity of cerebral cortical activity. Expert rifle shooters (N = 15) and novices (N = 21) completed 40 shots in the standing position during which the electroencephalogram (EEG) was recorded at 10 sites (F3, F4, C3, C4, T3, T4, P3, P4, O1, and O2) during a 5-s aiming period prior to trigger pull. D2 was derived for each trial and averaged across shots. A 2 x 2 x 5 (group x cerebral hemisphere x region) ANOVA was employed to contrast D2, while correlation analyses were used to determine the relationship between D2 and target shooting accuracy as well as variability of shot placement. As predicted, experts exhibited lower D2 (5.02 +/- 0.16 vs 5.49 +/- 0.13, respectively) and greater accuracy of shot placement ((339.8 +/- 44.7 vs 90.7 +/- 38.9 points out of 400 possible, respectively). Experts also exhibited an inverse relationship between D2 and shooting accuracy, while, in contrast, novices revealed a positive relationship. The results suggest that refinement and efficiency of cerebral cortical activity facilitates visuomotor performance. Lower complexity may be associated with less neuromotor "noise" in the brain, thus reducing interference with intended action.

  20. Surface active complexes formed between keratin polypeptides and ionic surfactants.

    PubMed

    Pan, Fang; Lu, Zhiming; Tucker, Ian; Hosking, Sarah; Petkov, Jordan; Lu, Jian R

    2016-12-15

    Keratins are a group of important proteins in skin and hair and as biomaterials they can provide desirable properties such as strength, biocompatibility, and moisture regaining and retaining. The aim of this work is to develop water-soluble keratin polypeptides from sheep wool and then explore how their surface adsorption behaves with and without surfactants. Successful preparation of keratin samples was demonstrated by identification of the key components from gel electrophoresis and the reproducible production of gram scale samples with and without SDS (sodium dodecylsulphate) during wool fibre dissolution. SDS micelles could reduce the formation of disulphide bonds between keratins during extraction, reducing inter-molecular crosslinking and improving keratin polypeptide solubility. However, Zeta potential measurements of the two polypeptide batches demonstrated almost identical pH dependent surface charge distributions with isoelectric points around pH 3.5, showing complete removal of SDS during purification by dialysis. In spite of different solubility from the two batches of keratin samples prepared, very similar adsorption and aggregation behavior was revealed from surface tension measurements and dynamic light scattering. Mixing of keratin polypeptides with SDS and C12TAB (dodecyltrimethylammonium bromide) led to the formation of keratin-surfactant complexes that were substantially more effective at reducing surface tension than the polypeptides alone, showing great promise in the delivery of keratin polypeptides via the surface active complexes. Neutron reflection measurements revealed the coexistence of surfactant and keratin polypeptides at the interface, thus providing the structural support to the observed surface tension changes associated with the formation of the surface active complexes.

  1. EEG activity during the performance of complex mental problems.

    PubMed

    Jausovec, N; Jausovec, K

    2000-04-01

    This study investigated differences in cognitive processes related to problem complexity. It was assumed that these differences would be reflected in respondents' EEG activity--spectral power and coherence. A second issue of the study was to compare differences between the lower (alpha(1) = 7.9-10.0 Hz), and upper alpha band (alpha(2) = 10.1-12.9 Hz). In the first experiment two well-defined problems with two levels of complexity were used. Only minor differences in EEG power and coherence measures related to problem complexity were observed. In the second experiment divergent production problems resembling tasks on creativity tests were compared with dialectic problems calling for creative solutions. Differences in EEG power measures were mainly related to the form of problem presentation (figural/verbal). In contrast, coherence was related to the level of creativity needed to solve a problem. Noticeable increased intra- and interhemispheric cooperation between mainly the far distant brain regions was observed in the EEG activity of respondents while solving the dialectic problems. These results are explained by the more intense involvement of the long cortico-cortical fiber system in creative thinking. Differences between the lower and upper alpha band were significant for the power and coherence measures. In Experiment 2, fewer differences were observed in power measures in the upper alpha band than in the lower alpha band. A reverse pattern was observed for the coherence measures. These results hint to a functional independence of the two alpha bands, however, they do not allow to draw firm conclusions about their functional meanings. The study showed that it is unlikely that individuals solve well- and ill-defined problems by employing similar cognitive strategies.

  2. The AIRE -230Y Polymorphism Affects AIRE Transcriptional Activity: Potential Influence on AIRE Function in the Thymus

    PubMed Central

    Lovewell, Thomas R. J.; McDonagh, Andrew J.; Messenger, Andrew G.; Azzouz, Mimoun; Tazi-Ahnini, Rachid

    2015-01-01

    Background The autoimmune regulator (AIRE) is expressed in the thymus, particularly in thymic medullary epithelial cells (mTECs), and is required for the ectopic expression of a diverse range of peripheral tissue antigens by mTECs, facilitating their ability to perform negative selection of auto-reactive immature T-cells. The expression profile of peripheral tissue antigens is affected not only by AIRE deficiency but also with variation of AIRE activity in the thymus. Method and Results Therefore we screened 591bp upstream of the AIRE transcription start site including AIRE minimal promoter for single nucleotide polymorphism (SNPs) and identified two SNPs -655R (rs117557896) and -230Y (rs751032) respectively. To study the effect of these variations on AIRE promoter activity we generated a Flp-In host cell line which was stably transfected with a single copy of the reporter vector. Relative promoter activity was estimated by comparing the luciferase specific activity for lysates of the different reporter AIRE promoter-reporter gene constructs including AIRE-655G AIRE-230C, AIRE-655G AIRE-230T and AIRE-655A AIRE-230C. The analysis showed that the commonest haplotype AIRE-655G AIRE-230C has the highest luciferase specific activity (p<0.001). Whereas AIRE-655G AIRE-230T has a luciferase specific activity value that approaches null. Both AIRE promoter polymorphic sites have one allele that forms a CpG methylation site which we determined can be methylated in methylation assays using the M.SssI CpG methyltransferase. Conclusion AIRE-230Y is in a conserved region of the promoter and is adjacent to a predicted WT1 transcription factor binding site, suggesting that AIRE-230Y affects AIRE expression by influencing the binding of biochemical factors to this region. Our findings show that AIRE-655GAIRE-230T haplotype could dramatically alter AIRE transcription and so have an effect on the process of negative selection and affect susceptibility to autoimmune conditions. PMID

  3. Fasting plasma free fatty acid concentrations and Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR) gamma2 gene in healthy individuals.

    PubMed

    Vaccaro, O; Mancini, F P; Ruffa, G; Sabatino, L; Iovine, C; Masulli, M; Colantuoni, V; Riccardi, G

    2002-10-01

    The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR) gamma gene has been associated in some, but not all, studies with lower body mass index (BMI) and improved insulin sensitivity; how an altered transcriptional activity of PPARgamma2 could influence insulin sensitivity is currently unclear. The free fatty acids (FFAs) released from adipose tissue triglycerides via lipolysis are key mediators of impaired insulin sensitivity; however, no study has described the relationship of the Pro12Ala mutation with circulating levels of FFAs under physiological conditions. To investigate in a population-based sample of Caucasians the relation of the Pro12Ala polymorphism with plasma concentrations of FFAs and other markers of lipid and glucose metabolism described as components of the insulin resistance syndrome. Four hundred and thirty-eight nondiabetic employees of the Italian Telephone Company, aged 35-65 years, randomly selected from a total population of 3900 participants in a company-sponsored health screening. The Pro12Ala polymorphism of the PPARgamma was studied together with plasma FFAs, insulin, glucose, triglycerides, high density lipoprotein (HDL) cholesterol, blood pressure and anthropometry. The Homeostatic Model Assessment (HOMA) index was calculated as a measure of insulin resistance. Carriers and noncarriers of the Pro12Ala polymorphism showed very similar circulating levels of FFA (0.46 +/- 0.2 vs. 0.47 +/- 0.2, NS); plasma glucose, triglycerides, HDL cholesterol and blood pressure were also similar in the two groups with or without the polymorphism. To allow for the possible confounding effect of obesity, a separate analysis was conducted in overweight (BMI > or = 25 kg/m(2)) and normal-weight people (BMI < 25 kg/m(2)). Circulating plasma FFA concentrations, as well as triglycerides, blood pressure and HOMA, were significantly higher in overweight than normal-weight, as expected, but no significant differences were detected

  4. A polymorphism at position 400 in the connection subdomain of HIV-1 reverse transcriptase affects sensitivity to NNRTIs and RNaseH activity.

    PubMed

    Wright, David W; Deuzing, Ilona P; Flandre, Philippe; van den Eede, Peter; Govaert, Micheline; Setiawan, Laurentia; Coveney, Peter V; Marcelin, Anne-Geneviève; Calvez, Vincent; Boucher, Charles A B; Beerens, Nancy

    2013-01-01

    Reverse transcriptase (RT) plays an essential role in HIV-1 replication, and inhibition of this enzyme is a key component of HIV-treatment. However, the use of RT inhibitors can lead to the emergence of drug-resistant variants. Until recently, most clinically relevant resistance mutations were found in the polymerase domain of RT. Lately, an increasing number of resistance mutations has been identified in the connection and RNaseH domain. To further explore the role of these domains we analyzed the complete RT sequence of HIV-1 subtype B patients failing therapy. Position A/T400 in the connection subdomain is polymorphic, but the proportion of T400 increases from 41% in naïve patients to 72% in patients failing therapy. Previous studies suggested a role for threonine in conferring resistance to nucleoside RT inhibitors. Here we report that T400 also mediates resistance to non-nucleoside RT inhibitors. The susceptibility to NVP and EFV was reduced 5-fold and 2-fold, respectively, in the wild-type subtype B NL4.3 background. We show that substitution A400T reduces the RNaseH activity. The changes in enzyme activity are remarkable given the distance to both the polymerase and RNaseH active sites. Molecular dynamics simulations were performed, which provide a novel atomistic mechanism for the reduction in RNaseH activity induced by T400. Substitution A400T was found to change the conformation of the RNaseH primer grip region. Formation of an additional hydrogen bond between residue T400 and E396 may play a role in this structural change. The slower degradation of the viral RNA genome may provide more time for dissociation of the bound NNRTI from the stalled RT-template/primer complex, after which reverse transcription can resume.

  5. A Polymorphism at Position 400 in the Connection Subdomain of HIV-1 Reverse Transcriptase Affects Sensitivity to NNRTIs and RNaseH Activity

    PubMed Central

    Flandre, Philippe; van den Eede, Peter; Govaert, Micheline; Setiawan, Laurentia; Coveney, Peter V.; Marcelin, Anne-Geneviève; Calvez, Vincent; Boucher, Charles A. B.; Beerens, Nancy

    2013-01-01

    Reverse transcriptase (RT) plays an essential role in HIV-1 replication, and inhibition of this enzyme is a key component of HIV-treatment. However, the use of RT inhibitors can lead to the emergence of drug-resistant variants. Until recently, most clinically relevant resistance mutations were found in the polymerase domain of RT. Lately, an increasing number of resistance mutations has been identified in the connection and RNaseH domain. To further explore the role of these domains we analyzed the complete RT sequence of HIV-1 subtype B patients failing therapy. Position A/T400 in the connection subdomain is polymorphic, but the proportion of T400 increases from 41% in naïve patients to 72% in patients failing therapy. Previous studies suggested a role for threonine in conferring resistance to nucleoside RT inhibitors. Here we report that T400 also mediates resistance to non-nucleoside RT inhibitors. The susceptibility to NVP and EFV was reduced 5-fold and 2-fold, respectively, in the wild-type subtype B NL4.3 background. We show that substitution A400T reduces the RNaseH activity. The changes in enzyme activity are remarkable given the distance to both the polymerase and RNaseH active sites. Molecular dynamics simulations were performed, which provide a novel atomistic mechanism for the reduction in RNaseH activity induced by T400. Substitution A400T was found to change the conformation of the RNaseH primer grip region. Formation of an additional hydrogen bond between residue T400 and E396 may play a role in this structural change. The slower degradation of the viral RNA genome may provide more time for dissociation of the bound NNRTI from the stalled RT-template/primer complex, after which reverse transcription can resume. PMID:24098331

  6. Body composition and muscular strength changes after moderate activity: association with matrix metalloproteinase polymorphisms.

    PubMed

    Fiotti, N; Deiuri, E; Altamura, N; De Colle, P; Moretti, M E; Toigo, G; Giansante, C

    2009-01-01

    Remodeling of skeletal muscles is regulated by matrix metalloproteinases (MMPs). Functional genetic polymorphism (PM), modulating the expression of some MMPs, might be associated to different body composition and muscular strength improvement after exercise. Genetic PM of MMP-1 (G+/- at -1607), MMP-3 (5A/6A at -1171) and MMP-9 (Cytosine-Adenine microsatellite=(13-27)CA) repeats, around -90), body cell mass (BCM), extracellular water (ECW) and isometric maximal extensor strength (MES) of both legs were determined in 17 old sedentary women at the beginning and at the end of a 24 week physical exercise program. A 12 and 72% increase in BCM and MES, respectively, and 11% reduction in ECW were observed at the end of the program. Carriers of G-insertion in MMP-1, PM increased their BCM (7 kg vs. -1.5, p=0.007) and lost ECW (9% of total body water vs. 0.1%, p=0.004) more than the non-carriers; homozygote for 21 or less CA repeats/allele in MMP-9 PM gained more MES (115 N, interquartile range=IQR=63-132) than carriers of longer microsatellites (63 N, IQR=40-86, p=0.028). MMP-3 did not show any association with body composition and exercise-related strength changes. Exercise in elderly women increases BCM and strength, these changes are associate to specific MMP genotypes.

  7. Polymorphism in the Tyrosine Hydroxylase (TH) Gene Is Associated with Activity-Impulsivity in German Shepherd Dogs

    PubMed Central

    Kubinyi, Enikő; Vas, Judit; Hejjas, Krisztina; Ronai, Zsolt; Brúder, Ildikó; Turcsán, Borbála; Sasvari-Szekely, Maria; Miklósi, Ádám

    2012-01-01

    We investigated the association between repeat polymorphism in intron 4 of the tyrosine hydroxylase (TH) gene and two personality traits, activity-impulsivity and inattention, in German Shepherd Dogs. The behaviour of 104 dogs was characterized by two instruments: (1) the previously validated Dog-Attention Deficit Hyperactivity Disorder Rating Scale (Dog-ADHD RS) filled in by the dog owners and (2) the newly developed Activity-impulsivity Behavioural Scale (AIBS) containing four subtests, scored by the experimenters. Internal consistency, inter-observer reliability, test-retest reliability and convergent validity were demonstrated for AIBS. Dogs possessing at least one short allele were proved to be more active-impulsive by both instruments, compared to dogs carrying two copies of the long allele (activity-impulsivity scale of Dog-ADHD RS: p = 0.007; AIBS: p = 0.023). The results have some potential to support human studies; however, further research should reveal the molecular function of the TH gene variants, and look for the effect in more breeds. PMID:22272320

  8. Prevalent Polymorphism in Thyroid Hormone-Activating Enzyme Leaves a Genetic Fingerprint That Underlies Associated Clinical Syndromes

    PubMed Central

    McAninch, Elizabeth A.; Jo, Sungro; Preite, Nailliw Z.; Farkas, Erzsébet; Mohácsik, Petra; Fekete, Csaba; Egri, Péter; Gereben, Balázs; Li, Yan; Deng, Youping; Patti, Mary-Elizabeth; Zevenbergen, Chantal; Peeters, Robin P.; Mash, Deborah C.

    2015-01-01

    Context: A common polymorphism in the gene encoding the activating deiodinase (Thr92Ala-D2) is known to be associated with quality of life in millions of patients with hypothyroidism and with several organ-specific conditions. This polymorphism results in a single amino acid change within the D2 molecule where its susceptibility to ubiquitination and proteasomal degradation is regulated. Objective: To define the molecular mechanisms underlying associated conditions in carriers of the Thr92Ala-D2 polymorphism. Design, Setting, Patients: Microarray analyses of 19 postmortem human cerebral cortex samples were performed to establish a foundation for molecular studies via a cell model of HEK-293 cells stably expressing Thr92 or Ala92 D2. Results: The cerebral cortex of Thr92Ala-D2 carriers exhibits a transcriptional fingerprint that includes sets of genes involved in CNS diseases, ubiquitin, mitochondrial dysfunction (chromosomal genes encoding mitochondrial proteins), inflammation, apoptosis, DNA repair, and growth factor signaling. Similar findings were made in Ala92-D2-expressing HEK-293 cells and in both cases there was no evidence that thyroid hormone signaling was affected ie, the expression level of T3-responsive genes was unchanged, but that several other genes were differentially regulated. The combined microarray analyses (brain/cells) led to the development of an 81-gene classifier that correctly predicts the genotype of homozygous brain samples. In contrast to Thr92-D2, Ala92-D2 exhibits longer half-life and was consistently found in the Golgi. A number of Golgi-related genes were down-regulated in Ala92-D2-expressing cells, but were normalized after 24-h-treatment with the antioxidant N-acetylecysteine. Conclusions: Ala92-D2 accumulates in the Golgi, where its presence and/or ensuing oxidative stress disrupts basic cellular functions and increases pre-apoptosis. These findings are reminiscent to disease mechanisms observed in other neurodegenerative

  9. Increased body mass index but not common vitamin D receptor, peroxisome proliferator-activated receptor γ, or cytokine polymorphisms confers predisposition to posttransplant diabetes.

    PubMed

    Wang, Ping; Hudspeth, Elissa

    2011-12-01

    Posttransplant diabetes mellitus (PTDM) is a major complication after solid organ transplantation. The use of corticosteroids and calcineurin inhibitors, especially tacrolimus, are significant risk factors. However, it is not clear what genetic factors modify the risk. Evidence suggests vitamin D deficiency, perturbed glucose homeostasis, and increased inflammation all play roles in the development of diabetes. To investigate whether common vitamin D receptor (VDR), cytokine, and peroxisome proliferator-activated receptor γ (PPARγ) polymorphisms are correlated with the development of PTDM. DNA was isolated from the peripheral blood of 51 kidney transplant recipients with PTDM and 72 patients without diabetes pretransplant or posttransplant at the time of follow-up. The genotypes for 5 polymorphisms, 1 each in VDR, PPARγ, INFγ, TGFβ1, and TNF, were determined using direct sequencing. Age, sex, number of acute rejection episodes, follow-up length, ethnicity, body mass index, and the frequency of alleles and genotypes for each polymorphism were compared between the 2 groups. Body mass index was the only factor that was statistically different between the 2 groups (P  =  .001). The frequency of different alleles and genotypes for each of the 5 polymorphisms did not differ between the 2 groups. These results indicate that increased body mass index is a significant risk factor for the development of PTDM. However, none of the genetic polymorphisms studied confer predisposition to PTDM with the current sample size.

  10. Association of peroxisome proliferator-activated receptor γ Pro12Ala gene polymorphism with type 2 diabetic nephropathy risk in Caucasian population.

    PubMed

    Zhou, Tian-Biao; Guo, Xue-Feng; Yin, Sheng-Sheng

    2014-06-01

    Association of peroxisome proliferator-activated receptor gamma (PPARγ) Pro12Ala gene polymorphism with type 2 diabetic nephropathy (T2DN) risk in Caucasians is still not clear. This investigation was conducted to assess if there was an association between the PPARγ Pro12Ala gene polymorphism and T2DN risk in Caucasians using meta-analysis. The relevant literatures were identified from PubMed, and Cochrane Library on 10 October 2013, and eligible studies were included and synthesized. Six reports including eight studies were recruited into this meta-analysis for the association of the PPARγ Pro12Ala gene polymorphism with T2DN risk in Caucasians. The Pro/Pro genotype was shown to be associated with T2DN risk in Caucasians. However, the Ala/Ala genotype and Ala allele were not associated with T2DN risk in Caucasians. In the sensitivity analysis, according to the control source from hospital, the control source from population, the genotyping methods using PCR-RFLP, Taqman, sample size of case <100, the association of the PPARγ Pro12Ala gene polymorphism with T2DN risk was similar to those in non-sensitivity analysis. In conclusion, the PPARγ Pro/Pro genotype was associated with T2DN risk in Caucasians, but the Ala/Ala genotype and Ala allele not. However, additional studies are required to firmly establish a correlation between the PPARγ Pro12Ala gene polymorphism and T2DN risk in Caucasians.

  11. Peroxisome proliferator-activated receptor γ Pro12Ala polymorphism decrease the risk of diabetic nephropathy in type 2 diabetes: a meta analysis.

    PubMed

    Ding, Jiarong; Zhu, Chao; Mei, Xiaobin; Zhou, Yangyang; Feng, Bing; Guo, Zhiyong

    2015-01-01

    The association between peroxisome proliferators-activated receptor γ (PPARγ) Pro12Ala polymorphism and T2DN risk is inconclusive and contradictory. Therefore, we performed a meta-analysis. All relevant studies were searched by using the PubMed and EMBASE. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated. Effect model selection was on the basis of heterogeneity test. A total of 20 case-control studies with 9357 subjects were included in this meta-analysis. We found that PPARγ Pro12Ala polymorphism significantly associated with decreased T2DN risk (OR = 0.74; 95% CI 0.59-0.94; P = 0.01). In the subgroup analysis by race, Caucasian with PPARγ Pro12Ala polymorphism showed decreased T2DN risk (OR = 0.63; 95% CI 0.46-0.88; P = 0.006). But Asian with PPARγ Pro12Ala polymorphism did not show decreased T2DN risk (OR = 0.87; 95% CI 0.62-1.22; P = 0.41). In conclusion, our meta-analysis study confirmed that PPARγ Pro12Ala polymorphism might contribute to the risk for T2DN.

  12. Peroxisome proliferator-activated receptor γ Pro12Ala polymorphism decrease the risk of diabetic nephropathy in type 2 diabetes: a meta analysis

    PubMed Central

    Ding, Jiarong; Zhu, Chao; Mei, Xiaobin; Zhou, Yangyang; Feng, Bing; Guo, Zhiyong

    2015-01-01

    Background: The association between peroxisome proliferators-activated receptor γ (PPARγ) Pro12Ala polymorphism and T2DN risk is inconclusive and contradictory. Therefore, we performed a meta-analysis. Methods: All relevant studies were searched by using the PubMed and EMBASE. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated. Effect model selection was on the basis of heterogeneity test. Results: A total of 20 case-control studies with 9357 subjects were included in this meta-analysis. We found that PPARγ Pro12Ala polymorphism significantly associated with decreased T2DN risk (OR = 0.74; 95% CI 0.59-0.94; P = 0.01). In the subgroup analysis by race, Caucasian with PPARγ Pro12Ala polymorphism showed decreased T2DN risk (OR = 0.63; 95% CI 0.46-0.88; P = 0.006). But Asian with PPARγ Pro12Ala polymorphism did not show decreased T2DN risk (OR = 0.87; 95% CI 0.62-1.22; P = 0.41). Conclusions: In conclusion, our meta-analysis study confirmed that PPARγ Pro12Ala polymorphism might contribute to the risk for T2DN. PMID:26221313

  13. Plasminogen activator inhibitor-1 polymorphisms (-844 G>A and HindIII C>G) in systemic lupus erythematosus: association with clinical variables.

    PubMed

    Padilla-Gutiérrez, Jorge Ramón; Palafox-Sánchez, Claudia Azucena; Valle, Yeminia; Orozco-Barocio, Gerardo; Oregón-Romero, Edith; Vázquez-Del Mercado, Mónica; Rangel-Villalobos, Héctor; Llamas-Covarrubias, Mara Anaís; Muñoz-Valle, José Francisco

    2011-03-01

    Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the presence of autoantibodies against nuclear autoantigens as well as cytoplasmic and circulating proteins. Recent studies have demonstrated mechanisms responsible for modulation of the immune response by the plasminogen activator inhibitor-1 (PAI-1). Furthermore, the endogenous PAI-1 has shown to promote a Th2 immune response. We assessed the -844 G>A and HindIII C>G PAI-1 polymorphisms in SLE. In a case-control study of 71 SLE patients classified according to ACR criteria and 71 healthy subjects (HS). The A allele of -844 PAI-1 polymorphism showed a significant difference in SLE patients (41%) when compared with HS (27%) [P = 0.01; OR = 1.8, 95%, CI = 1.1-3.0]. In addition, the -844 G>A PAI-1 polymorphism was associated with increased risk for SLE in a dominant genetic model (G/G vs. G/A + A/A; OR = 2.3, 95% CI = 1.14-4.44). Also, anti-RNP positive antibodies in SLE were associated with G/G -844 PAI-1 genotype. The HindIII polymorphism did not show any differences. The haplotype analysis showed that the AC haplotype confers susceptibility to SLE (OR = 3.1, 95% CI, 1.45-6.52; P = 0.003). The AC haplotype of the -844 and HindIII PAI-1 polymorphism might be an additional susceptibility factor to SLE in Mexicans.

  14. Lack of effects of peroxisome proliferator-activated receptor gamma genetic polymorphisms on breast cancer risk: a case-control study and pooled analysis.

    PubMed

    Park, Boyoung; Shin, Aesun; Kim, Kyee-Zu; Lee, Yeon-Su; Hwang, Jung-Ah; Kim, Yeonju; Sung, Joohon; Yoo, Keun-Young; Lee, Eun-Sook

    2014-01-01

    A growing body of evidence suggests that the peroxisome proliferator-activated receptor-gamma (PPARγ) gene may harbor targets for the chemoprevention of breast cancer. However, it is unclear whether polymorphisms in the PPARγ gene are associated with the susceptibility of breast cancer. We performed a candidate gene association study between PPARγ polymorphisms and breast cancer and a meta-analysis on the association of breast cancer with selected PPARγ variants. Six single nucleotide polymorphisms (SNPs) in the PPARγ gene were analyzed among 456 breast cancer patients and 461 controls from the National Cancer Center in Korea. Association between the polymorphisms and breast cancer risk were assessed using the Cochrane-Armitage test for trend and a multivariate logistic regression model. Two SNPs, rs3856806 and rs1801282, had been previously analyzed, thus enabling us to perform pooled analyses on their associations with breast cancer susceptibility. Our findings from the candidate gene association study showed no association between the PPARγ gene polymorphisms and breast cancer risk. A meta-analysis combining existing studies and our current study also refuted an association of the PPARγ gene with breast cancer. Our findings suggest that the PPARγ gene may not harbor variants that alter breast cancer susceptibility, although a moderate sample size might have precluded a decisive conclusion.

  15. Differentiation of strains in Mycobacterium tuberculosis complex by DNA sequence polymorphisms, including rapid identification of M. bovis BCG.

    PubMed Central

    Frothingham, R

    1995-01-01

    The Mycobacterium tuberculosis complex includes M. tuberculosis, M. bovis, M. microti, and M. africanum. Seven strains of the M. tuberculosis complex were sequenced in a region of about 300 bp which contains multiple 15-bp tandem repeats and which is part of a 1,551-bp open reading frame. Four distinct sequences were obtained, each defining a sequevar. A sequevar includes the strain or strains with a given sequence. The type strain M. tuberculosis TMC 102 (H37Rv) was designated sequevar MED-G. When compared to MED-G, sequevar LONG had an insertion of one 15-bp tandem repeat and sequevar SHORT had a deletion of one tandem repeat. Sequevar MED-C had a G-->C substitution, coding for the conservative change Ser-->Thr. BanI cuts only sequevar MED-C at the site of the substitution. PCR-restriction enzyme analysis was used to determine the sequevars of 92 M. tuberculosis complex strains. All 23 M. bovis BCG strains belonged to sequevar MED-C. The M. africanum type strain was sequevar SHORT. The remaining 68 strains of M. tuberculosis, M. bovis (not BCG), and M. microti were sequevars LONG (3 strains) or MED-G (65 strains). PCR-restriction enzyme analysis was applied to reference strains and clinical isolates with a worldwide distribution. This method provides rapid, sensitive, and specific identification of the important vaccine strain M. bovis BCG. PMID:7790448

  16. Obesity and Pro12Ala Polymorphism of Peroxisome Proliferator-Activated Receptor-Gamma Gene in Healthy Adults: A Systematic Review and Meta-Analysis.

    PubMed

    Mansoori, Anahita; Amini, Maryam; Kolahdooz, Fariba; Seyedrezazadeh, Ensiyeh

    2015-01-01

    The aim of this systematic review was to evaluate the relationship between obesity and peroxisome proliferator-activated receptor-gamma (PPARx03B3;) Pro12Ala polymorphism in healthy adults. Weighted mean differences (WMDs) of body mass index (BMI) were calculated for different inheritance models and subgroups. Fifty-six studies were eligible for inclusion in the meta-analysis. The result shows that the Ala allele of this polymorphism was associated with increased WMD in mean BMI (WMD = 0.29, 95% CI 0.10-0.48, p = 0.003). The Ala carriers were associated with increased WMD in mean BMI values in both genders and in the Caucasian subgroup. The associations were seen among people with higher levels of BMI (BMI ≥35). The Ala allele of the PPARx03B3; Pro12Ala polymorphism in healthy adults was associated with increased BMI under a dominant model of inheritance. © 2015 S. Karger AG, Basel.

  17. First isolated active titanium peroxo complex: characterization and theoretical study.

    PubMed

    Kholdeeva, Oxana A; Trubitsina, Tatiana A; Maksimovskaya, Raisa I; Golovin, Anatolii V; Neiwert, Wade A; Kolesov, Boris A; López, Xavier; Poblet, Josep M

    2004-04-05

    The protonated titanium peroxo complex [Bu(4)N](4)[HPTi(O(2))W(11)O(39)] (1) has been first prepared via interaction of the micro-oxo dimeric heteropolytungstate [Bu(4)N](8)[(PTiW(11)O(39))(2)O] (3) with an excess of 30% aqueous H(2)O(2) in MeCN. Peroxo complex 1 has been characterized by using elemental analysis, UV-vis, IR, resonance Raman (RR), (31)P and (183)W NMR spectroscopy, cyclic voltammetry, and potentiometric titration. The electronic and vibrational spectra of 1 are very similar to those of the well-known unprotonated titanium peroxo complex [Bu(4)N](5)[PTi(O(2))W(11)O(39)] (2), while (31)P and (183)W NMR spectra differ significantly. A compilation of the physicochemical techniques supports a monomeric Keggin type structure of 1 bearing one peroxo ligand attached to Ti(IV) in a eta(2)-coordination mode. The protonation of the titanium peroxo complex results in an increase of the redox potential of the peroxo group, E(1/2) = 1.25 and 0.88 V relative to Ag/AgCl reference electrode for 1 and 2, respectively. In contrast to 2, 1 readily reacts with 2,3,6-trimethylphenol (TMP) at 40 degrees C in MeCN to give 2,2',3,3',5,5'-hexamethyl-4,4'-biphenol (BP) and 2,3,5-trimethyl-p-benzoquinone (TMBQ). The proportion between BP and TMBQ in the reaction products depends on the TMP/1 ratio. When a 2-fold excess of TMP is used, the main reaction product is BP (90%), while using a 2-fold excess of 1 leads to TMBQ (95%). On the basis of the product study, a homolytic oxidation mechanism that implicates the formation of phenoxyl radicals is suggested. The RR deuterium labeling experiments show that the activating proton is most likely localized at a Ti-O-W bridging oxygen rather than at the peroxo group. Theoretical calculations carried out at the DFT level on the protonated and unprotonated titanium peroxo derivatives also propose that the most stable complex is formed preferentially after protonation of the Ti-O-W site; however, both Ti-OH-W and TiOO-H protonated anions

  18. Polymorphisms of peroxisome proliferator-activated receptors and survival of lung cancer and upper aero-digestive tract cancers.

    PubMed

    Yang, Ying; Burke, Rita V; Jeon, Christie Y; Chang, Shen-Chih; Chang, Po-Yin; Morgenstern, Hal; Tashkin, Donald P; Mao, Jenny; Cozen, Wendy; Mack, Thomas M; Rao, Jianyu; Zhang, Zuo-Feng

    2014-09-01

    Peroxisome proliferator-activated receptors (PPARs) are transcriptional factors involved in several biological processes such as inflammation, cancer growth, progression and apoptosis that are important in lung and upper aero-digestive tract (UADT) cancer outcomes. Nonetheless, there are no published studies of the relationship between PPARs gene polymorphisms and survival of patients with lung cancer or UADT cancers. 1212 cancer patients (611 lung, 303 oral, 100 pharyngeal, 90 laryngeal, and 108 esophageal) were followed for a median duration of 11 years. We genotyped three potentially functional single nucleotide polymorphisms (SNPs) using Taqman - rs3734254 of the gene PPARD and rs10865710 and rs1801282 of the gene PPARG - and investigated their associations with lung and UADT cancer survival using Cox regression. A semi-Bayesian shrinkage approach was used to reduce the potential for false positive findings when examining multiple associations. The variant homozygote CC (vs. TT) of PPARD rs3734254 was inversely associated with mortality of both lung cancer (adjusted hazard ratio [aHR]=0.63, 95% confidence interval [CI]=0.42, 0.96) and UADT cancers (aHR=0.51, 95% CI=0.27, 0.99). Use of the semi-Bayesian shrinkage approach yielded a posterior aHR for lung cancer of 0.66 (95% posterior limits=0.44, 0.98) and a posterior aHR for UADT cancers of 0.58 (95% posterior limits=0.33, 1.03). Our findings suggest that lung-cancer patients with the CC variant of PPARD rs3734254 may have a survival advantage over lung-cancer patients with other gene variants. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  19. Polymorphisms of peroxisome proliferator-activated receptors and survival of lung cancer and upper aero-digestive tract cancers

    PubMed Central

    Yang, Ying; Burke, Rita V.; Jeon, Christie Y.; Chang, Shen-Chih; Chang, Po-Yin; Morgenstern, Hal; Tashkin, Donald P.; Mao, Jenny; Cozen, Wendy; Mack, Thomas M.; Rao, Jianyu; Zhang, Zuo-Feng

    2014-01-01

    Background Peroxisome proliferator-activated receptors (PPARs) are transcriptional factors involved in several biological processes such as inflammation, cancer growth, progression and apoptosis that are important in lung and upper aero-digestive tract (UADT) cancer outcomes. Nonetheless, there are no published studies of the relationship between PPARs gene polymorphisms and survival of patients with lung cancer or UADT cancers. Methods 1,212 cancer patients (611 lung, 303 oral, 100 pharyngeal, 90 laryngeal, and 108 esophageal) were followed for a median duration of 11 years. We genotyped three potentially functional single nucleotide polymorphisms (SNPs) using Taqman--rs3734254 of the gene PPARD and rs10865710 and rs1801282 of the gene PPARG--and investigated their associations with lung and UADT cancer survival using Cox regression. A semi-Bayesian shrinkage approach was used to reduce the potential for false positive findings when examining multiple associations. Results The variant homozygote CC (vs. TT) of PPARD rs3734254 was inversely associated with mortality of both lung cancer (adjusted hazard ratio [aHR] = 0.63, 95% confidence interval [CI] = 0.42, 0.96) and UADT cancers (aHR = 0.51, 95% CI = 0.27, 0.99). Use of the semi-Bayesian shrinkage approach yielded a posterior aHR for lung cancer of 0.66 (95% posterior limits = 0.44, 0.98) and a posterior aHR for UADT cancers of 0.58 (95% posterior limits = 0.33, 1.03). Conclusion Our findings suggest that lung-cancer patients with the CC variant of PPARD rs3734254 may have a survival advantage over lung-cancer patients with other gene variants. PMID:25043640

  20. Physiologically based pharmacokinetic model for 6-mercpatopurine: exploring the role of genetic polymorphism in TPMT enzyme activity

    PubMed Central

    Ogungbenro, Kayode; Aarons, Leon

    2015-01-01

    Aims To extend the physiologically based pharmacokinetic (PBPK) model developed for 6-mercaptopurine to account for intracellular metabolism and to explore the role of genetic polymorphism in the TPMT enzyme on the pharmacokinetics of 6-mercaptopurine. Methods The developed PBPK model was extended for 6-mercaptopurine to account for intracellular metabolism and genetic polymorphism in TPMT activity. System and drug specific parameters were obtained from the literature or estimated using plasma or intracellular red blood cell concentrations of 6-mercaptopurine and its metabolites. Age-dependent changes in parameters were implemented for scaling, and variability was also introduced for simulation. The model was validated using published data. Results The model was extended successfully. Parameter estimation and model predictions were satisfactory. Prediction of intracellular red blood cell concentrations of 6-thioguanine nucleotide for different TPMT phenotypes (in a clinical study that compared conventional and individualized dosing) showed results that were consistent with observed values and reported incidence of haematopoietic toxicity. Following conventional dosing, the predicted mean concentrations for homozygous and heterozygous variants, respectively, were about 10 times and two times the levels for wild-type. However, following individualized dosing, the mean concentration was around the same level for the three phenotypes despite different doses. Conclusions The developed PBPK model has been extended for 6-mercaptopurine and can be used to predict plasma 6-mercaptopurine and tissue concentration of 6-mercaptopurine, 6-thioguanine nucleotide and 6-methylmercaptopurine ribonucleotide in adults and children. Predictions of reported data from clinical studies showed satisfactory results. The model may help to improve 6-mercaptopurine dosing, achieve better clinical outcome and reduce toxicity. PMID:25614061

  1. Polymorph control of luminescence properties in molecular crystals of a platinum and organoarsenic complex and formation of stable one-dimensional nanochannel.

    PubMed

    Unesaki, Hikaru; Kato, Takuji; Watase, Seiji; Matsukawa, Kimihiro; Naka, Kensuke

    2014-08-18

    The mononuclear diiodoplatinum(II) complex (trans-PtI2(cis-DHDAMe)2), where cis-DHDAMe = cis-1,4-dihydro-1,4-dimethyl-2,3,5,6-tetrakis(methoxycarbonyl)-1,4-diarsinine, forms three different crystalline polymorphs that can be either concomitantly or separately obtained on varying the recrystallization conditions. Cubic red crystals (α-phase) and red-orange needles (β-phase) exhibit solid-state red emissions at room temperature. Cubic red crystals of the γ-phase show no solid-state emission at room temperature. All crystalline structures were confirmed by X-ray crystallography. Room-temperature strongly luminescent crystals (α-phase) (λem = 657 nm, Φ = 0.52) have a triclinic P1 (No. 2) structure and no voids in the crystal structure. Red-orange needle-shaped crystals of the β-phase exhibit moderate red luminescence (λem = 695 nm, Φ = 0.09) at room temperature and have a trigonal, R3 (No. 148), structure. In the needlelike crystals of the β-phase, stable hexagonal arrays of nanoporous channels, 5.0 Å in diameter, are formed. Room-temperature nonluminescent crystals (γ-phase) have an orthorhombic, Pbca (No. 61), structure with a void volume that is 4.9% of the total crystal volume. After heating the α-phase crystals at 150 °C for 2 min, a powder XRD pattern different from the original crystal is obtained, and its solid-state emission at room temperature decreased. After heating the β-phase crystals at 150 °C for 2 min, the emission wavelength and the quantum yield of the solid-state emission at room temperature and the powder XRD pattern are the same as those of the α-phase after heating at 150 °C. A crystal-to-crystal transition triggered by the thermal stimulus produces a different stable polymorph of the mononuclear diiodoplatinum(II) complex. The one-dimensional nanoporous crystals encapsulated iodine without distorting the crystal packing.

  2. Evaluation of HLA-G 14 bp Ins/Del and +3142G>C Polymorphism with Susceptibility and Early Disease Activity in Rheumatoid Arthritis

    PubMed Central

    Sandoughi, Mahnaz; Fazeli, Seyed Amirhossein; Bahari, Gholamreza; Rezaei, Maryam

    2016-01-01

    Purpose/Background. Mounting evidence designates that HLA-G plays a role in the regulation of inflammatory processes and autoimmune diseases. There are controversial reports concerning the impact of HLA-G gene polymorphism on rheumatoid arthritis (RA). This study was aimed at examining the impact of 14 bp ins/del and +3142G>C polymorphism with susceptibility and early disease activity in RA patients in a sample of the Iranian population. Methods. This case-control study was done on 194 patients with RA and 158 healthy subjects. The HLA-G rs1063320 (+3142G>C) and rs66554220 (14 bp ins/del) variants were genotype by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFP) and PCR method, respectively. Results. The HLA-G +3142G>C polymorphism significantly decreased the risk of RA in codominant (OR = 0.61, 95% CI = 0.38–0.97, p = 0.038, GC versus GG; OR = 0.36, 95% CI = 0.14–0.92, p = 0.034, CC versus GG), dominant (OR = 0.56, 95% CI = 0.36–0.87, p = 0.011, GC + CC versus GG), and allele (OR = 0.58, 95% CI = 0.41–0.84, p = 0.004, C versus G) inheritance models tested. Our finding did not support an association between HLA-G 14 bp ins/del variant and risk/protection of RA. In addition, no significant association was found between the polymorphism and early disease activity. Conclusion. In summary, our results showed that HLA-G +3142G>C gene polymorphism significantly decreased the risk of RA in a sample of the Iranian population. PMID:27610404

  3. Structure-activity relationships for organometallic osmium arene phenylazopyridine complexes with potent anticancer activity.

    PubMed

    Fu, Ying; Habtemariam, Abraha; Basri, Aida M B H; Braddick, Darren; Clarkson, Guy J; Sadler, Peter J

    2011-10-28

    We report the synthesis and characterisation of 32 half sandwich phenylazopyridine Os(II) arene complexes [Os(η(6)-arene)(phenylazopyridine)X](+) in which X is chloride or iodide, the arene is p-cymene or biphenyl and the pyridine and phenyl rings contain a variety of substituents (F, Cl, Br, I, CF(3), OH or NO(2)). Ten X-ray crystal structures have been determined. Cytotoxicity towards A2780 human ovarian cancer cells ranges from high potency at nanomolar concentrations to inactivity. In general the introduction of an electron-withdrawing group (e.g. F, Cl, Br or I) at specific positions on the pyridine ring significantly increases cytotoxic activity and aqueous solubility. Changing the arene from p-cymene to biphenyl and the monodentate ligand X from chloride to iodide also increases the activity significantly. Activation by hydrolysis and DNA binding appears not to be the major mechanism of action since both the highly active complex [Os(η(6)-bip)(2-F-azpy)I]PF(6) (9) and the moderately active complex [Os(η(6)-bip)(3-Cl-azpy)I]PF(6) (23) are very stable and inert towards aquation. Studies of octanol-water partition coefficients (log P) and subcellular distributions of osmium in A2780 human ovarian cancer cells suggested that cell uptake and targeting to cellular organelles play important roles in determining activity. Although complex 9 induced the production of reactive oxygen species (ROS) in A2780 cells, the ROS level did not appear to play a role in the mechanism of anticancer activity. This class of organometallic osmium complexes has new and unusual features worthy of further exploration for the design of novel anticancer drugs.

  4. R-carrying genotypes of serum paraoxonase (PON1) 192 polymorphism and higher activity ratio are related to susceptibility against ischemic stroke.

    PubMed

    Mahrooz, Abdolkarim; Gohari, Ghorban; Hashemi, Mohammad-Bagher; Zargari, Mehryar; Musavi, Hadis; Abedini, Mahmoud; Alizadeh, Ahad

    2012-12-01

    The polymorphic gene of serum paraoxonase (PON1) and its activity involved in atherosclerosis. The purpose of the study was to analyze PON1 192 Q/R polymorphism and the enzyme activities in ischemic stroke. The polymorphism as the most common polymorphism in PON1 gene coding sequence is associated with variation in the enzyme activity and vascular disease. The study included 85 stroke patients and 71 control subjects. PON1 192 polymorphism was genotyped using PCR protocol. Paraoxonase activity (Para) and arylesterase activity (Aryl) were determined spectrophotometrically using paraoxon and phenylacetate as the substrates. The QR and RR genotypes were more frequent in stroke population compared to controls, resulting in a higher frequency of the R allele in patients (0.24 vs 0.18, OR = 1.41). Patients had significantly higher Para/Aryl ratio than that of controls (P = 0.016). In stroke patients, Para/Aryl and Para/HDL ratios increased with this order: QQ < QR < RR. Hypertension significantly increased the risk of ischemic stroke by 15-fold among R-containing people, while this was significantly increased 4-fold for QQ homozygotes. Smoking increased the risk of having ischemic stroke in both QQ homozygote and QR + RR group (OR = 2.84 and OR = 2.33, respectively). In conclusion, these data highlight the importance of PON1 192 R allele and high Para/Aryl ratio in susceptibility to ischemic stroke in the population. The presence of the 192 R allele potentiates the risk of stroke especially in hypertensive people. Decreased Aryl and increased Para/Aryl, Para/HDL and Aryl/HDL ratios may be markers indicated the increased susceptibility to ischemic stroke in the population.

  5. Thymidylate synthase genetic polymorphism and plasma total homocysteine level in a group of Turkish patients with rheumatoid arthritis: relationship with disease activity and methotrexate toxicity.

    PubMed

    Borman, Pınar; Taşbaş, Özgur; Karabulut, Halil; Tukun, Ajlan; Yorgancıoğlu, Rezan

    2015-01-01

    The polymorphism of thymidylate synthase (TS) gene and homocysteine are reported to have a relationship to methotrexate (MTX) metabolism, with conflicting results. The aim of this study was to determine homocysteine levels and the frequency of TS gene triple repeat (TS3R) and double repeat (TS2R) polymorphisms in a group of Turkish RA patients and evaluate its association with MTX toxicity and disease activity. Sixty-four patients with RA and 31 control subjects with a mean age of 48.7 ± 12.5 and 46.2 ± 13.4 years, were enrolled to the study. Demographic characteristics were obtained and number of patients with MTX-related adverse affects, were recorded in the patient group. The homocysteine levels and TS2R/TS3R polymorphisms of the TS gene were analyzed and the distribution of genotypes according to MTX toxicity and disease activity, were determined. The demographic properties were similar between the patient and control subjects. Folic acid supplementation with a mean dose of 5mg folic acid/week, was present in all patients. Thirty-six of the 64 patients showed adverse effects to MTX treatment. The frequency of TS2R and TS3R polymorphisms were found to be similar in the patient and control groups. TS2R and TS3R gene polymorphisms were found to be similar in patients with and without MTX-related adverse events. The mean homocysteine level was also similar in patients with and without TS gene polymorphism, but was found to be higher (12.45μmol/L vs 10.7μmol/L) in patients with MTX-related side effects than in patients without side effects. The mean level of homocysteine was correlated with levels of ESR in the patient group. In conclusion, homocysteine levels might effect the disease activity and toxicity of MTX but 2R and 3R polymorphisms in the TS gene, were not related with MTX-related toxicity in RA patients receiving folate supplementation. Further studies are needed to illuminate the polymorphisms in other enzymes that might be responsible from the MTX

  6. High selective antileishmanial activity of vanadium complex with stilbene derivative.

    PubMed

    Machado, Patrícia de Almeida; Mota, Vinícius Zamprogno; Cavalli, Ana Clara de Lima; de Carvalho, Gustavo Senra Gonçalves; Da Silva, Adilson David; Gameiro, Jacy; Cuin, Alexandre; Coimbra, Elaine Soares

    2015-08-01

    Leishmaniasis is a group of disease caused by different species of the parasite Leishmania affecting millions of people worldwide. Conventional therapy relies on multiple parenteral injections with pentavalent antimonials which exhibit high toxicity and various side effects have been reported. Hence, the research for an effective and low toxic effect drug is necessary. In the present work, the synthesis, spectroscopic and analytical characterizations of stilbene derivative (H2Salophen) and its vanadium complex (VOSalophen) are reported. Besides the chemical ancillary information, investigation of the leishmanicidal effects of these compounds were provided. The biological assays against promastigote and amastigote forms of L. amazonensis have been shown that VOSalophen exhibited a strong antiparasitic activity (IC50 of 6.65 and 3.51 μM, respectively). Furthermore, the leishmanicidal activity was concentration and time-dependent. Regarding toxicity and selectivity on mammalian cells, VOSalophen have not caused significant damage to human erythrocytes in all concentrations tested and VOSalophen was almost seven times more destructive for the intracellular parasite than for macrophages. Furthermore, the leishmanicidal activity of VOSalophen in promastigote forms of L. amazonensis could be associated to mitochondrial dysfunction and increase of the reactive oxygen species (ROS) production. In L. amazonensis-infected macrophages, VOSalophen induces ROS production and a microbicidal action NO-dependent. Our biological results indicate the effective and selective action of VOSalophen against L. amazonensis and the leishmanicidal effect can be associated to parasite disorders and immumodulatory effects. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Association of PON1 and PON2 polymorphisms with PON1 activity and significant coronary stenosis in a Tunisian population.

    PubMed

    Rejeb, Jihène; Omezzine, Asma; Rebhi, Lamia; Boumaiza, Imen; Mabrouk, Hajer; Rhif, Hamida; Rejeb, Nabila Ben; Nabli, Naoufel; Douki, Wahiba; Abdelaziz, Ahmed Ben; Boughzala, Essia; Bouslama, Ali

    2013-02-01

    PON1 and PON2 have attracted considerable attention as candidate genes for coronary heart disease because their enzymes function as key factors in lipoprotein catabolism pathways. We studied the distribution of PON1 and PON2 polymorphisms, including genotyping, lipid profile, and PON1 activity, and their association with PON1 activity and significant coronary stenosis (SCS) in a Tunisian population. PON1 activity was lower in patients with SCS than in controls. It increased with the R allele (QQ < QR < RR) in PON1-192 genotypes and with the L allele (MM < ML < LL) in PON1-55 genotypes. In the presence of metabolic syndrome and diabetes, PON1-192RR and PON2-311CC were associated with an increased risk of SCS and PON1-55MM seems to have lower risk. This association was evident among nonsmokers for PON1-55MM and among smokers for PON1-192RR and PON2-311CC. The GTGC haplotype seemed to increase the risk of SCS compared with the wild haplotype in a Tunisian population.

  8. Anticancer Activity of Metal Complexes: Involvement of Redox Processes

    PubMed Central

    Jungwirth, Ute; Kowol, Christian R.; Keppler, Bernhard K.; Hartinger, Christian G.; Berger, Walter; Heffeter, Petra

    2012-01-01

    Cells require tight regulation of the intracellular redox balance and consequently of reactive oxygen species for proper redox signaling and maintenance of metal (e.g., of iron and copper) homeostasis. In several diseases, including cancer, this balance is disturbed. Therefore, anticancer drugs targeting the redox systems, for example, glutathione and thioredoxin, have entered focus of interest. Anticancer metal complexes (platinum, gold, arsenic, ruthenium, rhodium, copper, vanadium, cobalt, manganese, gadolinium, and molybdenum) have been shown to strongly interact with or even disturb cellular redox homeostasis. In this context, especially the hypothesis of “activation by reduction” as well as the “hard and soft acids and bases” theory with respect to coordination of metal ions to cellular ligands represent important concepts to understand the molecular modes of action of anticancer metal drugs. The aim of this review is to highlight specific interactions of metal-based anticancer drugs with the cellular redox homeostasis and to explain this behavior by considering chemical properties of the respective anticancer metal complexes currently either in (pre)clinical development or in daily clinical routine in oncology. PMID:21275772

  9. Phase transition and vapochromism in molecular assemblies of a polymorphic zinc(II) Schiff-base complex.

    PubMed

    Oliveri, Ivan Pietro; Malandrino, Graziella; Di Bella, Santo

    2014-09-15

    This paper reports for the first time the irreversible thermally induced phase transition, accompanied by color change, and the vapochromic behavior of an amphiphilic, Lewis acidic Zn(II) Schiff-base complex, through detailed X-ray diffraction, thermogravimetric analysis and differential scanning calorimetry, and optical absorption studies. The unprecedented irreversible phase transition for such kind of complexes is associated with a thermal, lamellar-to-hexagonal columnar structural transition, which involves a different arrangement of each molecular unit within the assembled structure, H- and J-type aggregates, respectively, responsible for the thermochromic behavior. The vapochromism, investigated either in powder samples or in thermally annealed cast films, is related to the formation of 1:1 adducts upon exposure to vapors of strong Lewis bases and implies dramatic optical absorption variations and naked-eye observation of the change in color from red-brown to red. The chemisorption process is fast, completely reversible, reproducible, and selective for amines. The reversible switching of the chemisorption-desorption process in cast films is demonstrated by successive cycles, amine exposure and subsequent heating, by monitoring the substantial optical absorption changes in the visible region. Vapochromism of this material can potentially be used to detect vapors of volatile amines.

  10. Synthesis, characterization, and anticancer activity of ruthenium-pyrazole complexes.

    PubMed

    David, Solene; Perkins, Richard S; Fronczek, Frank R; Kasiri, Sahba; Mandal, Subhrangsu S; Srivastava, Radhey S

    2012-06-01

    A series of new water soluble Ru(III) pyrazole complexes mer-[RuCl(3)(DMSO-S)(pyz)(2)] 1, mer-[RuCl(3)(DMSO-S)(DMSO-O)(pyz)] 2, mer-[RuCl(3)(bpy)(dmpyz)] 3, and mer-[RuCl(3)(DMSO-S)(dmpyz)(2)] 4 (pyz=pyrazole; dmpyz=3,5-dimethylpyrazole, bpy=2,2'-bipyridine) have been synthesized and characterized by use of a combination of spectroscopy (IR and UV-visible), X-ray diffraction, and cyclic voltammetry. The molecular X-ray structure of all reported compounds (1-4) revealed distorted octahedral coordination around ruthenium. The cytotoxicity assay on human breast cancer cells (MCF7) demonstrated that compounds 1 and 4 affect cell viability, whereas compounds 2 and 3 do not show appreciable activity. The IC(50) values for 1 and 4 lie within the range of 71-32μM in MCF7 cells.

  11. False memories for shape activate the lateral occipital complex.

    PubMed

    Karanian, Jessica M; Slotnick, Scott D

    2017-10-01

    Previous functional magnetic resonance imaging evidence has shown that false memories arise from higher-level conscious processing regions rather than lower-level sensory processing regions. In the present study, we assessed whether the lateral occipital complex (LOC)-a lower-level conscious shape processing region-was associated with false memories for shape. During encoding, participants viewed intact or scrambled colored abstract shapes. During retrieval, colored disks were presented and participants indicated whether the corresponding item was previously "intact" or "scrambled." False memories for shape ("intact"/scrambled > "scrambled"/scrambled) activated LOC, which indicates lower-level sensory processing