WorldWideScience

Sample records for akh receptor variants

  1. Evolution of the AKH/corazonin/ACP/GnRH receptor superfamily and their ligands in the Protostomia

    DEFF Research Database (Denmark)

    Hauser, Frank; Grimmelikhuijzen, Cornelis

    2014-01-01

    In this review we trace the evolutionary connections between GnRH receptors from vertebrates and the receptors for adipokinetic hormone (AKH), AKH/corazonin-related peptide (ACP), and corazonin from arthropods. We conclude that these G protein-coupled receptors (GPCRs) are closely related and hav......QLTFSSDWSGamide), and the penis worm Priapulus caudatus (pQIFFSKGWRGamide). This is the first report, showing that AKH signaling is widespread in molluscs....

  2. Adipokinetic hormones (AKHs) of sphingid Lepidoptera, including the identification of a second M. sexta AKH.

    Science.gov (United States)

    Weaver, Robert J; Marco, Heather G; Simek, Petr; Audsley, Neil; Clark, Kevin D; Gäde, Gerd

    2012-03-01

    The adipokinetic hormones (AKHs) from the corpora cardiaca (CC) of representative species from all three subfamilies of the Sphingidae (hawkmoths) were investigated using matrix-assisted laser desorption-ionization time-of-flight (MALDI-TOF) and liquid chromatography electrospray ion trap mass spectrometry (LC-ESI MS), including a re-examination of the AKH complement of the tobacco hawkmoth, Manduca sexta. In addition to larvae and adults of M. sexta (subfamily: Sphinginae), adults from the following subfamilies were examined: Macroglossinae (large elephant hawkmoth, Deilephila elpenor), Smerinthinae (poplar hawkmoth, Laothoe populi and eyed hawkmoth, Smerinthus ocellata), and Sphinginae (death's head hawkmoth, Acherontia atropos). All moths are shown to have the nonapeptide Manse-AKH (pELTFTSSWGamide) [corrected] in their CC, together with a second AKH, which, on the basis of mass ions ([M+Na](+), [M+K](+)) and partial sequence analysis is identical in all species examined. The structure of this AKH was extracted from the CC [corrected] of adult M. sexta and shown, by ESI-collision-induced dissociation (CID) tandem mass spectrometry (MS/MS), to be a novel decapeptide AKH with a sequence of pELTFSSWGQamide. [corrected]. The new peptide has been code named Manse-AKH-II. Sequence confirmation was obtained from identical MS studies with synthetic Manse-AKH-II and with the native peptide. Manse-AKH-II has significant lipid-mobilizing activity when injected at low dose (5pmol) into newly emerged adult M. sexta. The potential implications of a second AKH, in M. sexta in particular, are discussed in relation to putative receptor(s). PMID:22285789

  3. The putative AKH receptor of the tobacco hornworm, Manduca sexta, and its expression.

    Science.gov (United States)

    Ziegler, R; Isoe, J; Moore, W; Riehle, M A; Wells, M A

    2011-01-01

    Adipokinetic hormones are peptide hormones that mobilize lipids and/or carbohydrates for flight in adult insects and activate glycogen Phosphorylase in larvae during starvation and during molt. We previously examined the functional roles of adipokinetic hormone in Manduca sexta L. (Lepidoptera: Sphingidae). Here we report the cloning of the full-length cDNA encoding the putative adipokinetic hormone receptor from the fat body of M. sexta. The sequence analysis shows that the deduced amino acid sequence shares common motifs of G protein-coupled receptors, by having seven hydrophobic transmembrane segments. We examined the mRNA expression pattern of the adipokinetic hormone receptor by quantitative Real-Time PCR in fat body during development and in different tissues and found the strongest expression in fat body of larvae two days after molt to the fifth instar. We discuss these results in relation to some of our earlier results. We also compare the M. sexta adipokinetic hormone receptor with the known adipokinetic hormone receptors of other insects and with gonadotropin releasing hormone-like receptors of invertebrates. PMID:21529255

  4. The Putative AKH Receptor of the Tobacco Hornworm, Manduca sexta, and Its Expression

    OpenAIRE

    Ziegler, R.; Isoe, J.; Moore, W.; Riehle, M. A.; Wells, M. A.

    2011-01-01

    Adipokinetic hormones are peptide hormones that mobilize lipids and/or carbohydrates for flight in adult insects and activate glycogen Phosphorylase in larvae during starvation and during molt. We previously examined the functional roles of adipokinetic hormone in Manduca sexta L. (Lepidoptera: Sphingidae). Here we report the cloning of the full-length cDNA encoding the putative adipokinetic hormone receptor from the fat body of M. sexta. The sequence analysis shows that the deduced amino aci...

  5. Cloning and characterization of the adipokinetic hormone receptor from the cockroach Periplaneta americana

    DEFF Research Database (Denmark)

    Hansen, Karina K; Hauser, Frank; Cazzamali, Giuseppe;

    2006-01-01

    americana. This receptor is only activated by various insect AKHs (we tested eight) and not by a library of 29 other insect or invertebrate neuropeptides and nine biogenic amines. Periplaneta has two intrinsic AKHs, Pea-AKH-1, and Pea-AKH-2. The Periplaneta AKH receptor is activated by low concentrations of...

  6. Identification of G protein-coupled receptors for Drosophila PRXamide peptides, CCAP, corazonin, and AKH supports a theory of ligand-receptor coevolution

    OpenAIRE

    Park, Yoonseong; KIM, YOUNG-JOON; Adams, Michael E.

    2002-01-01

    G-protein coupled receptors (GPCRs) are ancient, ubiquitous sensors vital to environmental and physiological signaling throughout organismal life. With the publication of the Drosophila genome, numerous “orphan” GPCRs have become available for functional analysis. Here we characterize two groups of GPCRs predicted as receptors for peptides with a C-terminal amino acid sequence motif consisting of −PRXamide (PRXa). Assuming ligand-receptor coevolution, two alternative hypotheses were construct...

  7. Characterization and expression analysis of adipokinetic hormone and its receptor in eusocial aphid Pseudoregma bambucicola.

    Science.gov (United States)

    Jedličková, Veronika; Jedlička, Pavel; Lee, How-Jing

    2015-11-01

    Aphids display an extraordinary phenotypic plasticity ranging from widespread reproductive and wing polyphenisms to the occurrence of sterile or subfertile soldier morphs restricted to eusocial species of the subfamilies Eriosomatinae and Hormaphidinae. Individual morphs are specialized by their behavior, anatomy, and physiology to perform different roles in aphid societies at different stages of the life cycle. The capacity of the insects to cope with environmental stressors is under the control of a group of neuropeptides of the adipokinetic hormone/red pigment-concentrating hormone family (AKH/RPCH) that bind to a specific receptor (AKHR). Here, we describe the molecular characteristics of AKH and AKHR in the eusocial aphid Pseudoregma bambucicola. The sequence of the bioactive AKH decapeptide and the intron position in P. bambucicola AKH preprohormone were found to be identical to those in a phylogenetically distant aphid Dreyfusia spp. (Adelgidae). We detected four transcript variants of AKHR that are translated into three protein isoforms. Further, we analyzed AKH/AKHR expression in different tissues and insects of different castes. In wingless females, a remarkable amount of AKH mRNA was only expressed in the heads. In contrast, AKHR transcript levels increased in the order gutAKH expression levels were recorded in winged, migratory females and soldiers, whereas reduced levels were found in wingless, sedentary females that are functionally oriented to reproduction. The highest AKHR expression was found in soldiers in gall-dwelling populations, whereas in bamboo colonies the highest transcript level was detected in winged females. We propose a possible explanation for the correlation between AKH and AKHR transcript levels and task partitioning among individual forms in P. bambucicola colonies. PMID:26432101

  8. Nuclear receptor variants in liver disease.

    Science.gov (United States)

    Zimmer, Vincent; Liebe, Roman; Lammert, Frank

    2015-01-01

    This snapshot reviews the current state of knowledge on genetic variants of nuclear receptors (NRs) involved in regulating various aspects of liver metabolism. Interindividual differences in responses to diet and other 'in-' and environmental stressors can be caused by variants in components of the NR regulatory gene network. We recapitulate recent evidence for the application of NRs in genetic diagnosis of monogenic liver disease. Genetic analysis of multifactorial liver diseases, such as nonalcoholic fatty liver disease and diabetes mellitus, pinpoints key players in disease predisposition and progression. In particular, NR1H4 variants have been associated with intrahepatic cholestasis of pregnancy and gallstone disease. Other examples include studies of NR1I2 and NR1I3 polymorphisms in patients with drug-induced liver injury and NR5A2 variation in cholangiocarcinoma. Associations of NR gene variants have been identified in patients with dyslipidemia and other metabolic syndrome-associated traits by genome-wide studies. Evidence from these analyses confirms a role for NR variation in common diseases, linking regulatory networks to complex and variable phenotypes. These new insights into the impact of NR variants offer perspectives for their future use in diagnosis and treatment of common diseases. PMID:26045277

  9. Variant in oxytocin receptor gene is associated with amygdala volume

    OpenAIRE

    Furman, Daniella J; Chen, Michael C.; Gotlib, Ian H.

    2011-01-01

    The oxytocin system plays a significant role in modulating stress responses in animals and humans; perturbations in this system may contribute to the pathogenesis of psychiatric disorder. Attempts to identify clinically relevant genetic variants in the oxytocin system have yielded associations between polymorphisms of the oxytocin receptor (OXTR) gene and both autism and major depression. To date, however, little is known about how such variants affect brain structures implicated in these dis...

  10. Molecular identification of the insect adipokinetic hormone receptors

    DEFF Research Database (Denmark)

    Staubli, Frank; Jørgensen, Thomas J. D.; Cazzamali, Giuseppe;

    2002-01-01

    The insect adipokinetic hormones (AKHs) are a large family of peptide hormones that are involved in the mobilization of sugar and lipids from the insect fat body during energy-requiring activities such as flight and locomotion, but that also contribute to hemolymph sugar homeostasis. Here, we have...... identified the first insect AKH receptors, namely those from the fruitfly Drosophila melanogaster and the silkworm Bombyx mori. These results represent a breakthrough for insect molecular endocrinology, because it will lead to the cloning of all AKH receptors from all model insects used in AKH research, and......, therefore, to a better understanding of AKH heterogeneity and actions. Interestingly, the insect AKH receptors are structurally and evolutionarily related to the gonadotropin-releasing hormone receptors from vertebrates....

  11. Melanocortin-1 receptor gene variants in four Chinese ethnic populations

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    There is strong relationship between melanocortin-1 receptor (MC1R) gene variants and human hair color and skin type.Based on a sequencing study of MC1R gene in 50 individuals from the Uygur,Tibetan,Wa and Dai ethnic populations,we discuss the occurrence of 7 mc1r variants consisting of 5 nonsynonymous sites (Val60Leu,Arg67Gln,Val92Met,Arg163Gln and Ala299Val) and 2 synonymous sites (C414T and A942G),among which C414T and Ala299Val were reported for the first time.Confirmation and analysis were also made of 122 individuals at three common point mutations (Val92Met,Arg163Gln,A942G) using PCR-SSCP.The frequency of Arg163Gln variant varies in the four ethnic populations,with percentage of 40%,85.0%,66.2% and 72.7%,respectively,while those of Val92Met and A942G are roughly similar in these four populations.The different environments,migration and admixture of various ethnic groups in China might have impact on the observed frequency of Arg163Gln.

  12. Variants in the vitamin D receptor gene and asthma

    Directory of Open Access Journals (Sweden)

    Wjst Matthias

    2005-01-01

    Full Text Available Abstract Background Early lifetime exposure to dietary or supplementary vitamin D has been predicted to be a risk factor for later allergy. Twin studies suggest that response to vitamin D exposure might be influenced by genetic factors. As these effects are primarily mediated through the vitamin D receptor (VDR, single base variants in this gene may be risk factors for asthma or allergy. Results 951 individuals from 224 pedigrees with at least 2 asthmatic children were analyzed for 13 SNPs in the VDR. There was no preferential transmission to children with asthma. In their unaffected sibs, however, one allele in the 5' region was 0.5-fold undertransmitted (p = 0.049, while two other alleles in the 3' terminal region were 2-fold over-transmitted (p = 0.013 and 0.018. An association was also seen with bronchial hyperreactivity against methacholine and with specific immunoglobulin E serum levels. Conclusion The transmission disequilibrium in unaffected sibs of otherwise multiple-affected families seem to be a powerful statistical test. A preferential transmission of vitamin D receptor variants to children with asthma could not be confirmed but raises the possibility of a protective effect for unaffected children.

  13. Interleukin-4 receptor alpha gene variants and allergic disease

    Directory of Open Access Journals (Sweden)

    Hall Ian P

    2000-06-01

    Full Text Available Abstract The interleukin-4 (IL-4 signalling cascade has been identified as a pathway potentially important in the development of asthma. Genetic variants within this signalling pathway might contribute to the risk of developing asthma in a given individual. A number of polymorphisms have been described within the IL-4 receptor α (IL-4Rα gene. In addition polymorphism occurs in the promoter for the IL-4 gene itself. This commentary accompanies a paper by C Ober et al describing the contribution of IL-4Rα polymorphism to susceptibility to asthma and atopy in the Hutterite population and other outbred populations collected during the collaborative studies on the genetics of asthma (CSGA programme.

  14. Characterization of the adipokinetic hormone receptor of the anautogenous flesh fly, Sarcophaga crassipalpis.

    Science.gov (United States)

    Bil, Magdalena; Timmermans, Iris; Verlinden, Heleen; Huybrechts, Roger

    2016-06-01

    Adipokinetic hormone (AKH) is an insect neuropeptide mainly involved in fat body energy mobilization. In flies (Phormia regina, Sarcophaga crassipalpis), bugs (Pyrrhocoris apterus) and cockroaches (Periplaneta americana) AKH was also demonstrated to be involved in the regulation of digestion. This makes AKH an important peptide for anautogenous female flies that need to feed on a supplementary protein meal to initiate vitellogenesis, the large scale synthesis of yolk proteins and their uptake by the developing oocytes. Flesh fly AKH, originally identified as Phormia terraenovae hypertrehalosemic hormone (PhoteHrTH), functions through activation of the AKH receptor (AKHR). This is a G protein-coupled receptor that is the orthologue of the human gonadotropin-releasing hormone receptor. Pharmacological characterization indicated that the receptor can be activated by two related dipteran AKH ligands with an EC50 value in the low nanomolar range, whereas micromolar concentrations of the Tribolium castaneum AKH were needed. Consistent with the energy mobilizing function of AKH, the receptor transcript levels were most abundant in the fat body tissue. Nonetheless, Sarcophaga crassipalpis AKHR transcript levels were also high in the brain, the foregut and the hindgut. Interestingly, the receptor transcript numbers were reduced in almost all measured tissues after protein feeding. These changes may enforce the use of ingested energy carrying molecules prior to stored energy mobilization. PMID:27063262

  15. Protease-Activated Receptor 4 Variant p.Tyr157Cys Reduces Platelet Functional Responses and Alters Receptor Trafficking

    OpenAIRE

    Norman, Jane E; Cunningham, Margaret R; Jones, Matthew L.; Walker, Mary E; Westbury, Sarah K; Sessions, Richard B.; Mundell, Stuart J.; Mumford, Andrew D.

    2016-01-01

    OBJECTIVE: Protease-activated receptor 4 (PAR4) is a key regulator of platelet reactivity and is encoded by F2RL3, which has abundant rare missense variants. We aimed to provide proof of principle that rare F2LR3 variants potentially affect platelet reactivity and responsiveness to PAR1 antagonist drugs and to explore underlying molecular mechanisms.APPROACH AND RESULTS: We identified 6 rare F2RL3 missense variants in 236 cardiac patients, of which the variant causing a tyrosine 157 to cystei...

  16. Association of vitamin D receptor gene variants with polycystic ovary syndrome: A case control study

    OpenAIRE

    Touraj Mahmoudi; Keivan Majidzadeh-A; Hamid Farahani; Mojgan Mirakhorli; Reza Dabiri; Hossein Nobakht; Asadollah Asadi

    2015-01-01

    Background: Vitamin D and insulin play an important role in susceptibility to polycystic ovary syndrome (PCOS), and therefore vitamin D receptor (VDR), parathyroid hormone (PTH), and insulin receptor (INSR) gene variants might be involved in the pathogenesis of PCOS. Objective: The present study was designed to investigate the possible associations between polymorphisms in VDR, PTH, and INSR genes and the risk of PCOS. Materials and Methods: VDR, PTH, and INSR gene variants were genoty...

  17. Association of vitamin D receptor gene variants with polycystic ovary syndrome: A case control study

    OpenAIRE

    Mahmoudi, Touraj; Majidzadeh-A, Keivan; Farahani, Hamid; Mirakhorli, Mojgan; Dabiri, Reza; Nobakht, Hossein; Asadi, Asadollah

    2015-01-01

    Background: Vitamin D and insulin play an important role in susceptibility to polycystic ovary syndrome (PCOS), and therefore vitamin D receptor (VDR), parathyroid hormone (PTH), and insulin receptor (INSR) gene variants might be involved in the pathogenesis of PCOS. Objective: The present study was designed to investigate the possible associations between polymorphisms in VDR, PTH, and INSR genes and the risk of PCOS. Materials and Methods: VDR, PTH, and INSR gene variants were genotyped in ...

  18. Multiple loss-of-function variants of taste receptors in modern humans.

    Science.gov (United States)

    Fujikura, Kohei

    2015-01-01

    Despite recent advances in the knowledge of interindividual taste differences, the underlying genetic backgrounds have remained to be fully elucidated. Much of the taste variation among different mammalian species can be explained by pseudogenization of taste receptors. Here I investigated whether the most recent disruptions of taste receptor genes segregate with their intact forms in modern humans by analyzing 14 ethnically diverse populations. The results revealed an unprecedented prevalence of 25 segregating loss-of-function (LoF) taste receptor variants, identifying one of the most pronounced cases of functional population diversity in the human genome. LoF variant frequency in taste receptors (2.10%) was considerably higher than the overall LoF frequency in human genome (0.16%). In particular, molecular evolutionary rates of candidate sour (14.7%) and bitter (1.8%) receptors were far higher in humans than those of sweet (0.02%), salty (0.05%), and umami (0.17%) receptors compared with other carnivorous mammals, although not all of the taste receptors were identified. Many LoF variants are population-specific, some of which arose even after population differentiation, not before divergence of the modern and archaic human. I conclude that modern humans might have been losing some sour and bitter receptor genes because of high-frequency LoF variants. PMID:26307445

  19. Mediation of buprenorphine analgesia by a combination of traditional and truncated mu opioid receptor splice variants.

    Science.gov (United States)

    Grinnell, Steven G; Ansonoff, Michael; Marrone, Gina F; Lu, Zhigang; Narayan, Ankita; Xu, Jin; Rossi, Grace; Majumdar, Susruta; Pan, Ying-Xian; Bassoni, Daniel L; Pintar, John; Pasternak, Gavril W

    2016-10-01

    Buprenorphine has long been classified as a mu analgesic, although its high affinity for other opioid receptor classes and the orphanin FQ/nociceptin ORL1 receptor may contribute to its other actions. The current studies confirmed a mu mechanism for buprenorphine analgesia, implicating several subsets of mu receptor splice variants. Buprenorphine analgesia depended on the expression of both exon 1-associated traditional full length 7 transmembrane (7TM) and exon 11-associated truncated 6 transmembrane (6TM) MOR-1 variants. In genetic models, disruption of delta, kappa1 or ORL1 receptors had no impact on buprenorphine analgesia, while loss of the traditional 7TM MOR-1 variants in an exon 1 knockout (KO) mouse markedly lowered buprenorphine analgesia. Loss of the truncated 6TM variants in an exon 11 KO mouse totally eliminated buprenorphine analgesia. In distinction to analgesia, the inhibition of gastrointestinal transit and stimulation of locomotor activity were independent of truncated 6TM variants. Restoring expression of a 6TM variant with a lentivirus rescued buprenorphine analgesia in an exon 11 KO mouse that still expressed the 7TM variants. Despite a potent and robust stimulation of (35) S-GTPγS binding in MOR-1 expressing CHO cells, buprenorphine failed to recruit β-arrestin-2 binding at doses as high as 10 µM. Buprenorphine was an antagonist in DOR-1 expressing cells and an inverse agonist in KOR-1 cells. Buprenorphine analgesia is complex and requires multiple mu receptor splice variant classes but other actions may involve alternative receptors. PMID:27223691

  20. Sexually dimorphic effects of oxytocin receptor gene (OXTR ) variants on Harm Avoidance

    OpenAIRE

    Stankova Trayana; Eichhammer Peter; Langguth Berthold; Sand Philipp G

    2012-01-01

    Abstract Background Recent research has suggested that oxytocin receptor gene (OXTR) variants may account for individual differences in social behavior, the effects of stress and parenting styles. Little is known, however, on a putative role of the gene in heritable temperamental traits. Methods We addressed effects of two common OXTR variants, rs237900 and rs237902, on personality dimensions in 99 healthy subjects using the Temperament and Character Inventory. Results When sex was controlled...

  1. Polymorphic Variants of LIGHT (TNF Superfamily-14) Alter Receptor Avidity and Bioavailability1

    OpenAIRE

    Cheung, Timothy C.; Coppieters, Ken; Sanjo, Hideki; Oborne, Lisa M.; Norris, Paula S.; Coddington, Amy; Granger, Steven W.; Elewaut, Dirk; Ware, Carl F.

    2010-01-01

    The TNF superfamily member, LIGHT (TNFSF14) is a key cytokine that activates T cells and dendritic cells, and is implicated as a mediator of inflammatory, metabolic and malignant diseases. LIGHT engages the Lymphotoxin-β receptor (LTβR) and herpesvirus entry mediator (HVEM, TNFRSF14), but is competitively limited in activating these receptors by soluble decoy receptor-3 (DcR3, TNFRSF6B). Two variants in the human LIGHT alter the protein at E214K (rs344560) in the receptor-binding domain and S...

  2. Differential Compartmentalization and Distinct Functions of GABAB Receptor Variants

    OpenAIRE

    Vigot, Réjan; Barbieri, Samuel; Bräuner-Osborne, Hans; Turecek, Rostislav; Shigemoto, Ryuichi; Zhang, Yan-Ping; Luján, Rafael; Jacobson, Laura H.; Biermann, Barbara; Fritschy, Jean-Marc; Vacher, Claire-Marie; Müller, Matthias; Sansig, Gilles; Guetg, Nicole; Cryan, John F.

    2006-01-01

    GABAB receptors are the G protein-coupled receptors for the main inhibitory neurotransmitter in the brain, γ-aminobutyric acid (GABA). Molecular diversity in the GABAB system arises from the GABAB1a and GABAB1b subunit isoforms that solely differ in their ectodomains by a pair of sushi repeats that is unique to GABAB1a. Using a combined genetic, physiological, and morphological approach, we now demonstrate that GABAB1 isoforms localize to distinct synaptic sites and convey separate functions ...

  3. Novel splicing variant of the human orphan nuclear receptor Nurr1 gene

    Institute of Scientific and Technical Information of China (English)

    徐评议; 乐卫东

    2004-01-01

    Background Nurr1 is a member of the nuclear receptor superfamily of transcription factors. The objective of the present study was to identify novel splicing variants of the gene in neuronal and non-neuronal tissues and determine their functions. Methods Reverse transcription-polymerase chain reaction (RT-PCR) analysis was used to screen for Nurr1 splice variants in the adult human central nervous system (CNS) and in other tissues such as lymphocytes, and liver, muscle, and kidney cells. Functional assays of the variants were performed by measuring Nurr1 response element (NuRE) transcriptional activity in vitro. Results In this study, the authors identified a novel splicing variant of Nurr1 within exon 5, found in multiple adult human tissues, including lymphocytes, and liver, muscle, and kidney cells, but not in the brain or spinal cord. Sequencing analysis showed the variant has a 75 bp deletion between nucleotides 1402 and 1476. A functional assay of the Nurr1-c splicing variant, performed by measuring NuRE transcriptional activity in vitro, detected a 39% lower level of luciferase (LUC) activity (P<0.05).Conclusion A novel splicing variant of Nurr1 exists in human non-neuronal tissues and functional assays suggest that the variant may act as an alternate transcription regulator.

  4. Differential compartmentalization and distinct functions of GABAB receptor variants

    DEFF Research Database (Denmark)

    Vigot, Réjan; Barbieri, Samuel; Bräuner-Osborne, Hans;

    2006-01-01

    GABAB receptors are the G protein-coupled receptors for the main inhibitory neurotransmitter in the brain, gamma-aminobutyric acid (GABA). Molecular diversity in the GABAB system arises from the GABAB1a and GABAB1b subunit isoforms that solely differ in their ectodomains by a pair of sushi repeats...... release, while predominantly GABAB1b mediates postsynaptic inhibition. Electron microscopy reveals a synaptic distribution of GABAB1 isoforms that agrees with the observed functional differences. Transfected CA3 neurons selectively express GABAB1a in distal axons, suggesting that the sushi repeats, a...

  5. Allelic variants of melanocortin 3 receptor gene (MC3R) and weight loss in obesity

    DEFF Research Database (Denmark)

    L. Santos, José; De la Cruz, Rolando; Holst, Claus;

    2011-01-01

    The melanocortin system plays an important role in energy homeostasis. Mice genetically deficient in the melanocortin-3 receptor gene have a normal body weight with increased body fat, mild hypophagia compared to wild-type mice. In humans, Thr6Lys and Val81Ile variants of the melanocortin-3 recep...

  6. No association of primary Sjögren's syndrome with Fcγ receptor gene variants.

    Science.gov (United States)

    Haldorsen, K; Appel, S; Le Hellard, S; Bruland, O; Brun, J G; Omdal, R; Kristjansdottir, G; Theander, E; Fernandes, C P D; Kvarnström, M; Eriksson, P; Rönnblom, L; Herlenius, M W; Nordmark, G; Jonsson, R; Bolstad, A I

    2013-06-01

    The genetic background of primary Sjögren's syndrome (pSS) is partly shared with systemic lupus erythematosus (SLE). Immunoglobulin G Fc receptors are important for clearance of immune complexes. Fcγ receptor variants and gene deletion have been found to confer SLE risk. In this study, four Fcγ receptor single-nucleotide polymorphisms (SNPs) and one copy number variation (CNV) were studied. Swedish and Norwegian pSS patients (N=527) and controls (N=528) were genotyped for the Fcγ receptor gene variant FCGR2A H131R (rs1801274) by the Illumina GoldenGate assay. FCGR3A F158V (rs396991) was analysed in 488 patients and 485 controls, FCGR3B rs447536 was analysed in 471 patients and 467 controls, and FCGR3B rs448740 was analysed in 478 cases and 455 controls, using TaqMan SNP genotyping assays. FCGR3B CNV was analysed in 124 patients and 139 controls using a TaqMan copy number assay. None of the SNPs showed any association with pSS. Also, no FCGR3B CNV association was detected. The lack of association of pSS with Fcγ receptor gene variants indicates that defective immune complex clearance may not be as important in pSS pathogenesis as in SLE, and may point to important differences between SLE and pSS. PMID:23552400

  7. Genomic organization of mouse orexin receptors: characterization of two novel tissue-specific splice variants.

    Science.gov (United States)

    Chen, Jing; Randeva, Harpal S

    2004-11-01

    In humans and rat, orexins orchestrate divergent actions through their G protein-coupled receptors, orexin-1 (OX1R) and orexin-2 (OX2R). Orexins also play an important physiological role in mouse, but the receptors through which they function are not characterized. To characterize the physiological role(s) of orexins in the mouse, we cloned and characterized the mouse orexin receptor(s), mOX1R and mOX2R, using rapid amplification of cDNA (mouse brain) ends, RT-PCR, and gene structure analysis. The mOX1R cDNA encodes a 416-amino acid (aa) receptor. We have identified two alternative C terminus splice variants of the mOX2R; mOX2 alpha R (443 aa) and mOX2 beta R (460 aa). Binding studies in human embryonic kidney 293 cells transfected with mOX1R, mOX2 alpha R, and the mOX2 beta R revealed specific, saturable sites for both orexin-A and -B. Activation of these receptors by orexins induced inositol triphosphate (IP(3)) turnover. However, human embryonic kidney 293 cells transfected with mOXRs demonstrated no cAMP response to either orexin-A or orexin-B challenge, although forskolin and GTP gamma S revealed a dose-dependent increase in cAMP. Although, orexin-A and -B showed no difference in binding characteristics between the splice variants; interestingly, orexin-B led to an increase in IP(3) production at all concentrations in the mOX2 beta R variant. Orexin-A, however, showed no difference in IP(3) production between the two variants. Additionally, in the mouse, we demonstrate that these splice variants are distributed in a tissue-specific manner, where OX2 alpha R mRNA was undetectable in skeletal muscle and kidney. Moreover, food deprivation led to a greater increase in hypothalamic mOX2 beta R gene expression, compared with both mOX1R and mOX2 alpha R. This potentially implicates a fundamental physiological role for these splice variants. PMID:15256537

  8. CNTF variants with increased biological potency and receptor selectivity define a functional site of receptor interaction.

    OpenAIRE

    Saggio, I; Gloaguen, I; Poiana, G; Laufer, R

    1995-01-01

    Human CNTF is a neurocytokine that elicits potent neurotrophic effects by activating a receptor complex composed of the ligand-specific alpha-receptor subunit (CNTFR alpha) and two signal transducing proteins, which together constitute a receptor for leukemia inhibitory factor (LIFR). At high concentrations, CNTF can also activate the LIFR and possibly other cross-reactive cytokine receptors in the absence of CNTFR alpha. To gain a better understanding of its structure-function relationships ...

  9. Novel variants in the putative peroxisome proliferator-activated receptor {gamma} promoter and relationships with obesity in men

    DEFF Research Database (Denmark)

    Larsen, Thomas M; Larsen, Lesli H; Torekov, Signe K; Ek, Jakob; Black, Eva; Toubro, Søren; Astrup, Arne; Sørensen, Thorkild I A; Hansen, Torben; Pedersen, Oluf

    2005-01-01

    Yet unidentified variants within the peroxisome proliferator-activated receptor gamma (PPARgamma) 2 promoter may explain the inconsistent reports on associations between variants in the coding region and obesity or diabetes. Thus, we examined the putative PPARgamma2 promoter (-3371 to +43 bp) for...

  10. Naturally Occurring Variants of Human A9 Nicotinic Receptor Differentially Affect Bronchial Cell Proliferation and Transformation

    OpenAIRE

    Chikova, Anna; Grando, Sergei A.

    2011-01-01

    Isolation of polyadenilated mRNA from human immortalized bronchial epithelial cell line BEP2D revealed the presence of multiple isoforms of RNA coded by the CHRNA9 gene for α9 nicotinic acetylcholine receptor (nAChR). BEP2D cells were homozygous for the rs10009228 polymorphism encoding for N442S amino acid substitution, and also contained mRNA coding for several truncated isoforms of α9 protein. To elucidate the biologic significance of the naturally occurring variants of α9 nAChR, we compare...

  11. Sexually dimorphic effects of oxytocin receptor gene (OXTR variants on Harm Avoidance

    Directory of Open Access Journals (Sweden)

    Stankova Trayana

    2012-07-01

    Full Text Available Abstract Background Recent research has suggested that oxytocin receptor gene (OXTR variants may account for individual differences in social behavior, the effects of stress and parenting styles. Little is known, however, on a putative role of the gene in heritable temperamental traits. Methods We addressed effects of two common OXTR variants, rs237900 and rs237902, on personality dimensions in 99 healthy subjects using the Temperament and Character Inventory. Results When sex was controlled for and an OXTR genotype*sex interaction term was included in the regression model, 11% of the variance in Harm Avoidance could be explained (uncorrected p ≤ 0.01. Female carriers of the minor alleles scored highest, and a novel A217T mutation emerged in the most harm avoidant male participant. Conclusions Findings lend support to a modulatory effect of common OXTR variants on Harm Avoidance in healthy caucasian women and invite resequencing of the gene in anxiety phenotypes to identify more explanatory functional variation.

  12. Association of vitamin D receptor gene variants with polycystic ovary syndrome: A case control study

    Science.gov (United States)

    Mahmoudi, Touraj; Majidzadeh-A, Keivan; Farahani, Hamid; Mirakhorli, Mojgan; Dabiri, Reza; Nobakht, Hossein; Asadi, Asadollah

    2015-01-01

    Background: Vitamin D and insulin play an important role in susceptibility to polycystic ovary syndrome (PCOS), and therefore vitamin D receptor (VDR), parathyroid hormone (PTH), and insulin receptor (INSR) gene variants might be involved in the pathogenesis of PCOS. Objective: The present study was designed to investigate the possible associations between polymorphisms in VDR, PTH, and INSR genes and the risk of PCOS. Materials and Methods: VDR, PTH, and INSR gene variants were genotyped in 35 women with PCOS and 35 controls using Polymerase chain reaction – Restriction fragment length polymorphism method. Furthermore, serum levels of glucose and insulin were measured in all participants. Results: No significant differences were observed for the VDR FokI, VDR Tru9I, VDR TaqI, PTH DraII, INSR NsiI, and INSR PmlI gene polymorphisms between the women with PCOS and controls. However, after adjustment for confounding factors, the VDR BsmI “Bb” genotype and the VDR ApaI "Aa" genotype were significantly under transmitted to the patients (p= 0.016; OR= 0.250; 95% CI= 0.081-0.769, and p= 0.017; OR= 0.260; 95% CI= 0.086-0.788, respectively). Furthermore, in the women with PCOS, insulin levels were lower in the participants with the INSR NsiI "NN" genotype compared with those with the "Nn + nn" genotypes (P= 0.045). Conclusion: The results showed an association between the VDR gene BsmI and ApaI polymorphisms and PCOS risk. These data also indicated that the INSR "NN" genotype was a marker of decreased insulin in women with PCOS. Our findings, however, do not lend support to the hypothesis that PTH gene DraII variant plays a role in susceptibility to PCOS. PMID:27141540

  13. Association of vitamin D receptor gene variants with polycystic ovary syndrome: A case control study

    Directory of Open Access Journals (Sweden)

    Touraj Mahmoudi

    2015-12-01

    Full Text Available Background: Vitamin D and insulin play an important role in susceptibility to polycystic ovary syndrome (PCOS, and therefore vitamin D receptor (VDR, parathyroid hormone (PTH, and insulin receptor (INSR gene variants might be involved in the pathogenesis of PCOS. Objective: The present study was designed to investigate the possible associations between polymorphisms in VDR, PTH, and INSR genes and the risk of PCOS. Materials and Methods: VDR, PTH, and INSR gene variants were genotyped in 35 women with PCOS and 35 controls using Polymerase chain reaction – Restriction fragment length polymorphism method. Furthermore, serum levels of glucose and insulin were measured in all participants. Results: No significant differences were observed for the VDR FokI, VDR Tru9I, VDR TaqI, PTH DraII, INSR NsiI, and INSR PmlI gene polymorphisms between the women with PCOS and controls. However, after adjustment for confounding factors, the VDR BsmI “Bb” genotype and the VDR ApaI "Aa" genotype were significantly under transmitted to the patients (p= 0.016; OR= 0.250; 95% CI= 0.081-0.769, and p= 0.017; OR= 0.260; 95% CI= 0.086-0.788, respectively. Furthermore, in the women with PCOS, insulin levels were lower in the participants with the INSR NsiI "NN" genotype compared with those with the "Nn + nn" genotypes (P= 0.045. Conclusion: The results showed an association between the VDR gene BsmI and ApaI polymorphisms and PCOS risk. These data also indicated that the INSR "NN" genotype was a marker of decreased insulin in women with PCOS. Our findings, however, do not lend support to the hypothesis that PTH gene DraII variant plays a role in susceptibility to PCOS.

  14. A novel epidermal growth factor receptor variant lacking multiple domains directly activates transcription and is overexpressed in tumors

    OpenAIRE

    Piccione, EC; Lieu, TJ; Gentile, CF; Williams, TR; Connolly, AJ; Godwin, AK; Koong, AC; Wong, AJ

    2011-01-01

    The epidermal growth factor receptor (EGFR) is essential to multiple physiological and neoplastic processes via signaling by its tyrosine kinase domain and subsequent activation of transcription factors. EGFR overexpression and alteration, including point mutations and structural variants, contribute to oncogenesis in many tumor types. In this study, we identified an in-frame splice variant of the EGFR called mini-LEEK (mLEEK) that is more broadly expressed than the EGFR and is overexpressed ...

  15. 1918 Influenza receptor binding domain variants bind and replicate in primary human airway cells regardless of receptor specificity.

    Science.gov (United States)

    Davis, A Sally; Chertow, Daniel S; Kindrachuk, Jason; Qi, Li; Schwartzman, Louis M; Suzich, Jon; Alsaaty, Sara; Logun, Carolea; Shelhamer, James H; Taubenberger, Jeffery K

    2016-06-01

    The 1918 influenza pandemic caused ~50 million deaths. Many questions remain regarding the origin, pathogenicity, and mechanisms of human adaptation of this virus. Avian-adapted influenza A viruses preferentially bind α2,3-linked sialic acids (Sia) while human-adapted viruses preferentially bind α2,6-linked Sia. A change in Sia preference from α2,3 to α2,6 is thought to be a requirement for human adaptation of avian influenza viruses. Autopsy data from 1918 cases, however, suggest that factors other than Sia preference played a role in viral binding and entry to human airway cells. Here, we evaluated binding and entry of five 1918 influenza receptor binding domain variants in a primary human airway cell model along with control avian and human influenza viruses. We observed that all five variants bound and entered cells efficiently and that Sia preference did not predict entry of influenza A virus to primary human airway cells evaluated in this model. PMID:27062579

  16. Androgen receptor variant-7: an important predictive biomarker in castrate resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Oliver Sartor

    2015-06-01

    Full Text Available The recent manuscript in New England Journal of Medicine by Antonarakis et al. [1] has important clinical implications. This study evaluates mRNA expression of a particular androgen receptor splice variant-7 (AR-V7, in circulating tumor cells (CTCs from metastatic castrate-resistant prostate cancer (mCRPC patients receiving enzalutamide or abiraterone. The findings were striking, none of the 18 patients with detectable AR-V7 in CTCs had prostate-specific antigen (PSA responses. Further, the median time to PSA progression after enzalutamide or abiraterone treatment was only 1.3-1.4 months in AR-V7-positive patients as compared to 5.3-6.1 months in AR-V7 negative patients. AR-V7 in CTCs was also associated with shorter survival.

  17. Variants in the dopamine-4-receptor gene promoter are not associated with sensation seeking in skiers.

    Directory of Open Access Journals (Sweden)

    Cynthia J Thomson

    Full Text Available Sensation seeking is a personality trait that has been associated with disinhibited behaviours including substance use and gambling, but also with high-risk sport practices including skydiving, paragliding, and downhill skiing. Twin studies have shown that sensation seeking is moderately heritable, and candidate genes encoding components involved in dopaminergic transmission have been investigated as contributing to this type of behaviour. To determine whether variants in the regulatory regions of the dopamine-4-receptor gene (DRD4 influenced sport-specific sensation seeking, we analyzed five polymorphisms (-1106T/C, -906T/C, -809G/A, -291C/T, 120-bp duplication in the promoter region of the gene in a cohort of skiers and snowboarders (n = 599 that represented a broad range of sensation seeking behaviours. We grouped subjects by genotype at each of the five loci and compared impulsive sensation seeking and domain-specific (skiing sensation seeking between groups. There were no significant associations between genotype(s and general or domain-specific sensation seeking in the skiers and snowboarders, suggesting that while DRD4 has previously been implicated in sensation seeking, the promoter variants investigated in this study do not contribute to sensation seeking in this athlete population.

  18. Investigation of the dominant positive effect of porcine farnesoid X receptor (FXR) splice variant 1.

    Science.gov (United States)

    Gray, Matthew A; James Squires, E

    2015-04-10

    Pigs are well recognized as a model for humans in research studies due to similarities in metabolism and physiology between the two species. The potential for pigs to model humans in studying metabolic diseases is highly dependent on similarities in hepatic metabolism between the two species, including similarities in the farnesoid X receptor (FXR; NR1H4) which regulate bile acid homeostasis. During initial cloning of porcine FXR (pFXR), an alternative splice variant (pFXR-SV1) was isolated which contained a four amino acid (MYTG) insert that exerted a dominant positive effect on the wild type receptor (pFXR-WT). The current study investigated the role of this insert in the dominant positive effect. Individual point mutations were made to the first three amino acids of the MYTG insert. Mutations of the methionine (M) or threonine (T) to alanine (A) reduced the dominant positive effect, while mutation of the tyrosine (Y) to either A or phenylalanine (F) completely abolished the dominant positive effect. Treatment with the tyrosine phosphatase inhibitor sodium orthovanadate (Na3VO4) increased the dominant positive effect of pFXR-SV1 by about 30%. These results suggest that the dominant positive effect may be dependent on the phosphorylation status of the tyrosine in the MYTG insert. The human variant hFXRα+ has the same MYTG insert as pFXR-SV1, but did not cause a dominant positive effect on hFXR-WT and significantly reduced the activity of hFXR-WT. Thus, although the MYTG insert is conserved in both human and pig, the effects of this insert are different in the two species. PMID:25623328

  19. Determination of the specifications of the AKH-Vienna whole body counter

    International Nuclear Information System (INIS)

    In the Department of Nuclear Medicine of the Vienna AKH (General Hospital) a high sensitive whole body counter has been built. Planning and manufacturing were realized by the Research Centre Seibersdorf. The large investment was made with the intention to use this facility for routine measurements of radiation workers, for research applications in medicine and to be available for an emergency in case of a nuclear accident. Since another, clinical oriented whole body counter is available for routine diagnostic, emphasis was put on features that should complete and extend routine clinical requirements. High sensitivity was obtained by using a heavily-shielded counting chamber (15 cm steel, 2 cm lead and 0.5 cm copper inside), combined with four large NaI(Tl) detectors (two above and two below the patient bed)

  20. Common Variants Near Melanocortin 4 Receptor Are Associated with General and Visceral Adiposity in European- and African-American Youth

    NARCIS (Netherlands)

    Liu, Gaifen; Zhu, Haidong; Lagou, Vasiliki; Gutin, Bernard; Barbeau, Paule; Treiber, Frank A.; Dong, Yanbin; Snieder, Harold

    2010-01-01

    Objective Recent genome-wide association studies found common variants near the melanocortin 4 receptor gene associated with obesity. This study aimed to assess the influence of the identified single nucleotide polymorphisms rs17782313 and rs17700633 on general and visceral adiposity in European-and

  1. An imaging agent to detect androgen receptor and its active splice variants in prostate cancer

    Science.gov (United States)

    Imamura, Yusuke; Tien, Amy H.; Pan, Jinhe; Leung, Jacky K.; Banuelos, Carmen A.; Jian, Kunzhong; Wang, Jun; Mawji, Nasrin R.; Fernandez, Javier Garcia; Lin, Kuo-Shyan; Andersen, Raymond J.; Sadar, Marianne D.

    2016-01-01

    Constitutively active splice variants of androgen receptor (AR-Vs) lacking ligand-binding domain (LBD) are a mechanism of resistance to androgen receptor LBD–targeted (AR LBD–targeted) therapies for metastatic castration-resistant prostate cancer (CRPC). There is a strong unmet clinical need to identify prostate cancer patients with AR-V–positive lesions to determine whether they will benefit from further AR LBD–targeting therapies or should receive taxanes or investigational drugs like EPI-506 or galeterone. Both EPI-506 (NCT02606123) and galeterone (NCT02438007) are in clinical trials and are proposed to have efficacy against lesions that are positive for AR-Vs. AR activation function-1 (AF-1) is common to the N-terminal domains of full-length AR and AR-Vs. Here, we provide proof of concept for developing imaging compounds that directly bind AR AF-1 to detect both AR-Vs and full-length AR. 123I-EPI-002 had specific binding to AR AF-1, which enabled direct visualization of CRPC xenografts that express full-length AR and AR-Vs. Our findings highlight the potential of 123I-EPI-002 as an imaging agent for the detection of full-length AR and AR-Vs in CRPC.

  2. Adipokinetic hormone receptor gene identification and its role in triacylglycerol metabolism in the blood-sucking insect Rhodnius prolixus.

    Science.gov (United States)

    Alves-Bezerra, Michele; De Paula, Iron F; Medina, Jorge M; Silva-Oliveira, Gleidson; Medeiros, Jonas S; Gäde, Gerd; Gondim, Katia C

    2016-02-01

    Adipokinetic hormone (AKH) has been associated with the control of energy metabolism in a large number of arthropod species due to its role on the stimulation of lipid, carbohydrate and amino acid mobilization/release. In the insect Rhodnius prolixus, a vector of Chagas' disease, triacylglycerol (TAG) stores must be mobilized to sustain the metabolic requirements during moments of exercise or starvation. Besides the recent identification of the R. prolixus AKH peptide, other components required for the AKH signaling cascade and its mode of action remain uncharacterized in this insect. In the present study, we identified and investigated the expression profile of the gene encoding the AKH receptor of R. prolixus (RhoprAkhr). This gene is highly conserved in comparison to other sequences already described and its transcript is abundant in the fat body and the flight muscle of the kissing bug. Moreover, RhoprAkhr expression is induced in the fat body at moments of increased TAG mobilization; the knockdown of this gene resulted in TAG accumulation both in fat body and flight muscle after starvation. The inhibition of Rhopr-AKHR transcription as well as the treatment of insects with the peptide Rhopr-AKH in its synthetic form altered the transcript levels of two genes involved in lipid metabolism, the acyl-CoA-binding protein-1 (RhoprAcbp1) and the mitochondrial glycerol-3-phosphate acyltransferase-1 (RhoprGpat1). These results indicate that the AKH receptor is regulated at transcriptional level and is required for TAG mobilization under starvation. In addition to the classical view of AKH as a direct regulator of enzymatic activity, we propose here that AKH signaling may account for the regulation of nutrient metabolism by affecting the expression profile of target genes. PMID:26163435

  3. Co-Expression of Wild-Type P2X7R with Gln460Arg Variant Alters Receptor Function

    Science.gov (United States)

    Aprile-Garcia, Fernando; Metzger, Michael W.; Paez-Pereda, Marcelo; Stadler, Herbert; Acuña, Matías; Liberman, Ana C.; Senin, Sergio A.; Gerez, Juan; Hoijman, Esteban; Refojo, Damian; Mitkovski, Mišo; Panhuysen, Markus; Stühmer, Walter; Holsboer, Florian; Deussing, Jan M.; Arzt, Eduardo

    2016-01-01

    The P2X7 receptor is a member of the P2X family of ligand-gated ion channels. A single-nucleotide polymorphism leading to a glutamine (Gln) by arginine (Arg) substitution at codon 460 of the purinergic P2X7 receptor (P2X7R) has been associated with mood disorders. No change in function (loss or gain) has been described for this SNP so far. Here we show that although the P2X7R-Gln460Arg variant per se is not compromised in its function, co-expression of wild-type P2X7R with P2X7R-Gln460Arg impairs receptor function with respect to calcium influx, channel currents and intracellular signaling in vitro. Moreover, co-immunoprecipitation and FRET studies show that the P2X7R-Gln460Arg variant physically interacts with P2X7R-WT. Specific silencing of either the normal or polymorphic variant rescues the heterozygous loss of function phenotype and restores normal function. The described loss of function due to co-expression, unique for mutations in the P2RX7 gene so far, explains the mechanism by which the P2X7R-Gln460Arg variant affects the normal function of the channel and may represent a mechanism of action for other mutations. PMID:26986975

  4. Functional variants of sphingosine-1-phosphate receptor 1 gene associate with asthma susceptibility

    Science.gov (United States)

    Sun, Xiaoguang; Ma, Shwu-Fan; Wade, Michael S.; Flores, Carlos; Pino-Yanes, Maria; Moitra, Jaideep; Ober, Carole; Kittles, Rick; Husain, Aliya N.; Ford, Jean G.; Garcia, Joe G. N.

    2012-01-01

    Background The genetic mechanisms underlying asthma remain unclear. Increased permeability of the microvasculature is a feature of asthma and the sphingosine-1-phosphate receptor, S1PR1, is an essential participant regulating lung vascular integrity and responses to lung inflammation. Objective We explored the contribution of polymorphisms in the S1PR1 gene (S1PR1) to asthma susceptibility. Methods A combination of gene re-sequencing for SNP discovery, case-control association, functional evaluation of associated SNPs, and protein immunochemistry studies was utilized. Results Immunohistochemistry studies demonstrated significantly decreased S1PR1 protein expression in pulmonary vessels in asthmatic lungs compared to non-asthmatic individuals (p<0.05). Direct DNA sequencing of 27 multiethnic samples identified 39 S1PR1 variants (18 novel SNPs). Association studies were performed based on genotyping results from cosmopolitan tagging SNPs in three case-control cohorts from Chicago and New York totaling 1061 subjects (502 cases and 559 controls). Promoter SNP rs2038366 (−1557G/T) was found to be associated with asthma (p=0.03) in European Americans. In African Americans, an association was found for both asthma and severe asthma for intronic SNP rs3753194 (c.−164+170A/G) (p=0.006 and p=0.040, respectively) and for promoter SNP rs59317557 (−532C/G) with severe asthma (p=0.028). Consistent with predicted in silico functionality, alleles of promoter SNPs rs2038366 (−1557G/T) and rs59317557 (−532C/G) influenced the activity of a luciferase S1PR1 reporter vector in transfected endothelial cells exposed to growth factors (EGF, PDGF, VEGF) known to be increased in asthmatic airways. Conclusion These data provide strong support for a role for S1PR1 gene variants in asthma susceptibility and severity. Clinical Implications Our results indicate S1PR1 is a novel asthma candidate gene and an attractive target for future therapeutic strategies. Capsule summary This study

  5. The Influence of Vitamin D Receptor Genetic Variants on Bone Mineral Density and Osteoporosis in Chinese Postmenopausal Women

    OpenAIRE

    Wei He; Ming Liu; Xiaonan Huang; Zuhong Qing; Wei Gao

    2015-01-01

    Growing evidence indicates that the vitamin D receptor (VDR) gene is an important candidate gene for influencing the development of osteoporosis. The aim of the study was to evaluate the potential association between genetic variants of VDR gene and bone mineral density (BMD) and osteoporosis in Chinese postmenopausal women. The study included 970 Chinese postmenopausal women at the postmenopausal osteoporosis (482) and healthy controls (488). The BMD of lumbar spine (L2–4 anterior-posterior ...

  6. Constitutive homo- and hetero-oligomerization of TbetaRII-B, an alternatively spliced variant of the mouse TGF-beta type II receptor

    DEFF Research Database (Denmark)

    Krishnaveni, Manda S; Hansen, Jakob Lerche; Seeger, Werner;

    2006-01-01

    , but the oligomerization pattern and dynamics of TbetaRII splice variants in live cells has not been demonstrated thus far. Using co-immunoprecipitation and bioluminescence resonance energy transfer (BRET), we demonstrate that the mouse TbetaRII receptor splice variant TbetaRII-B is capable of forming ligand...

  7. Corticotropin-releasing hormone receptor 1 gene variants in irritable bowel syndrome.

    Directory of Open Access Journals (Sweden)

    Naoko Sato

    Full Text Available BACKGROUND: Corticotropin-releasing hormone (CRH acts mainly via the CRH receptor 1 (CRH-R1 and plays a crucial role in the stress-induced pathophysiology of irritable bowel syndrome (IBS. Several studies have demonstrated that variants of the CRH-R1 gene carry a potential risk for depression, but evidence for an association between CRH-R1 genotypes and IBS is lacking. We tested the hypothesis that genetic polymorphisms and haplotypes of CRH-R1 moderate the IBS phenotype and negative emotion in IBS patients. METHODS: A total of 103 patients with IBS and 142 healthy controls participated in the study. Three single-nucleotide polymorphisms of the CRH-R1 gene (rs7209436, rs242924, and rs110402 were genotyped. Subjects' emotional states were evaluated using the Perceived-Stress Scale, the State-Trait Anxiety Inventory, and the Self-rating Depression Scale. RESULTS: The TT genotype of rs7209436 (P = 0.01 and rs242924 (P = 0.02 was significantly more common in patients with IBS than in controls. Total sample analysis showed significant association between bowel pattern (normal, diarrhea, constipation, or mixed symptoms and the T allele of rs7209436 (P = 0.008, T allele of rs242924 (P = 0.019, A allele of rs110402 (P = 0.047, and TAT haplocopies (P = 0.048. Negative emotion was not associated with the examined CRH-R1 SNPs. CONCLUSION: These findings suggest that genetic polymorphisms and the CRH-R1 haplotypes moderate IBS and related bowel patterns. There was no clear association between CRH-R1 genotypes and negative emotion accompanying IBS. Further studies on the CRH system are therefore warranted.

  8. Cloning and Characterization of Spliced Variants of the Porcine G Protein Coupled Receptor 120

    Directory of Open Access Journals (Sweden)

    Tongxing Song

    2015-01-01

    Full Text Available The polyunsaturated fatty acids (PUFAs receptor GPR120 exerts a significant impact on systemic nutrient homeostasis in human and rodents. However, the porcine GPR120 (pGPR120 has not been well characterized. In the current study, we found that pGPR120 had 3 spliced variants. Transcript 1 encoded 362-amino acids (aa wild type pGPR120-WT, which shared 88% homology with human short form GPR120. Transcript 1 was the mainly expressed transcript of pGPR120. It was expressed predominantly in ileum, jejunum, duodenum, spleen, and adipose. Transcript 3 (coding 320-aa isoform was detected in spleen, while the transcript 2 (coding 310-aa isoform was only slightly expressed in spleen. A selective agonist for human GPR120 (TUG-891 and PUFAs activated SRE-luc and NFAT-luc reporter in HEK293T cells transfected with construct for pGPR120-WT but not pGPR120-V2. However, 320-aa isoform was not a dominant negative isoform. The extracellular signal-regulated kinase 1/2 (ERK1/2 phosphorylation levels in cells transfected with construct for pGPR120-WT were well activated by PUFAs, especially n-3 PUFA. These results showed that although pGPR120 had 3 transcripts, transcript 1 which encoded pGPR120-WT was the mainly expressed transcript. TUG-891 and PUFAs, especially n-3 PUFA, well activated pGPR120-WT. The current study contributed to dissecting the molecular regulation mechanisms of n-3 PUFA in pigs.

  9. A variant in the fat mass and obesity-associated gene (FTO) and variants near the melanocortin-4 receptor gene (MC4R) do not influence dietary intake

    DEFF Research Database (Denmark)

    Hasselbalch, Ann L; Angquist, Lars; Christiansen, Lene;

    2010-01-01

    a population-based sample of 756 healthy adult twin pairs, we studied associations between FTO rs9939609, near-MC4R rs12970134, rs17700633, and rs17782313 single nucleotide polymorphisms (SNP) and habitual dietary intake. Habitual dietary intake was assessed by a 247-question FFQ. Nontransformed......We investigated the role of the fat mass and obesity associated gene (FTO) and variants near the melanocortin-4 receptor gene (MC4R) in modulating habitual intake of total energy and macronutrients, glycemic index, glycemic load, dietary energy density, and energy from 20 food groups in adults. In...... variables and variables transformed by natural logarithm were analyzed by linear regression and dichotomized variables were analyzed by logistic regression. FTO SNP rs9939609 was not associated with habitual dietary intake. For the near-MC4R SNP rs12970134 and rs17700633, we found significant positive...

  10. Re-evaluation of the PBAN receptor (PBANR molecule: characterization of PBANR variants expressed in the pheromone glands of moths

    Directory of Open Access Journals (Sweden)

    Jae Min Lee

    2012-01-01

    Full Text Available Sex pheromone production in most moths is initiated following pheromone biosynthesis activating neuropeptide receptor (PBANR activation. PBANR was initially cloned from pheromone glands (PGs of Helicoverpa zea and Bombyx mori. The B. mori PBANR is characterized by a relatively long C-terminus that is essential for ligand-induced internalization, whereas the H. zea PBANR has a shorter C-terminus that lacks features present in the B. mori PBANR critical for internalization. Multiple PBANRs have been reported to be concurrently expressed in the larval CNS of Heliothis virescens. In the current study, we sought to examine the prevalence of multiple PBANRs in the PGs of three moths and to ascertain their potential functional relevance. Multiple PBANR variants (As, A, B, and C were cloned from the PGs of all species examined with PBANR-C the most highly expressed. Alternative splicing of the C-terminal coding sequence of the PBAN gene gives rise to the variants, which are distinguishable only by the length and composition of their respective C-terminal tails. Transient expression of fluorescent PBANR chimeras in insect cells revealed that PBANR-B and PBANR-C localized exclusively to the cell surface while PBANR-As and PBANR-A exhibited varying degrees of cytosolic localization. Similarly, only the PBANR-B and PBANR-C variants underwent ligand-induced internalization. Taken together, our results suggest that PBANR-C is the principal receptor molecule involved in PBAN signaling regardless of moth species. The high GC content of the C-terminal coding sequence in the B and C variants, which makes amplification using conventional polymerases difficult, likely accounts for previous preferential amplification of PBANR-A like receptors from other species.

  11. Common variants of the genes encoding erythropoietin and its receptor modulate cognitive performance in schizophrenia

    DEFF Research Database (Denmark)

    Kästner, Anne; Grube, Sabrina; El-Kordi, Ahmed;

    2012-01-01

    ) genotypes with cognitive functions. To prove this hypothesis, schizophrenic patients (N > 1000) were genotyped for 5' upstream-located gene variants, EPO SNP rs1617640 (T/G) and EPORSTR(GA)(n). Associations of these variants were obtained for cognitive processing speed, fine motor skills and short...

  12. A new splice variant of the major subunit of human asialoglycoprotein receptor encodes a secreted form in hepatocytes.

    Directory of Open Access Journals (Sweden)

    Jia Liu

    Full Text Available BACKGROUND: The human asialoglycoprotein receptor (ASGPR is composed of two polypeptides, designated H1 and H2. While variants of H2 have been known for decades, the existence of H1 variants has never been reported. PRINCIPAL FINDINGS: We identified two splice variants of ASGPR H1 transcripts, designated H1a and H1b, in human liver tissues and hepatoma cells. Molecular cloning of ASGPR H1 variants revealed that they differ by a 117 nucleotide segment corresponding to exon 2 in the ASGPR genomic sequence. Thus, ASGPR variant H1b transcript encodes a protein lacking the transmembrane domain. Using an H1b-specific antibody, H1b protein and a functional soluble ASGPR (sASGPR composed of H1b and H2 in human sera and in hepatoma cell culture supernatant were identified. The expression of ASGPR H1a and H1b in Hela cells demonstrated the different cellular loctions of H1a and H1b proteins at cellular membranes and in intracellular compartments, respectively. In vitro binding assays using fluorescence-labeled sASGPR or the substract ASOR revealed that the presence of sASGPR reduced the binding of ASOR to cells. However, ASOR itself was able to enhance the binding of sASGPR to cells expressing membrane-bound ASGPR. Further, H1b expression is reduced in liver tissues from patients with viral hepatitis. CONCLUSIONS: We conclude that two naturally occurring ASGPR H1 splice variants are produced in human hepatocytes. A hetero-oligomeric complex sASGPR consists of the secreted form of H1 and H2 and may bind to free substrates in circulation and carry them to liver tissue for uptake by ASGPR-expressing hepatocytes.

  13. The influence of vitamin D receptor genetic variants on bone mineral density and osteoporosis in Chinese postmenopausal women.

    Science.gov (United States)

    He, Wei; Liu, Ming; Huang, Xiaonan; Qing, Zuhong; Gao, Wei

    2015-01-01

    Growing evidence indicates that the vitamin D receptor (VDR) gene is an important candidate gene for influencing the development of osteoporosis. The aim of the study was to evaluate the potential association between genetic variants of VDR gene and bone mineral density (BMD) and osteoporosis in Chinese postmenopausal women. The study included 970 Chinese postmenopausal women at the postmenopausal osteoporosis (482) and healthy controls (488). The BMD of lumbar spine (L(2-4) anterior-posterior view), femoral neck hip, and total hip was evaluated using the Norland XR-46 dual energy X-ray absorptiometry (DEXA). The genotypes of VDR genetic variants were determined by the created restriction site-PCR (CRS-PCR) and confirmed by DNA sequencing methods. Our data indicated that the VDR p.Glicine (Gly)14 alanine (Ala) and p.histidine (His) 305 glutanine (Gln) genetic variants were statistically associated with adjusted femoral neck hip BMD, adjusted lumbar spine BMD, and adjusted total hip BMD (P values < 0.05). Results from this study suggest that the VDR p.Gly14Ala and p.His305Gln genetic variants are significantly associated with BMD decrease in Chinese postmenopausal women and might be used as molecular markers for assessing the risk of BMD and osteoporosis. PMID:25784778

  14. Glucocorticoid receptor beta splice variant expression in patients with high and low activity of systemic lupus erythematosus.

    Directory of Open Access Journals (Sweden)

    Pawel P Jagodzinski

    2008-01-01

    Full Text Available The glucocorticoid receptor (GR occurs mainly in two alternative splice variants encoding GRalpha and GRbeta. The GRbeta variant does not contain a GC binding domain and cannot mediate anti-inflammatory GC effects. Peripheral blood mononuclear cells (PBMCs were isolated from venous whole blood of twelve patients with SLE. Ten of the SLE patients exhibited low disease activity while two patients displayed highly active stage of the disease. The quantitative analysis of GRalpha and GRbeta transcripts in PBMC was performed by reverse transcription and real-time quantitative PCR SYBR Green I system. The protein level of GRalpha and GRbeta isoforms in PBMCs was determined by western blotting analysis. We found that the two SLE patients with high disease activity exhibited significantly elevated GRbeta transcript levels and corresponding protein levels in PBMCs. These preliminary findings suggest that increased expression of GRbeta isoform may be associated with relatively more severe clinical presentation of SLE syndrome.

  15. NOVEL SPLICED VARIANTS OF IONOTROPIC GLUTAMATE RECEPTOR GLUR6 IN NORMAL HUMAN FIBROBLAST AND BRAIN CELLS ARE TRANSCRIBED BY TISSUE SPECIFIC PROMOTERS

    OpenAIRE

    Zhawar, Vikramjit K.; Kaur, Gurpreet; deRiel, Jon K.; Kaur, G. Pal; Raj P Kandpal; Athwal, Raghbir S.

    2010-01-01

    The members of the ionotropic glutamate receptor family, namely, a-amino-3-hydroxy-S-methyl-4-isoxazole propionate (AMPA), kainate, and N-methyl-D-aspartate (NMDA) receptors, are important mediators of the rapid synaptic transmission in the central nervous system. We have investigated the splicing pattern and expression of the kainate receptor subunit GluR6 in human fibroblast cell lines and brain tissue. We demonstrate the expression of GluR6A variant specifically in brain, and four variants...

  16. High-level expression, purification and characterization of a constitutively active thromboxane A2 receptor polymorphic variant.

    Directory of Open Access Journals (Sweden)

    Bing Xu

    Full Text Available G protein-coupled receptors (GPCRs exhibit some level of basal signaling even in the absence of a bound agonist. This basal or constitutive signaling can have important pathophysiological roles. In the past few years, a number of high resolution crystal structures of GPCRs have been reported, including two crystal structures of constitutively active mutants (CAM of the dim-light receptor, rhodopsin. The structural characterizations of CAMs are impeded by the lack of proper expression systems. The thromboxane A2 receptor (TP is a GPCR that mediates vasoconstriction and promotes thrombosis in response to the binding of thromboxane. Here, we report on the expression and purification of a genetic variant and CAM in TP, namely A160T, using tetracycline-inducible HEK293S-TetR and HEK293S (GnTI¯-TetR cell lines. Expression of the TP and the A160T genes in these mammalian cell lines resulted in a 4-fold increase in expression to a level of 15.8 ±0.3 pmol of receptor/mg of membrane protein. The receptors expressed in the HEK293S (GnTI(--TetR cell line showed homogeneous glycosylation. The functional yield of the receptors using a single step affinity purification was 45 µg/10⁶ cells. Temperature- dependent secondary structure changes of the purified TP and A160T receptors were characterized using circular dichroism (CD spectropolarimetry. The CD spectra shows that the loss of activity or thermal sensitivity that was previously observed for the A160T mutant, is not owing to large unfolding of the protein but rather to a more subtle effect. This is the first study to report on the successful high-level expression, purification, and biophysical characterization of a naturally occurring, diffusible ligand activated GPCR CAM.

  17. Low frequency genetic variants in the μ-opioid receptor (OPRM1) affect risk for addiction to heroin and cocaine.

    Science.gov (United States)

    Clarke, Toni-Kim; Crist, Richard C; Kampman, Kyle M; Dackis, Charles A; Pettinati, Helen M; O'Brien, Charles P; Oslin, David W; Ferraro, Thomas N; Lohoff, Falk W; Berrettini, Wade H

    2013-05-10

    The μ-opioid receptor (MOR) binds exogenous and endogenous opioids and is known to mediate the rewarding effects of drugs of abuse. Numerous genetic studies have sought to identify common genetic variation in the gene encoding MOR (OPRM1) that affects risk for drug addiction. The purpose of this study was to examine the contribution of rare coding variants in OPRM1 to the risk for addiction. Rare and low frequency variants were selected using the National Heart Lung and Blood Institute - Exome Sequencing Project (NHLBI-ESP) database, which has screened the exomes of over 6500 individuals. Two SNPs (rs62638690 and rs17174794) were selected for genotyping in 1377 European American individuals addicted to heroin and/or cocaine. Two different SNPs (rs1799971 and rs17174801) were genotyped in 1238 African American individuals addicted to heroin and/or cocaine. Using the minor allele frequencies from the NHLBI-ESP dataset as a comparison group, case-control association analyses were performed. Results revealed an association between rs62638690 and cocaine and heroin addiction in European Americans (p=0.02; 95% C.I. 0.47 [0.24-0.92]). This study suggests a potential role for rare OPRM1 variants in addiction disorders and highlights an area worthy of future study. PMID:23454283

  18. Low frequency genetic variants in the mu-opioid receptor (OPRM1) affect risk for addiction to heroin and cocaine

    Science.gov (United States)

    Clarke, Toni-Kim; Crist, Richard C.; Kampman, Kyle M.; Dackis, Charles A.; Pettinati, Helen M.; O’Brien, Charles P.; Oslin, David W.; Ferraro, Thomas N.; Lohoff, Falk W.; Berrettini, Wade H.

    2013-01-01

    The μ-opioid receptor (MOR) binds exogenous and endogenous opioids and is known to mediate the rewarding effects of drugs of abuse. Numerous genetic studies have sought to identify common genetic variation in the gene encoding MOR (OPRM1) that affects risk for drug addiction. The purpose of this study was to examine the contribution of rare coding variants in OPRM1 to the risk for addiction. Rare and low frequency variants were selected using the National Heart Lung and Blood Institute –Exome Sequencing Project (NHLBI-ESP) database, which has screened the exomes of over 6500 individuals. Two SNPs (rs62638690 and rs17174794) were selected for genotyping in 1377 European American individuals addicted to heroin and/or cocaine. Two different SNPs (rs1799971 and rs17174801) were genotyped in 1238 African American individuals addicted to heroin and/or cocaine. Using the minor allele frequencies from the NHLBI-ESP dataset as a comparison group, case-control association analyses were performed. Results revealed an association between rs62638690 and cocaine and heroin addiction in European Americans (p=0.02; 95% C.I. 0.47 [0.24–0.92]). This study suggests a potential role for rare OPRM1 variants in addiction disorders and highlights an area worthy of future study. PMID:23454283

  19. Genetic variants of glutamate receptor gene family in Taiwanese Kawasaki disease children with coronary artery aneurysms

    OpenAIRE

    Lin, Ying-Ju; Chang, Jeng-Sheng; Liu, Xiang(Research Center for Hadron and CSR Physics, Lanzhou University and Institute of Modern Physics of CAS, 730000, Lanzhou , China); Tsang, Hsinyi; Lin, Ting-Hsu; Liao, Chiu-Chu; Huang, Shao-Mei; Chien, Wen-Kuei; Chen, Jin-Hua; Wu, Jer-Yuarn; Chen, Chien-Hsiun; Chang, Li-Ching; Lin, Cheng-Wen; Ho, Tsung-Jung; Tsai, Fuu-Jen

    2014-01-01

    Background Patients with Kawasaki disease (KD), a pediatric systemic vasculitis, may develop coronary artery aneurysm (CAA) as a complication. To investigate the role of glutamate receptors in KD and its CAA development, we performed genetic association studies. Methods and results We examined the whole family of glutamate receptors by genetic association studies in a Taiwanese cohort of 262 KD patients. We identified glutamate receptor ionotropic, kainate 1 (GRIK1) as a novel susceptibility ...

  20. The Cannabinoid Receptor 2 Q63R Variant Modulates the Relationship between Childhood Obesity and Age at Menarche.

    Directory of Open Access Journals (Sweden)

    Giulia Bellini

    Full Text Available The ovary is an important site where gene variants modulate pubertal timing. The cannabinoid receptor 2 (CB2 is expressed in the ovary, plays a role in folliculogenesis and ovulation, and can be modulated by estrogens. Obesity is strictly associated with early menarche and is characterized by sex hormone and endocannabinoid derangement.In this study, we investigated the role of the CB2 receptor in determining the age at menarche in obese girls.We studied a cohort of 240 obese girls (age 11.9±3 years; BMI z-score 2.8±0.8. The age at menarche (if it had already occurred was recorded at the time of the visit or via phonecall. The CNR2 rs35761398 polymorphism, which leads to the CB2 Q63R variant, was detected by the TaqMan assay.In total, 105 patients were homozygous for the R63-coding allele (RR, 113 were QR and 22 were QQ. Variance analysis revealed a significantly earlier age of menarche in subjects carrying the Q63 allele, which was also found after adjusting for BMI z-score (11±1.2 vs. 11.6±1.2 years, p = 0.0003. Logistic regression analysis demonstrated that patients homozygous for the Q allele had a 2.2-fold higher risk (odds ratio = 2.2; CI1.1-3.4; p = 0.02 of presenting with an early menarche (age at menarche <12 years.We demonstrated for the first time the association between the CB2 Q63R functional variant and the age at menarche in a cohort of Italian obese girls.

  1. Variants in the Dopamine-4-Receptor Gene Promoter Are Not Associated with Sensation Seeking in Skiers

    OpenAIRE

    Thomson, Cynthia J.; Amelia K Rajala; Scott R Carlson; Jim L Rupert

    2014-01-01

    Sensation seeking is a personality trait that has been associated with disinhibited behaviours including substance use and gambling, but also with high-risk sport practices including skydiving, paragliding, and downhill skiing. Twin studies have shown that sensation seeking is moderately heritable, and candidate genes encoding components involved in dopaminergic transmission have been investigated as contributing to this type of behaviour. To determine whether variants in the regulatory regio...

  2. Variant repeats are interspersed throughout the telomeres and recruit nuclear receptors in ALT cells

    OpenAIRE

    Conomos, Dimitri; Stutz, Michael D.; Hills, Mark; Neumann, Axel A.; Bryan, Tracy M.; Reddel, Roger R; Hilda A Pickett

    2012-01-01

    Telomeres in cells that use the recombination-mediated alternative lengthening of telomeres (ALT) pathway elicit a DNA damage response that is partly independent of telomere length. We therefore investigated whether ALT telomeres contain structural abnormalities that contribute to ALT activity. Here we used next generation sequencing to analyze the DNA content of ALT telomeres. We discovered that variant repeats were interspersed throughout the telomeres of ALT cells. We found that the C-type...

  3. Multiple loss-of-function variants of taste receptors in modern humans

    OpenAIRE

    K. Fujikura

    2015-01-01

    Despite recent advances in the knowledge of interindividual taste differences, the underlying genetic backgrounds have remained to be fully elucidated. Much of the taste variation among different mammalian species can be explained by pseudogenization of taste receptors. Here I investigated whether the most recent disruptions of taste receptor genes segregate with their intact forms in modern humans by analyzing 14 ethnically diverse populations. The results revealed an unprecedented prevalenc...

  4. Functional and clinical consequences of Fc receptor polymorphic and copy number variants.

    Science.gov (United States)

    Bournazos, S; Woof, J M; Hart, S P; Dransfield, I

    2009-08-01

    Receptors for immunoglobulins (Fc receptors) play a central role during an immune response, as they mediate the specific recognition of antigens of almost infinite diversity by leucocytes, thereby linking the humoral and cellular components of immunity. Indeed, engagement of Fc receptors by immunoglobulins initiates a range of immunoregulatory processes that might also play a role in disease pathogenesis. In the circulation, five main types of immunoglobulins (Ig) exist - namely IgG, IgA, IgE, IgM and IgD and receptors with the ability to recognize and bind to IgG (Fc gamma receptor family), IgE (Fc epsilon RI and CD23), IgA (CD89; Fc alpha/microR) and IgM (Fc alpha/microR) have been identified and characterized. However, it is astonishing that nearly all the known human Fc receptors display extensive genetic variation with clear implications for their function, thus representing a substantial genetic risk factor for the pathogenesis of a range of chronic inflammatory disorders. PMID:19604264

  5. Evolution of Functional and Sequence Variants of the Mammalian XPR1 Receptor for Mouse Xenotropic Gammaretroviruses and the Human-Derived Retrovirus XMRV ▿ †

    OpenAIRE

    Yan, Yuhe; Liu, Qingping; Wollenberg, Kurt; Martin, Carrie; Buckler-White, Alicia; Kozak, Christine A.

    2010-01-01

    Genetic conflicts between retroviruses and their receptors result in the evolution of novel host entry restrictions and novel virus envelopes, and such variants can influence trans-species transmission. We screened rodents and other mammals for sequence variation in the Xpr1 receptor for the mouse xenotropic or polytropic mouse leukemia viruses (X-MLVs or P-MLVs, respectively) of the gammaretrovirus family and for susceptibility to mouse-derived X/P-MLVs and to XMRV (xenotropic murine leukemi...

  6. Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants

    Science.gov (United States)

    In rodents, hypothalamic brain-derived neurotrophic factor (BDNF) expression appears to be regulated by melanocortin-4 receptor (MC4R) activity. The impact of MC4R genetic variation on circulating BDNF in humans is unknown. The objective of this study is to compare BDNF concentrations of subjects wi...

  7. The human receptor for urokinase plasminogen activator. NH2-terminal amino acid sequence and glycosylation variants

    DEFF Research Database (Denmark)

    Behrendt, N; Rønne, E; Ploug, M;

    1990-01-01

    The receptor for human urokinase-type plasminogen activator (u-PA) was purified from phorbol 12-myristate 13-acetate-stimulated U937 cells by temperature-induced phase separation of detergent extracts, followed by affinity chromatography with immobilized diisopropyl fluorophosphate-treated u-PA. ...

  8. Single nucleotide polymorphism variants within tva and tvb receptor genes in Chinese chickens

    Science.gov (United States)

    Avian leukosis is an immunosuppressive neoplastic disease caused by avian leukosis viruses (ALV), which causes tremendous economic losses in the worldwide poultry industry. The susceptibility or resistance of chicken cells to subgroup A ALV and subgroup B, D, and E ALV are determined by the receptor...

  9. A comprehensive analysis and functional characterization of naturally occurring non-synonymous variants of nuclear receptor PXR.

    Science.gov (United States)

    Rana, Manjul; Devi, Suneeta; Gourinath, Samudrala; Goswami, Ravinder; Tyagi, Rakesh K

    2016-09-01

    Pregnane & Xenobiotic Receptor (PXR) acts as a xenosensing transcriptional regulator of many drug metabolizing enzymes and transporters of the 'detoxification machinery' that coordinate in elimination of xenobiotics and endobiotics from the cellular milieu. It is an accepted view that some individuals or specific populations display considerable differences in their ability to metabolize different drugs, dietary constituents, herbals etc. In this context we speculated that polymorphisms in PXR gene might contribute to variability in cytochrome P450 (CYP450) metabolizing enzymes of phase I, drug metabolizing components of phase II and efflux components of the detoxification machinery. Therefore, in this study, we have undertaken a comprehensive functional analysis of seventeen naturally occurring non-synonymous variants of human PXR. When compared, we observed that some of the PXR SNP variants exhibit distinct functional and dynamic responses on parameters which included transcriptional function, sub-cellular localization, mitotic chromatin binding, DNA-binding properties and other molecular interactions. One of the unique SNP located within the DNA-binding domain of PXR was found to be functionally null and distinct on other parameters. Similarly, some of the non-synonymous SNPs in PXR imparted reduced transactivation function as compared to wild type PXR. Interestingly, PXR is reported to be a mitotic chromatin binding protein and such an association has been correlated to an emerging concept of 'transcription memory' and altered transcription output. In view of the observations made herein our data suggest that some of the natural PXR variants may have adverse physiological consequences owing to its influence on the expression levels and functional output of drug-metabolizing enzymes and transporters. The present study is expected to explain not only the observed inter-individual responses to different drugs but may also highlight the mechanistic details and

  10. Expression of insulin receptor spliced variants and their functional correlates in muscle from patients with non-insulin-dependent diabetes mellitus

    DEFF Research Database (Denmark)

    Hansen, Torben; Bjørbaek, C; Vestergaard, H;

    1993-01-01

    Due to alternative splicing of exon 11 of the receptor gene, the human insulin receptor exists in two forms, that have distinct tissue-specific expression and are functionally different. Needle biopsies obtained from vastus lateralis muscle from 20 patients with noninsulin-dependent diabetes...... mellitus (NIDDM) and 20 normal control subjects were analyzed for the relative expression of insulin receptor mRNA variants in a novel assay using fluorescence-labeled primers and subsequent analysis on an automated DNA sequencer. In subgroups of patients and control subjects, insulin binding and tyrosine...

  11. LACKING EXON5 OF VARIANT ESTROGEN RECEPTOR IN HUMAN BREAST CANCER

    Institute of Scientific and Technical Information of China (English)

    Zhang Lei; Gong Ping; Sun Sulian; Dong Zhiwei

    1998-01-01

    Methods: The target sequence of ER RNA covering exon4~6(1082~1520bp) was amplified in 7 clinical human breast cancer tissues by reverse transcription and polymerase chain reaction (RT-PCR) techniques.Results: PCR products were transferred to nitrocellulose membranes and hybridized using a [r-32P]-ATP labeled ER 29 oligonulceotide probe representing the antisense strand of the ER Cdna sequence 1271~1299. Specific bands were found at 438 and 300 base pairs in two tumors. The 300 base pair of PCR product was recovered from ER+/PR+ and ER+/PR- tumor, respectively.Conclusion: Dideoxy sequence analysis revealed that they contained the variant ER completely missing exon 5.

  12. Discovery of naturally occurring splice variants of the rat histamine H3 receptor that act as dominant-negative isoforms.

    Science.gov (United States)

    Bakker, Remko A; Lozada, Adrian Flores; van Marle, André; Shenton, Fiona C; Drutel, Guillaume; Karlstedt, Kaj; Hoffmann, Marcel; Lintunen, Minnamaija; Yamamoto, Yumiko; van Rijn, Richard M; Chazot, Paul L; Panula, Pertti; Leurs, Rob

    2006-04-01

    We described previously the cDNA cloning of three functional rat histamine H3 receptor (rH3R) isoforms as well as the differential brain expression patterns of their corresponding mRNAs and signaling properties of the resulting rH3A, rH3B, and rH3C receptor isoforms (Mol Pharmacol 59:1-8). In the current report, we describe the cDNA cloning, mRNA localization in the rat central nervous system, and pharmacological characterization of three additional rH3R splice variants (rH3D, rH3E, and rH3F) that differ from the previously published isoforms in that they result from an additional alternative-splicing event. These new H3R isoforms lack the seventh transmembrane (TM) helix and contain an alternative, putatively extracellular, C terminus (6TM-rH3 isoforms). After heterologous expression in COS-7 cells, radioligand binding or functional responses upon the application of various H3R ligands could not be detected for the 6TM-rH3 isoforms. In contrast to the rH3A receptor (rH3AR), detection of the rH3D isoform using hemagglutinin antibodies revealed that the rH3D isoform remains mainly intracellular. The expression of the rH3D-F splice variants, however, modulates the cell surface expression-levels and subsequent functional responses of the 7TM H3R isoforms. Coexpression of the rH3AR and the rH3D isoforms resulted in the intracellular retention of the rH3AR and reduced rH3AR functionality. Finally, we show that in rat brain, the H3R mRNA expression levels are modulated upon treatment with the convulsant pentylenetetrazole, suggesting that the rH3R isoforms described herein thus represent a novel physiological mechanism for controlling the activity of the histaminergic system. PMID:16415177

  13. The role of toll-like receptor variants in acute anterior uveitis

    OpenAIRE

    Pratap, Divya S.; Lyndell L Lim; Wang, Jie Jin; Mackey, David A.; Kearns, Lisa S.; Stawell, Richard J.; ,; Kathryn P Burdon; Mitchell, Paul; Craig, Jamie E; Hall, Anthony J.; Hewitt, Alex W

    2011-01-01

    Purpose Acute anterior uveitis (AAU) is the most common form of uveitis; however, while it is presumed to have an immunological basis, the precise underlying etiology remains elusive. Toll-like receptors (TLRs) have a key role in linking innate and adaptive immunity, thereby forming a molecular bridge between microbial triggers and the development of AAU. The purpose of this study was to investigate the role of TLR2 and TLR4 gene polymorphisms in the pathogenesis of AAU. Methods The study com...

  14. Brain volumes in late life: gender, hormone treatment, and estrogen receptor variants.

    OpenAIRE

    Ryan, Joanne; Artero, Sylvaine; Carrière, Isabelle; Scali, Jacqueline; Maller, Jerome; Meslin, Chantal; Ritchie, Karen; Scarabin, Pierre-Yves; Ancelin, Marie-Laure

    2014-01-01

    Structural imaging studies suggest gender differences in brain volumes; however, whether hormone treatment (HT) can protect against age-related structural changes remains unknown, and no prior neuroimaging study has investigated potential interactions between HT and estrogen receptor (ESR) polymorphisms. Magnetic resonance imaging was used to measure gray and white matter, hippocampal volume, corpus callosum, cerebrospinal fluid (CSF), total intracranial volume (ICV) and white matter lesions ...

  15. Association of oxytocin receptor (OXTR) gene variants with multiple phenotype domains of autism spectrum disorder

    OpenAIRE

    Campbell, Daniel B.; Datta, Dibyadeep; Jones, Shaine T.; Batey Lee, Evon; Sutcliffe, James S.; Hammock, Elizabeth A.D.; Levitt, Pat

    2011-01-01

    Autism spectrum disorder (ASD) is characterized by core deficits in social behavior, communication, and behavioral flexibility. Several lines of evidence indicate that oxytocin, signaling through its receptor (OXTR), is important in a wide range of social behaviors. In attempts to determine whether genetic variations in the oxytocin signaling system contribute to ASD susceptibility, seven recent reports indicated association of common genetic polymorphisms in the OXTR gene with ASD. Each invo...

  16. Variants in nicotinic acetylcholine receptors α5 and α3 increase risks to nicotine dependence†

    OpenAIRE

    Chen, Xiangning; Chen, Jingchun; Williamson, Vernell S; An, Seon-Sook; Hettema, John M.; Aggen, Steven H.; Neale, Michael C.; Kendler, Kenneth S.

    2009-01-01

    Nicotinic acetylcholine receptors bind to nicotine and initiate the physiological and pharmacological responses to tobacco smoking. In this report, we studied the association of α5 and α3 subunits with nicotine dependence and with the symptoms of alcohol and cannabis abuse and dependence in two independent epidemiological samples (n = 815 and 1,121, respectively). In this study, seven single nucleotide polymorphisms were genotyped in the CHRNA5 and CHRNA3 genes. In both samples, we found that...

  17. Genetic Variants of Retinoic Acid Receptor-Related Orphan Receptor Alpha Determine Susceptibility to Type 2 Diabetes Mellitus in Han Chinese

    Science.gov (United States)

    Zhang, Yuwei; Liu, Yulan; Liu, Yin; Zhang, Yanjie; Su, Zhiguang

    2016-01-01

    Retinoic acid receptor-related orphan receptor alpha (RORA) plays a key role in the regulation of lipid and glucose metabolism and insulin expression that are implicated in the development of type 2 diabetes mellitus (T2DM). However, the effects of genetic variants in the RORA gene on the susceptibility to T2DM remain unknown. Nine tagging single-nucleotide polymorphisms (SNPs) were screened by using the SNaPshot method in 427 patients with T2DM and 408 normal controls. Association between genotypes and haplotypes derived from these SNPs with T2DM was analyzed using different genetic models. Allele and genotype frequencies at rs10851685 were significantly different between T2DM patients and control subjects (allele: p = 0.009, Odds ratios (OR) = 1.36 [95% Confidence intervals (CI) = 1.08–1.72]; genotype: p = 0.029). The minor allele T, at rs10851685, was potentially associated with an increased risk of T2DM in the dominant model, displaying OR of 1.38 (95% CI: 1.04–1.82, p = 0.025) in subjects with genotypes TA+TT vs. AA. In haplotype analysis, we observed that haplotypes GGTGTAACT, GGTGTAACC, and GATATAACT were significantly associated with increased risk of T2DM, while haplotypes GATGAAGTT, AGTGAAGTT, and AATGAAATT were protective against T2DM. These data suggest that the genetic variation in RORA might determine a Chinese Han individual’s susceptibility to T2DM. PMID:27556492

  18. Genetic Variants of Retinoic Acid Receptor-Related Orphan Receptor Alpha Determine Susceptibility to Type 2 Diabetes Mellitus in Han Chinese.

    Science.gov (United States)

    Zhang, Yuwei; Liu, Yulan; Liu, Yin; Zhang, Yanjie; Su, Zhiguang

    2016-01-01

    Retinoic acid receptor-related orphan receptor alpha (RORA) plays a key role in the regulation of lipid and glucose metabolism and insulin expression that are implicated in the development of type 2 diabetes mellitus (T2DM). However, the effects of genetic variants in the RORA gene on the susceptibility to T2DM remain unknown. Nine tagging single-nucleotide polymorphisms (SNPs) were screened by using the SNaPshot method in 427 patients with T2DM and 408 normal controls. Association between genotypes and haplotypes derived from these SNPs with T2DM was analyzed using different genetic models. Allele and genotype frequencies at rs10851685 were significantly different between T2DM patients and control subjects (allele: p = 0.009, Odds ratios (OR) = 1.36 [95% Confidence intervals (CI) = 1.08-1.72]; genotype: p = 0.029). The minor allele T, at rs10851685, was potentially associated with an increased risk of T2DM in the dominant model, displaying OR of 1.38 (95% CI: 1.04-1.82, p = 0.025) in subjects with genotypes TA+TT vs. AA. In haplotype analysis, we observed that haplotypes GGTGTAACT, GGTGTAACC, and GATATAACT were significantly associated with increased risk of T2DM, while haplotypes GATGAAGTT, AGTGAAGTT, and AATGAAATT were protective against T2DM. These data suggest that the genetic variation in RORA might determine a Chinese Han individual's susceptibility to T2DM. PMID:27556492

  19. UEV-1 is an ubiquitin-conjugating enzyme variant that regulates glutamate receptor trafficking in C. elegans neurons.

    Directory of Open Access Journals (Sweden)

    Lawrence B Kramer

    Full Text Available The regulation of AMPA-type glutamate receptor (AMPAR membrane trafficking is a key mechanism by which neurons regulate synaptic strength and plasticity. AMPAR trafficking is modulated through a combination of receptor phosphorylation, ubiquitination, endocytosis, and recycling, yet the factors that mediate these processes are just beginning to be uncovered. Here we identify the ubiquitin-conjugating enzyme variant UEV-1 as a regulator of AMPAR trafficking in vivo. We identified mutations in uev-1 in a genetic screen for mutants with altered trafficking of the AMPAR subunit GLR-1 in C. elegans interneurons. Loss of uev-1 activity results in the accumulation of GLR-1 in elongated accretions in neuron cell bodies and along the ventral cord neurites. Mutants also have a corresponding behavioral defect--a decrease in spontaneous reversals in locomotion--consistent with diminished GLR-1 function. The localization of other synaptic proteins in uev-1-mutant interneurons appears normal, indicating that the GLR-1 trafficking defects are not due to gross deficiencies in synapse formation or overall protein trafficking. We provide evidence that GLR-1 accumulates at RAB-10-containing endosomes in uev-1 mutants, and that receptors arrive at these endosomes independent of clathrin-mediated endocytosis. UEV-1 homologs in other species bind to the ubiquitin-conjugating enzyme Ubc13 to create K63-linked polyubiquitin chains on substrate proteins. We find that whereas UEV-1 can interact with C. elegans UBC-13, global levels of K63-linked ubiquitination throughout nematodes appear to be unaffected in uev-1 mutants, even though UEV-1 is broadly expressed in most tissues. Nevertheless, ubc-13 mutants are similar in phenotype to uev-1 mutants, suggesting that the two proteins do work together to regulate GLR-1 trafficking. Our results suggest that UEV-1 could regulate a small subset of K63-linked ubiquitination events in nematodes, at least one of which is critical

  20. The human receptor for urokinase plasminogen activator. NH2-terminal amino acid sequence and glycosylation variants

    DEFF Research Database (Denmark)

    Behrendt, N; Rønne, E; Ploug, M; Petri, T; Løber, D; Nielsen, L S; Schleuning, W D; Blasi, F; Appella, E; Danø, K

    1990-01-01

    -PA. The purified protein shows a single 55-60 kDa band after sodium dodecyl sulfate-polyacrylamide gel electrophoresis and silver staining. It is a heavily glycosylated protein, the deglycosylated polypeptide chain comprising only 35 kDa. The glycosylated protein contains N-acetyl-D-glucosamine and sialic...... acid, but no N-acetyl-D-galactosamine. Glycosylation is responsible for substantial heterogeneity in the receptor on phorbol ester-stimulated U937 cells, and also for molecular weight variations among various cell lines. The amino acid composition and the NH2-terminal amino acid sequence are reported...

  1. Charakterisierung der E179K-Variante des Transient Receptor Potential Ankyrin 1 Proteins in vitro

    OpenAIRE

    Baastrup, Jonas Marius

    2015-01-01

    Der TRPA1-Kanal gehört zur Familie der transient receptor potential-Kanäle (TRPs) und wird nach heutigem Wissensstand der Untergruppe der thermosensitiven TRP-Kanäle zugeordnet. Er wird bevorzugt im Nervensystem exprimiert, wo er hauptsächlich die Aufgabe eines Kälterezeptors, insbesondere für schmerzhafte Kälte erfüllt. Eine Transition von Guanin zu Adenin an Position 710 der TRPA1 DNA (710G>A) führt zu einer Aminosäuresubstitution von Glutamat (E) zu Lysin (K) an Position 179 (E179K) in der...

  2. An amino-terminal variant of the central cannabinoid receptor resulting from alternative splicing.

    Science.gov (United States)

    Shire, D; Carillon, C; Kaghad, M; Calandra, B; Rinaldi-Carmona, M; Le Fur, G; Caput, D; Ferrara, P

    1995-02-24

    The cDNA sequences encoding the central cannabinoid receptor, CB1, are known for two species, rat and human. However, little information concerning the flanking, noncoding regions is presently available. We have isolated two overlapping clones from a human lung cDNA library with CB1 cDNA inserts. One of these, cann7, contains a short stretch of the CB1 coding region and 4 kilobase pairs (kb) of the 3'-untranslated region (UTR), including two polyadenylation signals. The other, cann6, is identical to cann7 upstream from the first polyadenylation signal, and in addition, it contains the whole coding region and extends for 1.8 kb into the 5'-UTR. Comparison of cann6 with the published sequence (Gérard, C. M., Mollereau, C., Vassart, G., and Parmentier, M. (1991) Biochem. J. 279, 129-134) shows the coding regions to be identical, but reveals important differences in the flanking regions. Notably, the cann6 sequence appears to be that of an immature transcript, containing 1.8 kb of an intronic sequence in the 5'-UTR. In addition, polymerase chain reaction amplification of the CB1 coding region in the IM-9 cell line cDNA resulted in two fragments, one containing the whole CB1 coding region and the second lacking a 167-base pair intron within the sequence encoding the amino-terminal tail of the receptor. This alternatively spliced form would translate to an NH2-terminal modified isoform (CB1A) of the receptor, shorter than CB1 by 61 amino acids. In addition, the first 28 amino acids of the putative truncated receptor are completely different from those of CB1, containing more hydrophobic residues. Rat CB1 mRNA is similarly alternatively spliced. A study of the distribution of the human CB1 and CB1A mRNAs by reverse transcription-polymerase chain reaction analysis showed the presence of both CB1 and CB1A throughout the brain and in all the peripheral tissues examined, with CB1A being present in amounts of up to 20% of CB1. PMID:7876112

  3. Novel Splice Variants of Bovine Interleukin-1 Receptor-Associated Kinase 2(IRAK2)

    Institute of Scientific and Technical Information of China (English)

    WANG Xing-ping; LUOREN Zhuo-ma; XU Shang-zhong; GAO Xue; LI Jun-ya; REN Hong-yan; CHEN Jin-bao

    2009-01-01

    Interleukin-1 receptor-associated kinases(IRAKs)are important signaling elements of the toll-like receptors family,which play a role in innate immune responses by coordinating host defense mechanisms.Presently different isoforms of human and murine IRAK2 molecules are cloned,but there is no report on the sequences and structure of bovine IRAK2 gene.In this study,we cloned the bovine IRAK2 gene by RT-PCR and RACE and discovered that there exist two alternative splicing of bovine IRAK2 genes,IRAK2a and IRAK2b(GenBank accession no.EU528620 and EU528621).IRAK2a gene is 2148 bp coding 622 aa,which contains a death domain(aa 14-94)and a kinase domain(aa 205-440),but IRAK2b lacks 147 bp of exon 3 corresponding to IRAK2a,and codes 386 aa which contains only partly kinase domain.

  4. The rs1143679 (R77H) lupus associated variant of ITGAM (CD11b) impairs complement receptor 3 mediated functions in human monocytes

    OpenAIRE

    Rhodes, B.; Furnrohr, B. G.; Roberts, A.L.; Tzircotis, G.; Schett, G; Spector, T. D.; Vyse, T J

    2012-01-01

    Objectives The rs1143679 variant of ITGAM, encoding the R77H variant of CD11b (part of complement receptor 3; CR3), is among the strongest genetic susceptibility effects in human systemic lupus erythematosus (SLE). The authors aimed to demonstrate R77H function in ex-vivo human cells. Methods Monocytes/monocyte-derived macrophages from healthy volunteers homozygous for either wild type (WT) or 77H CD11b were studied. The genotype-specific expression of CD11b, and CD11b activation using confor...

  5. Cloning of an apparent splice variant of the rat N-methyl-D-aspartate receptor NMDAR1 with altered sensitivity to polyamines and activators of protein kinase C.

    OpenAIRE

    Durand, G M; Gregor, P.; X. Zheng; Bennett, M V; Uhl, G. R.; Zukin, R S

    1992-01-01

    Molecular cloning identified complementary DNA species, from a rat ventral midbrain library, encoding apparent splice variants of the N-methyl-D-aspartate (NMDA) receptor NMDAR1 (which we now term NR1a). Sequencing revealed that one variant, NR1b, differs from NR1a by the presence of a 21-amino acid insert near the amino end of the N-terminal domain and by an alternate C-terminal domain in which the last 75 amino acids are replaced by an unrelated sequence of 22 amino acids. NR1b is virtually...

  6. Six host range variants of the xenotropic/polytropic gammaretroviruses define determinants for entry in the XPR1 cell surface receptor

    Directory of Open Access Journals (Sweden)

    Kozak Christine A

    2009-10-01

    Full Text Available Abstract Background The evolutionary interactions between retroviruses and their receptors result in adaptive selection of restriction variants that can allow natural populations to evade retrovirus infection. The mouse xenotropic/polytropic (X/PMV gammaretroviruses rely on the XPR1 cell surface receptor for entry into host cells, and polymorphic variants of this receptor have been identified in different rodent species. Results We screened a panel of X/PMVs for infectivity on rodent cells carrying 6 different XPR1 receptor variants. The X/PMVs included 5 well-characterized laboratory and wild mouse virus isolates as well as a novel cytopathic XMV-related virus, termed Cz524, isolated from an Eastern European wild mouse-derived strain, and XMRV, a xenotropic-like virus isolated from human prostate cancer. The 7 viruses define 6 distinct tropisms. Cz524 and another wild mouse isolate, CasE#1, have unique species tropisms. Among the PMVs, one Friend isolate is restricted by rat cells. Among the XMVs, two isolates, XMRV and AKR6, differ from other XMVs in their PMV-like restriction in hamster cells. We generated a set of Xpr1 mutants and chimeras, and identified critical amino acids in two extracellular loops (ECLs that mediate entry of these different viruses, including 3 residues in ECL3 that are involved in PMV entry (E500, T507, and V508 and can also influence infectivity by AKR6 and Cz524. Conclusion We used a set of natural variants and mutants of Xpr1 to define 6 distinct host range variants among naturally occurring X/PMVs (2 XMV variants, 2 PMVs, 2 different wild mouse variants. We identified critical amino acids in XPR1 that mediate entry of these viruses. These gammaretroviruses and their XPR1 receptor are thus highly functionally polymorphic, a consequence of the evolutionary pressures that favor both host resistance and virus escape mutants. This variation accounts for multiple naturally occurring virus resistance phenotypes and

  7. Association between variants in the genes for leptin, leptin receptor, and proopiomelanocortin with chronic heart failure in the Czech population.

    Science.gov (United States)

    Bienertová-Vasků, Julie Anna; Spinarová, Lenka; Bienert, Petr; Vasků, Anna

    2009-03-01

    Patients with chronic heart failure (CHF) express enhanced catabolic metabolism finally resulting in overall weight loss, whereas adipokines might play a crucial role in signaling among tissues. The aim of this study was to investigate the possible associations of defined variability in leptin (dbSNP ID rs7799039), proopiomelanocortin (dbSNP ID rs3754860 and dbSNP ID rs1009388), and leptin receptor gene (dbSNP rs1137101) with CHF and evaluate their potential as the CHF susceptibility genes. The case-control study comprised a total of 372 patients of Caucasian origin with chronic heart failure (New York Heart Association [NYHA] functional classes II-IV, ejection fraction (EF) <40%) and 407 healthy controls. They were genotyped for the leptin (LEP) -2548 G/A, leptin receptor (LEPR) Gln223Arg, and proopiomelanocortin (POMC) RsaI (5'-untranslated region) and C1032G variants (intron 1) using PCR-based methodology. No case-control differences in genotype as well as allele frequencies were observed between CHF patients and controls. We constructed POMC RsaI/C1032G haplotypes, having found no significant association with body mass index (BMI), left ventricle ejection fraction (LVEF), left ventricle hypertrophy (LVH) and diabetes mellitus (DM). Multivariate regression analyses revealed an approximately 2-fold risk for NYHA class IV associated with the LEPR Gln223Arg (P = 0.0000001, odds ratio [OR] = 2.10, 95% confidence interval [CI] = 1.56-2.84); it also displayed an independent prediction role for LVEF in heart failure cases of all etiologies (P = 0.002, OR = 4.05, 95% CI = 1.36-10.06). In subanalyses according to CHF etiology the LEPR Gln223Arg showed an independent prediction role for NYHA IV in IHD patients (P = 0.0001, OR = 2.50, 95% CI = 1.69-3.82) and both for NYHA IV(P = 0.007, OR = 2.04, 95% CI = 1.20-3.84) and LVEF (P = 0.004, OR = 11.87, 95% CI = 2.08-55.6) in DCMP patients. The role of the polymorphic variants in the genes encoding for adipokines as potential

  8. Neutral endopeptidase-resistant C-type natriuretic peptide variant represents a new therapeutic approach for treatment of fibroblast growth factor receptor 3-related dwarfism.

    Science.gov (United States)

    Wendt, Daniel J; Dvorak-Ewell, Melita; Bullens, Sherry; Lorget, Florence; Bell, Sean M; Peng, Jeff; Castillo, Sianna; Aoyagi-Scharber, Mika; O'Neill, Charles A; Krejci, Pavel; Wilcox, William R; Rimoin, David L; Bunting, Stuart

    2015-04-01

    Achondroplasia (ACH), the most common form of human dwarfism, is caused by an activating autosomal dominant mutation in the fibroblast growth factor receptor-3 gene. Genetic overexpression of C-type natriuretic peptide (CNP), a positive regulator of endochondral bone growth, prevents dwarfism in mouse models of ACH. However, administration of exogenous CNP is compromised by its rapid clearance in vivo through receptor-mediated and proteolytic pathways. Using in vitro approaches, we developed modified variants of human CNP, resistant to proteolytic degradation by neutral endopeptidase, that retain the ability to stimulate signaling downstream of the CNP receptor, natriuretic peptide receptor B. The variants tested in vivo demonstrated significantly longer serum half-lives than native CNP. Subcutaneous administration of one of these CNP variants (BMN 111) resulted in correction of the dwarfism phenotype in a mouse model of ACH and overgrowth of the axial and appendicular skeletons in wild-type mice without observable changes in trabecular and cortical bone architecture. Moreover, significant growth plate widening that translated into accelerated bone growth, at hemodynamically tolerable doses, was observed in juvenile cynomolgus monkeys that had received daily subcutaneous administrations of BMN 111. BMN 111 was well tolerated and represents a promising new approach for treatment of patients with ACH. PMID:25650377

  9. Evolution of functional and sequence variants of the mammalian XPR1 receptor for mouse xenotropic gammaretroviruses and the human-derived retrovirus XMRV.

    Science.gov (United States)

    Yan, Yuhe; Liu, Qingping; Wollenberg, Kurt; Martin, Carrie; Buckler-White, Alicia; Kozak, Christine A

    2010-11-01

    Genetic conflicts between retroviruses and their receptors result in the evolution of novel host entry restrictions and novel virus envelopes, and such variants can influence trans-species transmission. We screened rodents and other mammals for sequence variation in the Xpr1 receptor for the mouse xenotropic or polytropic mouse leukemia viruses (X-MLVs or P-MLVs, respectively) of the gammaretrovirus family and for susceptibility to mouse-derived X/P-MLVs and to XMRV (xenotropic murine leukemia virus-related virus), an X-MLV-like virus isolated from humans with prostate cancer and chronic fatigue syndrome. We identified multiple distinct susceptibility phenotypes; these include the four known Xpr1 variants in Mus and a novel fifth Xpr1 gene found in Mus molossinus and Mus musculus. We describe the geographic and species distribution of the Mus Xpr1 variants but failed to find the X-MLV-restrictive laboratory mouse allele in any wild mouse. We used mutagenesis and phylogenetic analysis to evaluate the functional contributions made by constrained, variable, and deleted residues. Rodent Xpr1 is under positive selection, indicating a history of host-pathogen conflicts; several codons under selection have known roles in virus entry. All non-Mus mammals are susceptible to mouse X-MLVs, but some restrict other members of the X/P-MLV family, and the resistance of hamster and gerbil cells to XMRV indicates that XMRV has unique receptor requirements. We show that the hypervariable fourth extracellular XPR1 loop (ECL4) contains three evolutionarily constrained residues that do not contribute to receptor function, we identify two novel residues important for virus entry (I579 and T583), and we describe a unique pattern of ECL4 variation in the three virus-restrictive Xpr1 variants found in MLV-infected house mice; these mice carry different deletions in ECL4, suggesting either that these sites or loop size affects receptor function. PMID:20844050

  10. Joint Association of Nicotinic Acetylcholine Receptor Variants with Abdominal Obesity in American Indians: The Strong Heart Family Study

    OpenAIRE

    Yun Zhu; Jingyun Yang; Fawn Yeh; Cole, Shelley A.; Karin Haack; Lee, Elisa T.; Howard, Barbara V.; Jinying Zhao

    2014-01-01

    Cigarette smoke is a strong risk factor for obesity and cardiovascular disease. The effect of genetic variants involved in nicotine metabolism on obesity or body composition has not been well studied. Though many genetic variants have previously been associated with adiposity or body fat distribution, a single variant usually confers a minimal individual risk. The goal of this study is to evaluate the joint association of multiple variants involved in cigarette smoke or nicotine dependence wi...

  11. Stability of the aryl hydrocarbon receptor and its regulated genes in the low activity variant of Hepa-1 cell line.

    Science.gov (United States)

    Humphrey-Johnson, Andria; Abukalam, Rawia; Eltom, Sakina E

    2015-03-01

    We examined the expression kinetics of some of the aryl hydrocarbon receptor (AhR)-regulated genes in LA1 variant cells compared to wild type (WT) Hepa-1 mouse hepatoma cell lines, and we investigated the stability of AhR protein as a key step in the function of this receptor. Treatment of both cell types with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in increased CYP1A1 and CYP1B1 mRNA with a subsequent down regulation of AhR. We show here that co-treatment with transcription inhibitor actinomycin D (ActD) has reversed the TCDD-induced depletion of AhR protein in WT. However, the proteolytic degradation of AhR in absence of TCDD was significantly higher in LA1 cells than in WT, and ActD treatment reduced this loss. Induction of CYP1A1 and CYP1B1 mRNA by TCDD in WT cells each exhibited bursts of activity in the initial hour which were about 3-fold greater than in LAI cells. The induced mRNA levels in LA1 exhibited a slow and sustained increase approximating the WT levels by 20h. The induction of two other AhR-regulated genes also showed comparable turnover differences between the two types of cell. Thus, altered regulation of the AhR responsive genes in LA1 may result from a difference in AhR stability. PMID:25637755

  12. Droplet Digital PCR Based Androgen Receptor Variant 7 (AR-V7) Detection from Prostate Cancer Patient Blood Biopsies

    Science.gov (United States)

    Ma, Yafeng; Luk, Alison; Young, Francis P.; Lynch, David; Chua, Wei; Balakrishnar, Bavanthi; de Souza, Paul; Becker, Therese M.

    2016-01-01

    Androgen receptor splice variant V7 (AR-V7) was recently identified as a valuable predictive biomarker in metastatic castrate-resistant prostate cancer. Here, we report a new, sensitive and accurate screen for AR-V7 mRNA expression directly from circulating tumor cells (CTCs): We combined EpCAM-based immunomagnetic CTC isolation using the IsoFlux microfluidic platform with droplet digital polymerase chain reaction (ddPCR) to analyze total AR and AR-V7 expression from prostate cancer patients CTCs. We demonstrate that AR-V7 is reliably detectable in enriched CTC samples with as little as five CTCs, even considering tumor heterogeneity, and confirm detection of AR-V7 in CTC samples from advanced prostate cancer (PCa) patients with AR-V7 detection limited to castrate resistant disease status in our sample set. Sensitive molecular analyses of circulating tumor cells (CTCs) or circulating tumor nucleic acids present exciting strategies to detect biomarkers, such as AR-V7 from non-invasive blood samples, so-called blood biopsies. PMID:27527157

  13. Droplet Digital PCR Based Androgen Receptor Variant 7 (AR-V7 Detection from Prostate Cancer Patient Blood Biopsies

    Directory of Open Access Journals (Sweden)

    Yafeng Ma

    2016-08-01

    Full Text Available Androgen receptor splice variant V7 (AR-V7 was recently identified as a valuable predictive biomarker in metastatic castrate-resistant prostate cancer. Here, we report a new, sensitive and accurate screen for AR-V7 mRNA expression directly from circulating tumor cells (CTCs: We combined EpCAM-based immunomagnetic CTC isolation using the IsoFlux microfluidic platform with droplet digital polymerase chain reaction (ddPCR to analyze total AR and AR-V7 expression from prostate cancer patients CTCs. We demonstrate that AR-V7 is reliably detectable in enriched CTC samples with as little as five CTCs, even considering tumor heterogeneity, and confirm detection of AR-V7 in CTC samples from advanced prostate cancer (PCa patients with AR-V7 detection limited to castrate resistant disease status in our sample set. Sensitive molecular analyses of circulating tumor cells (CTCs or circulating tumor nucleic acids present exciting strategies to detect biomarkers, such as AR-V7 from non-invasive blood samples, so-called blood biopsies.

  14. Hypersensitive K303R oestrogen receptorvariant not found in invasive carcinomas

    International Nuclear Information System (INIS)

    Genetic abnormalities or mutations in premalignant breast lesions may have a role in progression toward malignancy or influence the behaviour of subsequent disease. The A908G (Lys303→Arg) change in the gene encoding oestrogen receptor-α (ER-α) creates a hypersensitivity to oestradiol and would have significant consequences if present in breast carcinoma, especially those treated with endocrine therapy. We have therefore examined a panel of endocrine-treated invasive carcinomas for the presence of this mutation. Sequencing of control DNA was shown to detect mutation present in as little as 15% of the starting material. Enrichment for the mutation by using MboII restriction digestion allowed the detection of mutant present at 1% or less. We applied these techniques to genomic DNA and cDNA from 136 invasive breast carcinomas. No evidence of the A908G mutation was found with either technique. The incidence of this mutation in our panel of tumours is therefore significantly less than previously reported. The fact that the mutation was not found leads us to believe that this mutation is absent from most cells in invasive carcinomas and furthermore that the major expression product of the ER-α gene in cancers does not contain the K303R mutation. It is therefore unlikely to influence the effectiveness of endocrine treatment

  15. Association analysis of bitter receptor genes in five isolated populations identifies a significant correlation between TAS2R43 variants and coffee liking.

    Directory of Open Access Journals (Sweden)

    Nicola Pirastu

    Full Text Available Coffee, one of the most popular beverages in the world, contains many different physiologically active compounds with a potential impact on people's health. Despite the recent attention given to the genetic basis of its consumption, very little has been done in understanding genes influencing coffee preference among different individuals. Given its markedly bitter taste, we decided to verify if bitter receptor genes (TAS2Rs variants affect coffee liking. In this light, 4066 people from different parts of Europe and Central Asia filled in a field questionnaire on coffee liking. They have been consequently recruited and included in the study. Eighty-eight SNPs covering the 25 TAS2R genes were selected from the available imputed ones and used to run association analysis for coffee liking. A significant association was detected with three SNP: one synonymous and two functional variants (W35S and H212R on the TAS2R43 gene. Both variants have been shown to greatly reduce in vitro protein activity. Surprisingly the wild type allele, which corresponds to the functional form of the protein, is associated to higher liking of coffee. Since the hTAS2R43 receptor is sensible to caffeine, we verified if the detected variants produced differences in caffeine bitter perception on a subsample of people coming from the FVG cohort. We found a significant association between differences in caffeine perception and the H212R variant but not with the W35S, which suggests that the effect of the TAS2R43 gene on coffee liking is mediated by caffeine and in particular by the H212R variant. No other significant association was found with other TAS2R genes. In conclusion, the present study opens new perspectives in the understanding of coffee liking. Further studies are needed to clarify the role of the TAS2R43 gene in coffee hedonics and to identify which other genes and pathways are involved in its genetics.

  16. Role of 5-HT2C receptor gene variants in antipsychotic-induced weight gain

    Directory of Open Access Journals (Sweden)

    Brandl EJ

    2011-08-01

    Full Text Available Tessa JM Wallace, Clement C Zai, Eva J Brandl, Daniel J MüllerNeurogenetics Section, Center for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, ON, CanadaAbstract: Antipsychotic-induced weight gain is a serious side effect of antipsychotic medication that can lead to increased morbidity, mortality, and non-compliance in patients. Numerous single nucleotide polymorphisms have been studied for association with antipsychotic-induced weight gain in an attempt to find genetic predictors of this side effect. An ability to predict this side effect could lead to personalized treatment plans for predisposed individuals, which could significantly decrease the prevalence and severity of weight gain. Variations in the serotonin receptor 2c gene (HTR2C have emerged as promising candidates for prediction of antipsychotic-induced weight gain. Specifically, the well-studied -759C/T promoter polymorphism has been associated with weight gain in diverse populations, although some studies have reported no association. This discrepancy is likely due to heterogeneity in study design with respect to ethnicity, treatment duration, and other variables. Notably, the association between HTR2C and antipsychotic-induced weight gain appears strongest in short-term studies on patients with limited or no previous antipsychotic treatment. Other, less extensively studied promoter polymorphisms (-697C/G, -997G/A, and -1165A/G have also emerged as potential predictors of antipsychotic-induced weight gain. Conversely, the well-studied intronic polymorphism Cys23Ser does not appear to be associated. With further research on both HTR2C and other genetic and environmental predictors of antipsychotic-induced weight gain, a predictive test could one day be created to screen patients and provide preventative or alternative treatment for those who are predisposed to this serious side effect.Keywords: HTR2C, pharmacogenomics, promoter polymorphism

  17. Inherited functional variants of the lymphocyte receptor CD5 influence melanoma survival.

    Science.gov (United States)

    Potrony, Miriam; Carreras, Esther; Aranda, Fernando; Zimmer, Lisa; Puig-Butille, Joan-Anton; Tell-Martí, Gemma; Armiger, Noelia; Sucker, Antje; Giménez-Xavier, Pol; Martínez-Florensa, Mario; Carrera, Cristina; Malvehy, Josep; Schadendorf, Dirk; Puig, Susana; Lozano, Francisco

    2016-09-15

    Despite the recent progress in treatment options, malignant melanoma remains a deadly disease. Besides therapy, inherited factors might modulate clinical outcome, explaining in part widely varying survival rates. T-cell effector function regulators on antitumor immune responses could also influence survival. CD5, a T-cell receptor inhibitory molecule, contributes to the modulation of antimelanoma immune responses as deduced from genetically modified mouse models. The CD5 SNPs rs2241002 (NM_014207.3:c.671C > T, p.Pro224Leu) and rs2229177 (NM_014207.3:c.1412C > T, p.Ala471Val) constitute an ancestral haplotype (Pro224-Ala471) that confers T-cell hyper-responsiveness and worsens clinical autoimmune outcome. The assessment of these SNPs on survival impact from two melanoma patient cohorts (Barcelona, N = 493 and Essen, N = 215) reveals that p.Ala471 correlates with a better outcome (OR= 0.57, 95% CI = 0.33-0.99, Adj. p = 0.043, in Barcelona OR = 0.63, 95% CI = 0.40-1.01, Adj. p = 0.051, in Essen). While, p.Leu224 was associated with increased melanoma-associated mortality in both cohorts (OR = 1.87, 95% CI = 1.07-3.24, Adj. p = 0.030 in Barcelona and OR = 1.84, 95% CI = 1.04-3.26, Adj. p = 0.037, in Essen). Furthermore survival analyses showed that the Pro224-Ala471 haplotype in homozygosis improved melanoma survival in the entire set of patients (HR = 0.27, 95% CI 0.11-0.67, Adj. p = 0.005). These findings highlight the relevance of genetic variability in immune-related genes for clinical outcome in melanoma. PMID:27169428

  18. Analyzing Interaction of μ-, δ- and κ-opioid Receptor Gene Variants on Alcohol or Drug Dependence Using a Pattern Discovery-based Method

    OpenAIRE

    Li, Zhong; Zhang, Huiping

    2013-01-01

    Background Polymorphisms in the μ-, δ- and κ-opioid receptor genes (OPRM1, OPRD1 and OPRK1) have been reported to be associated with substance (alcohol or drug) dependence. The influence of an individual gene on a disease trait should be more evident when analyzed in the context of gene-gene interactions. Thus, we assessed the joint effect of variants in these three opioid receptor genes on alcohol, cocaine, or opioid dependence. Methods Genotype data for 13 OPRM1 Single Nucleotide Polymorphi...

  19. The Monoclonal Antibody CH12 Enhances the Sorafenib-Mediated Growth Inhibition of Hepatocellular Carcinoma Xenografts Expressing Epidermal Growth Factor Receptor Variant III

    OpenAIRE

    Yaqiong Yang; Hua Jiang; Huiping Gao; Juan Kong; Pengwei Zhang; Suwen Hu; Bizhi Shi; Pengfei Zhang; Ming Yao; Zonghai Li

    2012-01-01

    The multikinase inhibitor sorafenib is the first oral agent to show activity against human hepatocellular carcinoma (HCC). Although the clinical application of sorafenib has shown good tolerability in the studied populations, it also causes multiple human dose-limiting toxicities. Thus, there is a strong need to reduce the overall dose of sorafenib. We have reported that the epidermal growth factor receptor variant III (EGFRvIII) expression can decrease the sensitivity of HCC cells to chemoth...

  20. The Monoclonal Antibody CH12 Enhances the Sorafenib-Mediated Growth Inhibition of Hepatocellular Carcinoma Xenografts Expressing Epidermal Growth Factor Receptor Variant III1

    OpenAIRE

    Yang, Yaqiong; Jiang, Hua; Gao, Huiping; Kong, Juan; Zhang, Pengwei; Hu, Suwen; Shi, Bizhi; Zhang, Pengfei; Yao, Ming; Li, Zonghai

    2012-01-01

    The multikinase inhibitor sorafenib is the first oral agent to show activity against human hepatocellular carcinoma (HCC). Although the clinical application of sorafenib has shown good tolerability in the studied populations, it also causes multiple human dose-limiting toxicities. Thus, there is a strong need to reduce the overall dose of sorafenib. We have reported that the epidermal growth factor receptor variant III (EGFRvIII) expression can decrease the sensitivity of HCC cells to chemoth...

  1. The cardiovascular and hypothalamus-pituitary-adrenal axis response to stress is controlled by glucocorticoid receptor sequence variants and promoter methylation

    OpenAIRE

    Li-Tempel, Ting; Larra, Mauro F.; Sandt, Estelle; Mériaux, Sophie B.; Schote, Andrea B.; Schächinger, Hartmut; Claude P Muller; Turner, Jonathan D.

    2016-01-01

    Background Gender, genetic makeup, and prior experience interact to determine physiological responses to an external perceived stressor. Here, we investigated the contribution of both genetic variants and promoter methylation of the NR3C1 (glucocorticoid receptor) gene to the cardiovascular and hypothalamus-pituitary-adrenal (HPA) axis response to the socially evaluated cold pressor test (seCPT). Results Two hundred thirty-two healthy participants were recruited and underwent the experiment. ...

  2. Corticotropin-Releasing Hormone Receptor 2 Gene Variants in Irritable Bowel Syndrome.

    Directory of Open Access Journals (Sweden)

    Hazuki Komuro

    Full Text Available Corticotropin-releasing hormone (CRH plays an important role in the pathophysiology of irritable bowel syndrome (IBS and regulates the stress response through two CRH receptors (R1 and R2. Previously, we reported that a CRHR1 gene polymorphism (rs110402, rs242924, and rs7209436 and haplotypes were associated with IBS. However, the association between the CRHR2 gene and IBS was not investigated. We tested the hypothesis that genetic polymorphisms and haplotypes of CRHR2 are associated with IBS pathophysiology and negative emotion in IBS patients.A total of 142 IBS patients and 142 healthy controls participated in this study. Seven single nucleotide polymorphisms (SNPs of the CRHR2 gene (rs4722999, rs3779250, rs2240403, rs2267710, rs2190242, rs2284217, and rs2284220 were genotyped. Subjects' psychological states were evaluated using the Perceived-Stress Scale, the State-Trait Anxiety Inventory, and the Self-Rating Depression Scale.We found that rs4722999 and rs3779250, located in intronic region, were associated with IBS in terms of genotype frequency (rs4722999: P = 0.037; rs3779250: P = 0.017 and that the distribution of the major allele was significantly different between patients and controls. There was a significant group effect (controls vs. IBS, and a CRHR2 genotype effect was observed for three psychological scores, but the interaction was not significant. We found a haplotype of four SNPs (rs4722999, rs3779250, rs2240403, and rs2267710 and two SNPs (rs2284217 and rs2284220 in strong linkage disequilibrium (D' > 0.90. We also found that haplotypes of the CRHR2 gene were significantly different between IBS patients and controls and that they were associated with negative emotion.Our findings support the hypothesis that genetic polymorphisms and haplotypes of CRHR2 are related to IBS. In addition, we found associations between CRHR2 genotypes and haplotypes and negative emotion in IBS patients and controls. Further studies on IBS and the CRH

  3. The melanocortin 1 receptor (Mc1r) variants do not account for the co-occurrence of Parkinson's disease and malignant melanoma.

    Science.gov (United States)

    Elincx-Benizri, Sandra; Inzelberg, Rivka; Greenbaum, Lior; Cohen, Oren S; Yahalom, Gilad; Laitman, Yael; Djaldetti, Ruth; Orlev, Yael; Scope, Alon; Azizi, Esther; Friedman, Eitan; Hassin-Baer, Sharon

    2014-12-01

    Parkinson's disease (PD) is characterized by loss of melanin-positive dopaminergic neurons in the substantia nigra. Malignant melanoma (MM), a melanocyte-derived neoplasm, occurs with higher than expected frequency among PD patients. Red-haired individuals exhibit a threefold risk for developing MM than dark-haired people; PD risk also increases with lighter hair color. One plausible explanation for the associations between MM, hair color, and PD is the melanocortin-1 receptor (MC1R) gene that plays a key role in hair and skin pigmentation as well as in MM predisposition. We hypothesized that specific MC1R variants may predispose to both MM and PD. Genotyping of the MC1R gene was performed for 16 PD patients with MM (PD+ MM+) and for three sets of age, sex, and ethnically matched controls, including 36 patients with PD (PD+ MM-), 37 with MM (PD- MM+) and 37 with neither diagnosis (PD- MM-). No association was found between MC1R variants and the co-occurrence of PD and MM. The risk for MM was higher in carriers of two MC1R variants versus with no MC1R variant (odds ratio (OR)=5.0, 95% confidence interval (CI) 1.7-14.4, p=0.003). The risk for PD in carriers of two MC1R variants was markedly lower (OR=0.213, 95% CI 0.063-0.725) compared with individuals with no MC1R variant (p=0.013). In this study, MC1R variants were not associated with both MM and PD. Further studies in larger cohorts are necessary to confirm these preliminary results. PMID:25284244

  4. Identification of novel subgroup A variants with enhanced receptor binding and replicative capacity in primary isolates of anaemogenic strains of feline leukaemia virus

    Directory of Open Access Journals (Sweden)

    Stewart Hazel

    2012-05-01

    Full Text Available Abstract Background The development of anaemia in feline leukaemia virus (FeLV-infected cats is associated with the emergence of a novel viral subgroup, FeLV-C. FeLV-C arises from the subgroup that is transmitted, FeLV-A, through alterations in the amino acid sequence of the receptor binding domain (RBD of the envelope glycoprotein that result in a shift in the receptor usage and the cell tropism of the virus. The factors that influence the transition from subgroup A to subgroup C remain unclear, one possibility is that a selective pressure in the host drives the acquisition of mutations in the RBD, creating A/C intermediates with enhanced abilities to interact with the FeLV-C receptor, FLVCR. In order to understand further the emergence of FeLV-C in the infected cat, we examined primary isolates of FeLV-C for evidence of FeLV-A variants that bore mutations consistent with a gradual evolution from FeLV-A to FeLV-C. Results Within each isolate of FeLV-C, we identified variants that were ostensibly subgroup A by nucleic acid sequence comparisons, but which bore mutations in the RBD. One such mutation, N91D, was present in multiple isolates and when engineered into a molecular clone of the prototypic FeLV-A (Glasgow-1, enhanced replication was noted in feline cells. Expression of the N91D Env on murine leukaemia virus (MLV pseudotypes enhanced viral entry mediated by the FeLV-A receptor THTR1 while soluble FeLV-A Env bearing the N91D mutation bound more efficiently to mouse or guinea pig cells bearing the FeLV-A and -C receptors. Long-term in vitro culture of variants bearing the N91D substitution in the presence of anti-FeLV gp70 antibodies did not result in the emergence of FeLV-C variants, suggesting that additional selective pressures in the infected cat may drive the subsequent evolution from subgroup A to subgroup C. Conclusions Our data support a model in which variants of FeLV-A, bearing subtle differences in the RBD of Env, may be

  5. Conserved Expression of the Glutamate NMDA Receptor 1 Subunit Splice Variants during the Development of the Siberian Hamster Suprachiasmatic Nucleus

    Science.gov (United States)

    Duffield, Giles E.; Mikkelsen, Jens D.; Ebling, Francis J. P.

    2012-01-01

    Glutamate neurotransmission and the N-methyl-D-aspartate receptor (NMDAR) are central to photic signaling to the master circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). NMDARs also play important roles in brain development including visual input circuits. The functional NMDAR is comprised of multiple subunits, but each requiring the NR1 subunit for normal activity. The NR1 can be alternatively spliced to produce isoforms that confer different functional properties on the NMDAR. The SCN undergoes extensive developmental changes during postnatal life, including synaptogenesis and acquisition of photic signaling. These changes are especially important in the highly photoperiodic Siberian hamster, in which development of sensitivity to photic cues within the SCN could impact early physiological programming. In this study we examined the expression of NR1 isoforms in the hamster at different developmental ages. Gene expression in the forebrain was quantified by in situ hybridization using oligonucleotide probes specific to alternatively spliced regions of the NR1 heteronuclear mRNA, including examination of anterior hypothalamus, piriform cortex, caudate-putamen, thalamus and hippocampus. Gene expression analysis within the SCN revealed the absence of the N1 cassette, the presence of the C2 cassette alone and the combined absence of C1 and C2 cassettes, indicating that the dominant splice variants are NR1-2a and NR1-4a. Whilst we observe changes at different developmental ages in levels of NR1 isoform probe hybridization in various forebrain structures, we find no significant changes within the SCN. This suggests that a switch in NR1 isoform does not underlie or is not produced by developmental changes within the hamster SCN. Consistency of the NR1 isoforms would ensure that the response of the SCN cells to photic signals remains stable throughout life, an important aspect of the function of the SCN as a responder to environmental changes

  6. Conserved expression of the glutamate NMDA receptor 1 subunit splice variants during the development of the Siberian hamster suprachiasmatic nucleus.

    Directory of Open Access Journals (Sweden)

    Giles E Duffield

    Full Text Available Glutamate neurotransmission and the N-methyl-D-aspartate receptor (NMDAR are central to photic signaling to the master circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN. NMDARs also play important roles in brain development including visual input circuits. The functional NMDAR is comprised of multiple subunits, but each requiring the NR1 subunit for normal activity. The NR1 can be alternatively spliced to produce isoforms that confer different functional properties on the NMDAR. The SCN undergoes extensive developmental changes during postnatal life, including synaptogenesis and acquisition of photic signaling. These changes are especially important in the highly photoperiodic Siberian hamster, in which development of sensitivity to photic cues within the SCN could impact early physiological programming. In this study we examined the expression of NR1 isoforms in the hamster at different developmental ages. Gene expression in the forebrain was quantified by in situ hybridization using oligonucleotide probes specific to alternatively spliced regions of the NR1 heteronuclear mRNA, including examination of anterior hypothalamus, piriform cortex, caudate-putamen, thalamus and hippocampus. Gene expression analysis within the SCN revealed the absence of the N1 cassette, the presence of the C2 cassette alone and the combined absence of C1 and C2 cassettes, indicating that the dominant splice variants are NR1-2a and NR1-4a. Whilst we observe changes at different developmental ages in levels of NR1 isoform probe hybridization in various forebrain structures, we find no significant changes within the SCN. This suggests that a switch in NR1 isoform does not underlie or is not produced by developmental changes within the hamster SCN. Consistency of the NR1 isoforms would ensure that the response of the SCN cells to photic signals remains stable throughout life, an important aspect of the function of the SCN as a responder to

  7. A functional variant at miR-34a binding site in toll-like receptor 4 gene alters susceptibility to hepatocellular carcinoma in a Chinese Han population.

    Science.gov (United States)

    Jiang, Zi-Cheng; Tang, Xian-Mei; Zhao, Ying-Ren; Zheng, Lei

    2014-12-01

    Toll-like receptor 4 (TLR4) plays a key role in prompting the innate or immediate response. A growing body of evidence suggests that genetic variants of TLR4 gene were associated with the development of cancers. This study aimed to investigate the relationship of a functional variant (rs1057317) at microRNA-34a (miR-34a) binding site in toll-like receptor 4 gene and the risk of hepatocellular carcinoma. A single center-based case-control study was conducted. In this study, the polymerase chain reaction (PCR) and direct sequencing were used to genotype sequence variants of TLR4 in 426 hepatocellular carcinoma cases and 438 controls. The modification of rs1057317 on the binding of hsa-miR-34a to TLR4 messenger RNA (mRNA) was measured by luciferase activity assay. Individuals carrying the AA genotypes for the rs1057317 were associated significantly with increased risk of hepatocellular carcinoma comparing with those carrying wild-type homozygous CC genotypes (adjusted odds ratio [OR] by sex and age, from 1.116 to 2.452, P = 0.013). The activity of the reporter vector was lower in the reporter vector carrying C allele than the reporter vector carrying A allele. Furthermore, the expression of TLR4 was detected in the peripheral blood mononucleated cell of hepatocellular carcinoma (HCC) patients, suggesting that mRNA and protein levels of TLR4 might be associated with SNP rs1057317. Collectively, these results suggested that the risk of hepatocellular carcinoma was associated with a functional variant at miR-34a binding site in toll-like receptor 4 gene. miR-34a/TLR4 axis may play an important role in the development of hepatocellular carcinoma. PMID:25179842

  8. Transgenic mouse lines expressing rat AH receptor variants - A new animal model for research on AH receptor function and dioxin toxicity mechanisms

    International Nuclear Information System (INIS)

    Han/Wistar (Kuopio; H/W) rats are exceptionally resistant to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity mainly because of their mutated aryl hydrocarbon receptor (AHR) gene. In H/W rats, altered splicing of the AHR mRNA generates two AHR proteins: deletion (DEL) and insertion (INS) variants, with the INS isoform being predominantly expressed. To gain further insight into their functional properties, cDNAs of these and rat wild-type (rWT) isoform were transferred into C57BL/6J-derived mice by microinjection. The endogenous mouse AHR was eliminated by selective crossing with Ahr-null mice. A single mouse line was obtained for each of the three constructs. The AHR mRNA levels in tissues were generally close to those of C57BL/6 mice in INS and DEL mice and somewhat higher in rWT mice; in testis, however, all 3 constructs exhibited marked overexpression. The transgenic mouse lines were phenotypically normal except for increased testis weight. Induction of drug-metabolizing enzymes by TCDD occurred similarly to that in C57BL/6 mice, but there tended to be a correlation with AHR concentrations, especially in testis. In contrast to C57BL/6 mice, the transgenics did not display any major gender difference in susceptibility to the acute lethality and hepatotoxicity of TCDD; rWT mice were highly sensitive, DEL mice moderately resistant and INS mice highly resistant. Co-expression of mouse AHR and rWT resulted in augmented sensitivity to TCDD and abolished the natural resistance of female C57BL/6 mice, whereas mice co-expressing mouse AHR and INS were resistant. Thus, these transgenic mouse lines provide a novel promising tool for molecular studies on dioxin toxicity and AHR function.

  9. Human Herpesvirus 6 Variant A but Not Variant B Induces Fusion from Without in a Variety of Human Cells through a Human Herpesvirus 6 Entry Receptor, CD46

    OpenAIRE

    Mori, Yasuko; Seya, Tsukasa; Huang, Hong Lan; Akkapaiboon, Pilailuk; Dhepakson, Panadda; Yamanishi, Koichi

    2002-01-01

    Human herpesvirus 6 (HHV-6) is a lymphotropic betaherpesvirus that productively infects T cells and monocytes. HHV-6 isolates can be differentiated into two groups, variants A and B (HHV-6A and HHV-6B). Here, we show a functional difference between HHV-6A and -6B in that HHV-6A induced syncytium formation of diverse human cells but HHV-6B did not. The syncytium formation induced by HHV-6A was observed 2 h after infection; moreover, it was found in the presence of cycloheximide, indicating tha...

  10. Agouti signalling protein is an inverse agonist to the wildtype and agonist to the melanic variant of the melanocortin-1 receptor in the grey squirrel (Sciurus carolinensis).

    Science.gov (United States)

    McRobie, Helen R; King, Linda M; Fanutti, Cristina; Symmons, Martyn F; Coussons, Peter J

    2014-06-27

    The melanocortin-1 receptor (MC1R) is a key regulator of mammalian pigmentation. Melanism in the grey squirrel is associated with an eight amino acid deletion in the mutant melanocortin-1 receptor with 24 base pair deletion (MC1RΔ24) variant. We demonstrate that the MC1RΔ24 exhibits a higher basal activity than the wildtype MC1R (MC1R-wt). We demonstrate that agouti signalling protein (ASIP) is an inverse agonist to the MC1R-wt but is an agonist to the MC1RΔ24. We conclude that the deletion in the MC1RΔ24 leads to a receptor with a high basal activity which is further activated by ASIP. This is the first report of ASIP acting as an agonist to MC1R. PMID:24879893

  11. Identification of a truncated splice variant of IL-18 receptor alpha in the human and rat, with evidence of wider evolutionary conservation

    Directory of Open Access Journals (Sweden)

    Chris S. Booker

    2014-09-01

    Full Text Available Interleukin-18 (IL-18 is a pro-inflammatory cytokine which stimulates activation of the nuclear factor kappa beta (NF-κB pathway via interaction with the IL-18 receptor. The receptor itself is formed from a dimer of two subunits, with the ligand-binding IL-18Rα subunit being encoded by the IL18R1 gene. A splice variant of murine IL18r1, which has been previously described, is formed by transcription of an unspliced intron (forming a ‘type II’ IL18r1 transcript and is predicted to encode a receptor with a truncated intracellular domain lacking the capacity to generate downstream signalling. In order to examine the relevance of this finding to human IL-18 function, we assessed the presence of a homologous transcript by reverse transcription-polymerase chain reaction (RT-PCR in the human and rat as another common laboratory animal. We present evidence for type II IL18R1 transcripts in both species. While the mouse and rat transcripts are predicted to encode a truncated receptor with a novel 5 amino acid C-terminal domain, the human sequence is predicted to encode a truncated protein with a novel 22 amino acid sequence bearing resemblance to the ‘Box 1’ motif of the Toll/interleukin-1 receptor (TIR domain, in a similar fashion to the inhibitory interleukin-1 receptor 2. Given that transcripts from these three species are all formed by inclusion of homologous unspliced intronic regions, an analysis of homologous introns across a wider array of 33 species with available IL18R1 gene records was performed, which suggests similar transcripts may encode truncated type II IL-18Rα subunits in other species. This splice variant may represent a conserved evolutionary mechanism for regulating IL-18 activity.

  12. Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects.

    Science.gov (United States)

    Majumdar, Susruta; Grinnell, Steven; Le Rouzic, Valerie; Burgman, Maxim; Polikar, Lisa; Ansonoff, Michael; Pintar, John; Pan, Ying-Xian; Pasternak, Gavril W

    2011-12-01

    Pain remains a pervasive problem throughout medicine, transcending all specialty boundaries. Despite the extraordinary insights into pain and its mechanisms over the past few decades, few advances have been made with analgesics. Most pain remains treated by opiates, which have significant side effects that limit their utility. We now describe a potent opiate analgesic lacking the traditional side effects associated with classical opiates, including respiratory depression, significant constipation, physical dependence, and, perhaps most important, reinforcing behavior, demonstrating that it is possible to dissociate side effects from analgesia. Evidence indicates that this agent acts through a truncated, six-transmembrane variant of the G protein-coupled mu opioid receptor MOR-1. Although truncated splice variants have been reported for a number of G protein-coupled receptors, their functional relevance has been unclear. Our evidence now suggests that truncated variants can be physiologically important through heterodimerization, even when inactive alone, and can comprise new therapeutic targets, as illustrated by our unique opioid analgesics with a vastly improved pharmacological profile. PMID:22106286

  13. Genetic variants in toll-like receptors are not associated with rheumatoid arthritis susceptibility or anti-tumour necrosis factor treatment outcome.

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    Marieke J H Coenen

    Full Text Available BACKGROUND: Several studies point to a role of Toll-like receptors (TLRs in the development of rheumatoid arthritis (RA. We investigated if genetic variants in TLR genes are associated with RA and response to tumour necrosis factor blocking (anti-TNF medication. METHODOLOGY AND PRINCIPAL FINDINGS: 22 single nucleotide polymorphisms (SNPs in seven TLR genes were genotyped in a Dutch cohort consisting of 378 RA patients and 294 controls. Significantly associated variants were investigated in replication cohorts from The Netherlands, United Kingdom and Sweden (2877 RA patients and 2025 controls. 182 of the Dutch patients were treated with anti-TNF medication. Using these patients and a replication cohort (269 Swedish patients we analysed if genetic variants in TLR genes were associated with anti-TNF outcome. In the discovery phase of the study we found a significant association of SNPs rs2072493 in TLR5 and rs3853839 in TLR7 with RA disease susceptibility. Meta-analysis of discovery and replication cohorts did not confirm these findings. SNP rs2072493 in TLR5 was associated with anti-TNF outcome in the Dutch but not in the Swedish population. CONCLUSION: We conclude that genetic variants in TLRs do not play a major role in susceptibility for developing RA nor in anti-TNF treatment outcome in a Caucasian population.

  14. Genetic Variants at the PDZ-Interacting Domain of the Scavenger Receptor Class B Type I Interact with Diet to Influence the Risk of Metabolic Syndrome in Obese Men and Women

    Science.gov (United States)

    The scaffolding protein PDZ domain containing 1 (PDZK1) regulates the HDL receptor scavenger receptor class B type I. However, the effect of PDZK1 genetic variants on lipids and metabolic syndrome (MetS) traits remains unknown. This study evaluated the association of 3 PDZK1 single nucleotide polymo...

  15. Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival.

    Directory of Open Access Journals (Sweden)

    Emma Hörnberg

    Full Text Available BACKGROUND: Constitutively active androgen receptor variants (AR-V lacking the ligand binding domain (LBD may promote the development of castration-resistant prostate cancer (CRPC. The expression of AR-Vs in the clinically most important metastatic site, the bone, has, however, not been well documented. Our aim was therefore to compare levels of AR-Vs in hormone-naive (HN and CRPC bone metastases in comparison to primary PC and non-malignant prostate tissue, as well as in relation to AR protein expression, whole-genome transcription profiles and patient survival. METHODOLOGY/PRINCIPAL FINDINGS: Hormone-naïve (n = 10 and CRPC bone metastases samples (n = 30 were obtained from 40 patients at metastasis surgery. Non-malignant and malignant prostate samples were acquired from 13 prostatectomized men. Levels of full length AR (ARfl and AR-Vs termed AR-V1, AR-V7, and AR-V567es mRNA were measured with RT-PCR and whole-genome transcription profiles with an Illumina Beadchip array. Protein levels were examined by Western blotting and immunohistochemistry. Transcripts for ARfl, AR-V1, and AR-V7 were detected in most primary tumors and metastases, and levels were significantly increased in CRPC bone metastases. The AR-V567es transcript was detected in 23% of the CRPC bone metastases only. A sub-group of CRPC bone metastases expressed LBD-truncated AR proteins at levels comparable to the ARfl. Detectable AR-V567es and/or AR-V7 mRNA in the upper quartile, seen in 1/3 of all CRPC bone metastases, was associated with a high nuclear AR immunostaining score, disturbed cell cycle regulation and short survival. CONCLUSIONS/SIGNIFICANCE: Expression of AR-Vs is increased in CRPC compared to HN bone metastases and associated with a particularly poor prognosis. Further studies are needed to test if patients expressing such AR-Vs in their bone metastases benefit more from drugs acting on or down-stream of these AR-Vs than from therapies inhibiting androgen synthesis.

  16. Distinct signal transduction processes by IL-4 and IL-13 and influences from the Q551R variant of the human IL-4 receptor alpha chain

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    Braun Sandra

    2002-08-01

    Full Text Available Abstract Background Although IL-4 and IL-13 share the IL-13 receptor, IL-13 exhibits unique functions. To elicit the cellular basis of these differences, signal transduction processes have been compared. Additionally, the role of the IL-4 receptor alpha (IL-4Rα variant Q551R was investigated. Methods Peripheral blood mononuclear cells from donors were stimulated with IL-4 and IL-13. The phosphorylation status of effector substrates was detected by immunostaining. Binding of SHP-2 to IL-4Rα was investigated by using synthetic peptides. Results SHP-2 bound IL-4Rα synthetic peptide; this binding was reduced in the presence of the R551 variant. Stimulation with IL-4 increased SHP-1 phosphorylation, however, stimulation with IL-13 increased SHP-2 phosphorylation. PI3-kinase phosphorylation was elevated following stimulation with IL-13 in all individuals and with IL-4 only in R551 individuals. Jak1, Tyk2 and IRS-2 signals were reduced after IL-13 stimulation in Q551 individuals. STAT3 phosphorylation was markedly increased in R551 individuals, following stimulation with both IL-4 and IL-13. However, STAT3 was only detected immediately in nuclear extracts from variant individuals after stimulation with IL-13; in wildtype individuals STAT3 was only detected after IL-4 treatment. Conclusion IL-4 and IL-13 appear to promote distinct signal transduction cascades. SHP-1 seems to be predominately activated by IL-4 and to influence the PI3-kinase, in contrast, SHP-2 seems to be predominately activated by IL-13 and to influence Jak1, Tyk2 and IRS-2. Both phosphatases control STAT3. In the presence of the variant R551, SHP-1/2 activation is reduced and signal transduction is altered. STAT3 signaling appears be further regulated on the level of nuclear translocation.

  17. Resequencing of genes for transforming growth factor β1 (TGFB1 type 1 and 2 receptors (TGFBR1, TGFBR2, and association analysis of variants with diabetic nephropathy

    Directory of Open Access Journals (Sweden)

    Patterson Chris C

    2007-02-01

    Full Text Available Abstract Background Diabetic nephropathy is the leading cause of end stage renal failure in the western world. There is substantial epidemiological evidence supporting a genetic predisposition to diabetic nephropathy, however the exact molecular mechanisms remain unknown. Transforming growth factor (TGFβ1 is a crucial mediator in the pathogenesis of diabetic nephropathy. Methods We investigated the role of five known single nucleotide polymorphisms (SNPs in the TGFB1 gene for their association with diabetic nephropathy in an Irish, type 1 diabetic case (n = 272 control (n = 367 collection. The activity of TGFβ1 is facilitated by the action of type 1 and type 2 receptors, with both receptor genes (TGFBR1 and TGFBR2 shown to be upregulated in diabetic kidney disease. We therefore screened TGFBR1 and TGFBR2 genes for genomic variants using WAVE™ (dHPLC technology and confirmed variants by direct capillary sequencing. Allele frequencies were determined in forty-eight healthy individuals. Data for all SNPs was assessed for Hardy Weinberg equilibrium, with genotypes and allele frequencies compared using the χ2 test for contingency tables. Patterns of linkage disequilibrium were established and common haplotypes estimated. Results Fifteen variants were identified in these genes, seven of which are novel, and putatively functional SNPs were subsequently genotyped using TaqMan™, Invader™ or Pyrosequencing® technology. No significant differences (p > 0.1 were found in genotype or allele distributions between cases and controls for any of the SNPs assessed. Conclusion Our results suggest common variants in TGFB1, TGFBR1 and TGFBR2 genes do not strongly influence genetic susceptibility to diabetic nephropathy in an Irish Caucasian population.

  18. Association of the insulin-receptor variant Met-985 with hyperglycemia and non-insulin-dependent diabetes mellitus in the Netherlands: A population-based study

    Energy Technology Data Exchange (ETDEWEB)

    `t Hart, L.M.; Maassen, J.A. [Leiden Univ. (Netherlands); Does, F.E.E. van der [Free Univ., Amsterdam (Netherlands)] [and others

    1996-11-01

    One of the characteristics of non-insulin-dependent diabetes mellitus (NIDDM) is the presence of insulin. Most NIDDM patients have a normal sequence of the insulin receptor, indicating that, if insulin-receptor mutations contribute to the development of NIDDM, they will be present only in a minor fraction of the NIDDM population. The goal of the present study was to examine whether insulin-receptor mutations contribute to the development of NIDDM. We examined 161 individuals with NIDDM and 538 healthy controls from the population-based Rotterdam study for the presence of mutations in the insulin-receptor gene by SSCP. A heterozygous mutation changing valine-985 into methionine was detected in 5.6% of diabetic subjects and in 1.3% of individuals with normal oral glucose tolerance test. Adjusted for age, gender, and body-mass index, this revealed a relative risk for diabetes of 4.49 (95% confidence interval 1.59-12.25) for Met-985 carriers. When the total study group was analyzed, the prevalence of the mutation increased with increasing serum glucose levels (test for trend P < .005). We conclude that the Met-985 insulin-receptor variant associates with hyperglycemia and represents a risk factor for NIDDM. 30 refs., 3 figs., 1 tab.

  19. The expression of the pituitary growth hormone-releasing hormone receptor and its splice variants in normal and neoplastic human tissues

    OpenAIRE

    Havt, Alexandre; Andrew V. Schally; Varga József L.; Toller Gábor L.; Horváth Judit E. (New Orleans); Szepesházi Károly; Köster, Frank; Kovitz, Kevin; Groot, Kate; Zarándi Márta; Kanashiro, Celia A.; Halmos Gábor (1962-) (gyógyszerész, receptorfarmakológus, experimentális onkológus)

    2005-01-01

    Various attempts to detect human pituitary growth hormone-releasing hormone receptor (pGHRH-R) in neoplastic extrapituitary tissues have thus far failed. Recently, four splice variants (SVs) of GHRH-R have been described, of which SV1 has the highest structural homology to pGHRH-R and likely plays a role in tumor growth. The aim of this study was to reinvestigate whether human tumors and normal human extrapituitary tissues express the pGHRH-R and to corroborate our previous findings on its SV...

  20. Variants of Interleukin-7/Interleukin-7 Receptor Alpha are Associated with Both Neuromyelitis Optica and Multiple Sclerosis Among Chinese Han Population in Southeastern China

    Science.gov (United States)

    Zhuang, Jing-Cong; Wu, Lei; Qian, Mei-Zhen; Cai, Ping-Ping; Liu, Qi-Bing; Zhao, Gui-Xian; Li, Zhen-Xin; Wu, Zhi-Ying

    2015-01-01

    Background: Neuromyelitis optica (NMO) and multiple sclerosis (MS) are autoimmune demyelinating diseases of the central nerve system. Interleukin-7 (IL-7) and interleukin-7 receptor alpha (IL-7Rα) were proved to be important in the pathogenesis of both diseases because of the roles they played in the differentiations of autoimmune lymphocytes. The variants of both genes had been identified to be associated with MS susceptibility in Caucasian, Japanese and Korean populations. However, the association of these variants with NMO and MS has not been well studied in Chinese Southeastern Han population. Here, we aimed to evaluate the association of six IL-7 variants (rs1520333, rs1545298, rs4739140, rs6993386, rs7816065, and rs2887502) and one variant of IL-7RA (rs6897932) with NMO and MS among Chinese Han population in southeastern China. Methods: Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MassARRAY system) and Sanger sequencing were used to determine the variants of IL-7 and IL-7RA in 167 NMO patients, 159 MS patients and 479 healthy controls among Chinese Han population in southeastern China. Samples were excluded if the genotyping success rate <90%. Results: Statistical differences were observed in the genotypes of IL-7 rs1520333 in MS patients and IL-7RA rs6897932 in NMO patients, compared with healthy controls (P = 0.035 and 0.034, respectively). There was a statistically significant difference in the genotypes of IL-7 rs2887502 between MS and NMO patients (P = 0.014). And there were statistically significant differences in the rs6897932 genotypes (P = 0.004) and alleles (P = 0.042) between NMO-IgG positive patients and healthy controls. Conclusions: The study suggested that among Chinese Han population in southeastern China, the variant of IL-7RA (rs6897932) was associated with NMO especially NMO-IgG positive patients while the variant of IL-7 (rs1520333) with MS patients. And the genotypic differences of IL-7 rs2887502 between

  1. Variants of Interleukin-7/Interleukin-7 Receptor Alpha are Associated with Both Neuromyelitis Optica and Multiple Sclerosis Among Chinese Han Population in Southeastern China

    Directory of Open Access Journals (Sweden)

    Jing-Cong Zhuang

    2015-01-01

    Full Text Available Background: Neuromyelitis optica (NMO and multiple sclerosis (MS are autoimmune demyelinating diseases of the central nerve system. Interleukin-7 (IL-7 and interleukin-7 receptor alpha (IL-7Rα were proved to be important in the pathogenesis of both diseases because of the roles they played in the differentiations of autoimmune lymphocytes. The variants of both genes had been identified to be associated with MS susceptibility in Caucasian, Japanese and Korean populations. However, the association of these variants with NMO and MS has not been well studied in Chinese Southeastern Han population. Here, we aimed to evaluate the association of six IL-7 variants (rs1520333, rs1545298, rs4739140, rs6993386, rs7816065, and rs2887502 and one variant of IL-7RA (rs6897932 with NMO and MS among Chinese Han population in southeastern China. Methods: Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MassARRAY system and Sanger sequencing were used to determine the variants of IL-7 and IL-7RA in 167 NMO patients, 159 MS patients and 479 healthy controls among Chinese Han population in southeastern China. Samples were excluded if the genotyping success rate <90%. Results: Statistical differences were observed in the genotypes of IL-7 rs1520333 in MS patients and IL-7RA rs6897932 in NMO patients, compared with healthy controls (P = 0.035 and 0.034, respectively. There was a statistically significant difference in the genotypes of IL-7 rs2887502 between MS and NMO patients (P = 0.014. And there were statistically significant differences in the rs6897932 genotypes (P = 0.004 and alleles (P = 0.042 between NMO-IgG positive patients and healthy controls. Conclusions: The study suggested that among Chinese Han population in southeastern China, the variant of IL-7RA (rs6897932 was associated with NMO especially NMO-IgG positive patients while the variant of IL-7 (rs1520333 with MS patients. And the genotypic differences of IL-7 rs2887502

  2. Variants of Interleukin-7/Interleukin-7 Receptor Alpha are Associated with Both Neuromyelitis Optica and Multiple Sclerosis Among Chinese Han Population in Southeastern China

    Institute of Scientific and Technical Information of China (English)

    Jing-Cong Zhuang; Lei Wu; Mei-Zhen Qian; Ping-Ping Cai; Qi-Bing Liu; Gui-Xian Zhao; Zhen-Xin Li

    2015-01-01

    Background: Neuromyelitis optica (NMO) and multiple sclerosis (MS) are autoimmune demyelinating diseases of the central nerve system.Interleukin-7 (IL-7) and interleukin-7 receptor alpha (IL-7Rα) were proved to be important in the pathogenesis of both diseases because of the roles they played in the differentiations of autoimmune lymphocytes.The variants of both genes had been identified to be associated with MS susceptibility in Caucasian, Japanese and Korean populations.However, the association of these variants with NMO and MS has not been well studied in Chinese Southeastern Han population.Here, we aimed to evaluate the association of six IL-7 variants (rs 1520333, rs1545298, rs4739140, rs6993386, rs7816065, and rs2887502) and one variant of IL-7RA (rs6897932) with NMO and MS among Chinese Han population in southeastem China.Methods: Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MassARRAY system) and Sanger sequencing were used to determine the variants ofIL-7 and IL-7RA in 167 NMO patients, 159 MS patients and 479 healthy controls among Chinese Han population in southeastern China.Samples were excluded if the genotyping success rate <90%.Results: Statistical differences were observed in the genotypes ofIL-7 rs 1520333 in MS patients and IL-7RA rs6897932 in NMO patients,compared with healthy controls (P =0.035 and 0.034, respectively).There was a statistically significant difference in the genotypes of IL-7 rs2887502 between MS and NMO patients (P =0.014).And there were statistically significant differences in the rs6897932 genotypes (P =0.004) and alleles (P =0.042) between NMO-IgG positive patients and healthy controls.Conclusions: The study suggested that among Chinese Han population in southeastern China, the variant of IL-7RA (rs6897932) was associated with NMO especially NMO-IgG positive patients while the variant of IL-7 (rs1520333) with MS patients.And the genotypic differences ofIL-7 rs2887502 between MS and NMO

  3. Genetic variants in anti-Mullerian hormone and anti-Mullerian hormone receptor genes and breast cancer risk in Caucasians and African Americans.

    Science.gov (United States)

    Nan, Hongmei; Dorgan, Joanne F; Rebbeck, Timothy R

    2014-01-01

    Anti-Mullerian hormone (AMH) regulates ovarian folliculogenesis by signaling via its receptors, and elevated serum AMH levels are associated with an increased risk of breast cancer. No previous studies have examined the effects of genetic variants in AMH-related genes on breast cancer risk. We evaluated the associations of 62 single nucleotide polymorphisms (SNPs) in AMH and its receptor genes, including AMH type 1 receptor (ACVR1) and AMH type 2 receptor (AMHR2), with the risk of breast cancer in the Women's Insights and Shared Experiences (WISE) Study of Caucasians (346 cases and 442 controls), as well as African Americans (149 cases and 246 controls). Of the 62 SNPs evaluated, two showed a nominal significant association (P for trend < 0.05) with breast cancer risk among Caucasians, and another two among African Americans. The age-adjusted additive odds ratios (ORs) (95% confidence interval (95% CI)) of those two SNPs (ACVR1 rs12694937[C] and ACVR1 rs2883605[T]) for the risk of breast cancer among Caucasian women were 2.33 (1.20-4.52) and 0.68 (0.47-0.98), respectively. The age-adjusted additive ORs (95% CI) of those two SNPs (ACVR1 rs1146031[G] and AMHR2 functional SNP rs2002555[G]) for the risk of breast cancer among African American women were 0.63 (0.44-0.92) and 1.67 (1.10-2.53), respectively. However, these SNPs did not show significant associations after correction for multiple testing. Our findings do not provide strong supportive evidence for the contribution of genetic variants in AMH-related genes to the risk of developing breast cancer in either Caucasians or African Americans. PMID:25379134

  4. Allele-specific adaptation of poliovirus VP1 B-C loop variants to mutant cell receptors.

    OpenAIRE

    Liao, S.; Racaniello, V

    1997-01-01

    Previous work has shown that three different mutations in domain 1 of the poliovirus receptor (Pvr), two in the predicted C'-C" ridge and one in the D-E loop, abolish binding of the P1/Mahoney strain. All three receptor defects could be suppressed by a mutation in the VP1 B-C loop of the viral capsid that was present in all 16 P1/Mahoney isolates adapted to the mutant receptors. To identify allele-specific mutations that enable poliovirus to utilize mutant receptors, and to understand the rol...

  5. Association of adiponectin receptor 1 gene −106 C > T variant with susceptibility to colorectal cancer

    Directory of Open Access Journals (Sweden)

    Touraj Mahmoudi

    2016-09-01

    Conclusions: Our findings suggest for the first time that the −106 C > T (rs2275738 variant of ADIPOR1 gene may be a genetic contributor to CRC and obesity risk in the cases with CRC. However, further studies with bigger sample size are needed to validate these findings.

  6. Structure–activity correlations of variant forms of the B pentamer of Escherichia coli type II heat-labile enterotoxin LT-IIb with Toll-like receptor 2 binding

    International Nuclear Information System (INIS)

    Structural data for the S74D variant of the pentameric B subunit of type II heat-labile enterotoxin of Escherichia coli reveal a smaller pore opening that may explain its reduced Toll-like receptor binding affinity compared to that of the wild type enterotoxin. The explanation for the enhanced Toll-like receptor binding affinity of the S74A variant is more complex than simply being attributed to the pore opening. The pentameric B subunit of the type II heat-labile enterotoxin of Escherichia coli (LT-IIb-B5) is a potent signaling molecule capable of modulating innate immune responses. It has previously been shown that LT-IIb-B5, but not the LT-IIb-B5 Ser74Asp variant [LT-IIb-B5(S74D)], activates Toll-like receptor (TLR2) signaling in macrophages. Consistent with this, the LT-IIb-B5(S74D) variant failed to bind TLR2, in contrast to LT-IIb-B5 and the LT-IIb-B5 Thr13Ile [LT-IIb-B5(T13I)] and LT-IIb-B5 Ser74Ala [LT-IIb-B5(S74A)] variants, which displayed the highest binding activity to TLR2. Crystal structures of the Ser74Asp, Ser74Ala and Thr13Ile variants of LT-IIb-B5 have been determined to 1.90, 1.40 and 1.90 Å resolution, respectively. The structural data for the Ser74Asp variant reveal that the carboxylate side chain points into the pore, thereby reducing the pore size compared with that of the wild-type or the Ser74Ala variant B pentamer. On the basis of these crystallographic data, the reduced TLR2-binding affinity of the LT-IIb-B5(S74D) variant may be the result of the pore of the pentamer being closed. On the other hand, the explanation for the enhanced TLR2-binding activity of the LT-IIb-B5(S74A) variant is more complex as its activity is greater than that of the wild-type B pentamer, which also has an open pore as the Ser74 side chain points away from the pore opening. Data for the LT-IIb-B5(T13I) variant show that four of the five variant side chains point to the outside surface of the pentamer and one residue points inside. These data are consistent with

  7. Viral and bacterial septicaemic infections modulate the expression of PACAP splicing variants and VIP/PACAP receptors in brown trout immune organs.

    Science.gov (United States)

    Gorgoglione, Bartolomeo; Carpio, Yamila; Secombes, Christopher J; Taylor, Nick G H; Lugo, Juana María; Estrada, Mario Pablo

    2015-12-01

    Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and PACAP-Related Peptide (PRP) are structurally similar peptides encoded in the same transcripts. Their transcription has been detected not only in the brain but also in a wide range of peripheral tissues, even including organs of the immune system. PACAP exerts pleiotropic activities through G-protein coupled membrane receptors: the PACAP-specific PAC-1 and the VPAC-1 and VPAC-2 receptors that exhibit similar affinities for the Vasoactive Intestinal Peptide (VIP) and PACAP. Recent findings added PACAP and its receptors to the growing list of mediators that allow cross-talk between the nervous, endocrine and immune systems in fish. In this study the expression of genes encoding for PACAP and PRP, as well as VIP/PACAP receptors was studied in laboratory-reared brown trout (Salmo trutta) after septicaemic infections. Respectively Viral Haemorrhagic Septicaemia Virus (VHSV-Ia) or the Gram-negative bacterium Yersinia ruckeri (ser. O1 - biot. 2) were used in infection challenges. Kidney and spleen, the teleost main lymphopoietic organs, were sampled during the first two weeks post-infection. RT-qPCR analysis assessed specific pathogens burden and gene expression levels. PACAP and PRP transcription in each organ was positively correlated to the respective pathogen burden, assessed targeting the VHSV-glycoprotein or Y. ruckeri 16S rRNA. Results showed as the transcription of PACAP splicing variants and VIP/PACAP receptors is modulated in these organs during an acute viral and bacterial septicaemic infections in brown trout. These gene expression results provide clues as to how the PACAP system is modulated in fish, confirming an involvement during active immune responses elicited by both viral and bacterial aetiological agents. However, further experimental evidence is still required to fully elucidate and characterize the role of PACAP and PRP for an efficient immune response against pathogens. PMID:26481517

  8. Development of quantitative RT-PCR assays for wild-type urokinase receptor (uPAR-wt) and its splice variant uPAR-del5

    International Nuclear Information System (INIS)

    The receptor for the serine protease urokinase-type plasminogen activator, uPAR (CD 87), plays an important role in tumor cell invasion and metastasis of solid malignant tumors. uPAR is a highly glycosylated, glycan lipid-anchored membrane protein, consisting of three homologous domains. Each individual domain is encoded by two exons: DI by exons 2+3, DII by exons 4+5, and DIII by exons 6+7. Beside the wild-type (wt) uPAR mRNA, two splice variants either lacking exon 5 (uPAR-del5) or both exons 4 and 5 (uPARdel4/ 5) have been described. Previously, we studied expression of the mRNA variant uPAR-del4/5 and uPAR mRNA encompassing exons 2, 3, and 4 (i.e. uPAR-wt plus uPAR-del5) applying real-time RT-PCR assays for quantification of the mRNA concentration. In the present paper, we established two additional specific, robust and highly sensitive RT-PCR assays, based on the LightCycler technology, to specifically quantify either uPAR-wt or its splice variant, uPARdel5. Expression of uPAR-wt and uPAR-del5 was analyzed in different human malignant cell lines (ovarian cancer cell lines OVMZ-6 and OVMZ-10; breast cancer cell lines MDA-MB 231, MDA-MB 231 BAG, MDA-MB 435, and aMCF-7; brain tumor cell line LN 18) as well as in a set of 174 breast cancer tissue samples. uPAR-del5 mRNA was found to be expressed very frequently at a rather low level (typically less than 1% of uPAR-wt mRNA). In tumor tissue from breast cancer patients, a statistically significant correlation between uPAR-del5 and uPAR-wt mRNA (r = 0.779; P < 0.001) was observed. There was no association between the expression level of either mRNA and clinical parameters such as nodal status, tumor size and grade. In estrogen receptor negative tumors, a significantly higher uPAR-del5 expression was found (P 0.023). The two developed quantitative RT-PCR assays described here may aid further analysis of the function and clinical relevance of uPAR-wt and one of its splice variants, uPAR-del5, in malignant tumors

  9. Allelic variants of melanocortin 3 receptor gene (MC3R and weight loss in obesity: a randomised trial of hypo-energetic high- versus low-fat diets.

    Directory of Open Access Journals (Sweden)

    José L Santos

    Full Text Available INTRODUCTION: The melanocortin system plays an important role in energy homeostasis. Mice genetically deficient in the melanocortin-3 receptor gene have a normal body weight with increased body fat, mild hypophagia compared to wild-type mice. In humans, Thr6Lys and Val81Ile variants of the melanocortin-3 receptor gene (MC3R have been associated with childhood obesity, higher BMI Z-score and elevated body fat percentage compared to non-carriers. The aim of this study is to assess the association in adults between allelic variants of MC3R with weight loss induced by energy-restricted diets. SUBJECTS AND METHODS: This research is based on the NUGENOB study, a trial conducted to assess weight loss during a 10-week dietary intervention involving two different hypo-energetic (high-fat and low-fat diets. A total of 760 obese patients were genotyped for 10 single nucleotide polymorphisms covering the single exon of MC3R gene and its flanking regions, including the missense variants Thr6Lys and Val81Ile. Linear mixed models and haplotype-based analysis were carried out to assess the potential association between genetic polymorphisms and differential weight loss, fat mass loss, waist change and resting energy expenditure changes. RESULTS: No differences in drop-out rate were found by MC3R genotypes. The rs6014646 polymorphism was significantly associated with weight loss using co-dominant (p = 0.04 and dominant models (p = 0.03. These p-values were not statistically significant after strict control for multiple testing. Haplotype-based multivariate analysis using permutations showed that rs3827103-rs1543873 (p = 0.06, rs6014646-rs6024730 (p = 0.05 and rs3746619-rs3827103 (p = 0.10 displayed near-statistical significant results in relation to weight loss. No other significant associations or gene*diet interactions were detected for weight loss, fat mass loss, waist change and resting energy expenditure changes. CONCLUSION: The study

  10. Akhénaton

    OpenAIRE

    Laboury, Dimitri

    2010-01-01

    Amenhotep IV, ninth Pharaoh of the 18th Dynasty (ca 1352 - 1335 B.C.), who changed his name into Akhenaten, is probably the most debated figure of Ancient Egyptian History. Known as the first founder of a monotheistic religion in the history of mankind, he holds an exceptional position in modern collective memories about Ancient Egypt, despite the fact that he was rejected into oblivion by his direct successors. His modern fame is fundamentally due to the reappropriation of his character by v...

  11. Association between variants of the leptin receptor gene (LEPR and overweight: a systematic review and an analysis of the CoLaus study.

    Directory of Open Access Journals (Sweden)

    Nicole Bender

    Full Text Available BACKGROUND: Three non-synonymous single nucleotide polymorphisms (Q223R, K109R and K656N of the leptin receptor gene (LEPR have been tested for association with obesity-related outcomes in multiple studies, showing inconclusive results. We performed a systematic review and meta-analysis on the association of the three LEPR variants with BMI. In addition, we analysed 15 SNPs within the LEPR gene in the CoLaus study, assessing the interaction of the variants with sex. METHODOLOGY/PRINCIPAL FINDINGS: We searched electronic databases, including population-based studies that investigated the association between LEPR variants Q223R, K109R and K656N and obesity- related phenotypes in healthy, unrelated subjects. We furthermore performed meta-analyses of the genotype and allele frequencies in case-control studies. Results were stratified by SNP and by potential effect modifiers. CoLaus data were analysed by logistic and linear regressions and tested for interaction with sex. The meta-analysis of published data did not show an overall association between any of the tested LEPR variants and overweight. However, the choice of a BMI cut-off value to distinguish cases from controls was crucial to explain heterogeneity in Q223R. Differences in allele frequencies across ethnic groups are compatible with natural selection of derived alleles in Q223R and K109R and of the ancient allele in K656N in Asians. In CoLaus, the rs10128072, rs3790438 and rs3790437 variants showed interaction with sex for their association with overweight, waist circumference and fat mass in linear regressions. CONCLUSIONS: Our systematic review and analysis of primary data from the CoLaus study did not show an overall association between LEPR SNPs and overweight. Most studies were underpowered to detect small effect sizes. A potential effect modification by sex, population stratification, as well as the role of natural selection should be addressed in future genetic association studies.

  12. The interaction of genetic variants and DNA methylation of the interleukin-4 receptor gene increase the risk of asthma at age 18 years

    Directory of Open Access Journals (Sweden)

    Soto-Ramírez Nelís

    2013-01-01

    Full Text Available Abstract Background The occurrence of asthma is weakly explained by known genetic variants. Epigenetic marks, DNA methylation (DNA-M in particular, are considered to add to the explanation of asthma. However, no etiological model has yet been developed that integrates genetic variants and DNA-M. To explore a new model, we focused on one asthma candidate gene, the IL-4 receptor (IL4R. We hypothesized that genetic variants of IL4R in interaction with DNA-M at cytosine-phosphate-guanine (CpG sites jointly alter the risk of asthma during adolescence. Blood samples were collected at age 18 years from 245 female cohort participants randomly selected for methylation analysis from a birth cohort (n = 1,456, Isle of Wight, UK. Genome-wide DNA-M was assessed using the Illumina Infinium HumanMethylation450 BeadChip. Results Thirteen single nucleotide polymorphisms (SNPs and twelve CpG sites of IL4R gene were analyzed. Based on linkage disequilibrium and association with asthma, eight SNPs and one CpG site were selected for further analyses. Of the twelve CpG sites in the IL4R gene, only methylation levels of cg09791102 showed an association with asthma at age 18 years (Wilcoxon test: P = 0.01. Log-linear models were used to estimate risk ratios (RRs for asthma adjusting for uncorrelated SNPs within the IL4R gene and covariates. Testing for interaction between the eight SNPs and the methylation levels of cg09791102 on the risk for asthma at age 18 years, we identified the statistically significant interaction term of SNP rs3024685 × methylation levels of cg09791102 (P = 0.002; after adjusting for false discovery rate. A total of 84 participants had methylation levels ≤0.88, 112 participants between 0.89 and 0.90, and 35 between 0.91 and 0.92. For the SNP rs3024685 (‘CC’ vs. ‘TT’ at methylation levels of ≤0.85, 0.86, 0.90, 0.91, and 0.92, the RRs were 0.01, 0.04, 4.65, 14.76, 14.90, respectively (interaction effect, P = 0.0003. Conclusions

  13. Placental expression of estrogen receptor beta and its hormone binding variant – comparison with estrogen receptor alpha and a role for estrogen receptors in asymmetric division and differentiation of estrogen-dependent cells

    Directory of Open Access Journals (Sweden)

    Henley Donald C

    2003-04-01

    Full Text Available Abstract During human pregnancy, the production of 17-beta-estradiol (E2 rises steadily to eighty fold at term, and placenta has been found to specifically bind estrogens. We have recently demonstrated the expression of estrogen receptor alpha (ER-alpha protein in human placenta and its localization in villous cytotrophoblast (CT, vascular pericytes, and amniotic fibroblasts. In vitro, E2 stimulated development of large syncytiotrophoblast (ST aggregates. In the present study we utilized ER-beta affinity purified polyclonal (N19:sc6820 and ER-alpha monoclonal (clone h-151 antibodies. Western blot analysis revealed a single ~52 kDa ER-beta band in chorionic villi (CV protein extracts. In CV, strong cytoplasmic ER-beta immunoreactivity was confined to ST. Dual color immunohistochemistry revealed asymmetric segregation of ER-alpha in dividing villous CT cells. Prior to separation, the cell nuclei more distant from ST exhibited high ER-alpha, while cell nuclei associated with ST showed diminution of ER-alpha and appearance of ER-beta. In trophoblast cultures, development of ST aggregates was associated with diminution of ER-alpha and appearance of ER-beta immunoreactivity. ER-beta was also detected in endothelial cells, amniotic epithelial cells and fibroblasts, extravillous trophoblast (nuclear and cytoplasmic and decidual cells (cytoplasmic only. In addition, CFK-E12 (E12 and CWK-F12 (F12 monoclonal antibodies, which recognize ~64 kDa ER-beta with hormone binding domain, showed nuclear-specific reactivity with villous ST, extravillous trophoblast, and amniotic epithelium and fibroblasts. Western blot analysis indicated abundant expression of a ~64 kDa ER-beta variant in trophoblast cultures, significantly higher when compared to the chorionic villi and freshly isolated trophoblast cell protein extracts. This is the first report on ER-beta expression in human placenta and cultured trophoblast. Our data indicate that during trophoblast

  14. Chemokine Ligand 5 (CCL5 and chemokine receptor (CCR5 genetic variants and prostate cancer risk among men of African Descent: a case-control study

    Directory of Open Access Journals (Sweden)

    Kidd LaCreis R

    2012-11-01

    Full Text Available Abstract Background Chemokine and chemokine receptors play an essential role in tumorigenesis. Although chemokine-associated single nucleotide polymorphisms (SNPs are associated with various cancers, their impact on prostate cancer (PCA among men of African descent is unknown. Consequently, this study evaluated 43 chemokine-associated SNPs in relation to PCA risk. We hypothesized inheritance of variant chemokine-associated alleles may lead to alterations in PCA susceptibility, presumably due to variations in antitumor immune responses. Methods Sequence variants were evaluated in germ-line DNA samples from 814 African-American and Jamaican men (279 PCA cases and 535 controls using Illumina’s Goldengate genotyping system. Results Inheritance of CCL5 rs2107538 (AA, GA+AA and rs3817655 (AA, AG, AG+AA genotypes were linked with a 34-48% reduction in PCA risk. Additionally, the recessive and dominant models for CCR5 rs1799988 and CCR7 rs3136685 were associated with a 1.52-1.73 fold increase in PCA risk. Upon stratification, only CCL5 rs3817655 and CCR7 rs3136685 remained significant for the Jamaican and U.S. subgroups, respectively. Conclusions In summary, CCL5 (rs2107538, rs3817655 and CCR5 (rs1799988 sequence variants significantly modified PCA susceptibility among men of African descent, even after adjusting for age and multiple comparisons. Our findings are only suggestive and require further evaluation and validation in relation to prostate cancer risk and ultimately disease progression, biochemical/disease recurrence and mortality in larger high-risk subgroups. Such efforts will help to identify genetic markers capable of explaining disproportionately high prostate cancer incidence, mortality, and morbidity rates among men of African descent.

  15. ASC-J9 Suppresses Castration-Resistant Prostate Cancer Growth through Degradation of Full-length and Splice Variant Androgen Receptors

    Directory of Open Access Journals (Sweden)

    Shinichi Yamashita

    2012-01-01

    Full Text Available Early studies suggested androgen receptor (AR splice variants might contribute to the progression of prostate cancer (PCa into castration resistance. However, the therapeutic strategy to target these AR splice variants still remains unresolved. Through tissue survey of tumors from the same patients before and after castration resistance, we found that the expression of AR3, a major AR splice variant that lacks the AR ligand-binding domain, was substantially increased after castration resistance development. The currently used antiandrogen, Casodex, showed little growth suppression in CWR22Rv1 cells. Importantly, we found that AR degradation enhancer ASC-J9 could degrade both full-length (fAR and AR3 in CWR22Rv1 cells as well as in C4-2 and C81 cells with addition of AR3. The consequences of such degradation of both fAR and AR3 might then result in the inhibition of AR transcriptional activity and cell growth in vitro. More importantly, suppression of AR3 specifically by short-hairpin AR3 or degradation of AR3 by ASC-J9 resulted in suppression of AR transcriptional activity and cell growth in CWR22Rv1-fARKD (fAR knockdown cells in which DHT failed to induce, suggesting the importance of targeting AR3. Finally, we demonstrated the in vivo therapeutic effects of ASC-J9 by showing the inhibition of PCa growth using the xenografted model of CWR22Rv1 cells orthotopically implanted into castrated nude mice with undetectable serum testosterone. These results suggested that targeting both fAR- and AR3-mediated PCa growth by ASC-J9 may represent the novel therapeutic approach to suppress castration-resistant PCa. Successful clinical trials targeting both fAR and AR3 may help us to battle castration-resistant PCa in the future.

  16. Common variants of chemokine receptor gene CXCR3 and its ligands CXCL10 and CXCL11 associated with vascular permeability of dengue infection in peninsular Malaysia.

    Science.gov (United States)

    Hoh, B P; Umi-Shakina, H; Zuraihan, Z; Zaiharina, M Z; Rafidah-Hanim, S; Mahiran, M; Khairudin, N Y Nik; Benedict, L H Sim; Masliza, Z; Christopher, K C Lee; Sazaly, A B

    2015-06-01

    Dengue causes significantly more human disease than any other arboviruses. It causes a spectrum of illness, ranging from mild self-limited fever, to severe and fatal dengue hemorrhagic fever, as evidenced by vascular leakage and multifactorial hemostatic abnormalities. There is no specific treatment available till date. Evidence shows that chemokines CXCL10, CXCL11 and their receptor CXCR3 are involved in severity of dengue, but their genetic association with the susceptibility of vascular leakage during dengue infection has not been reported. We genotyped 14 common variants of these candidate genes in 176 patients infected with dengue. rs4859584 and rs8878 (CXCL10) were significantly associated with vascular permeability of dengue infection (Pdengue infection. PMID:25858769

  17. Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and Type 2 diabetes susceptibility

    DEFF Research Database (Denmark)

    Guigas, B; de Leeuw van Weenen, J E; van Leeuwen, N;

    2014-01-01

    functional variants in the coding region of the DRD2/ANKK1 locus (rs1079597, rs6275, rs6277, rs1800497) were genotyped and analysed for Type 2 diabetes susceptibility in up to 25 000 people (8148 with Type 2 diabetes and 17687 control subjects) from two large independent Dutch cohorts and one Danish cohort......AIMS: Modulation of dopamine receptor D2 (DRD2) activity affects insulin secretion in both rodents and isolated pancreatic β-cells. We hypothesized that single nucleotide polymorphisms in the DRD2/ANKK1 locus may affect susceptibility to Type 2 diabetes in humans. METHODS: Four potentially....... In addition, 340 Dutch subjects underwent a 2-h hyperglycaemic clamp to investigate insulin secretion. Since sexual dimorphic associations related to DRD2 polymorphisms have been previously reported, we also performed a gender-stratified analysis. RESULTS: rs1800497 at the DRD2/ANKK1 locus was...

  18. Impaired coactivator activity of the Gly482 variant of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) on mitochondrial transcription factor A (Tfam) promoter

    International Nuclear Information System (INIS)

    Mitochondrial dysfunction may cause diabetes or insulin resistance. Peroxisome proliferation-activated receptor-γ (PPAR-γ) coactivator-1 α (PGC-1α) increases mitochondrial transcription factor A (Tfam) resulting in mitochondrial DNA content increase. An association between a single nucleotide polymorphism (SNP), G1444A(Gly482Ser), of PGC-1α coding region and insulin resistance has been reported in some ethnic groups. In this study, we investigated whether a change of glycine to serine at codon 482 of PGC-1α affected the Tfam promoter activity. The cDNA of PGC-1α variant bearing either glycine or serine at 482 codon was transfected into Chang human hepatocyte cells. The PGC-1α protein bearing glycine had impaired coactivator activity on Tfam promoter-mediated luciferase. We analyzed the PGC-1α genotype G1444A and mitochondrial DNA (mtDNA) copy number from 229 Korean leukocyte genomic DNAs. Subjects with Gly/Gly had a 20% lower amount of peripheral blood mtDNA than did subjects with Gly/Ser and Ser/Ser (p < 0.05). No correlation was observed between diabetic parameters and PGC-1α genotypes in Koreans. These results suggest that PGC-1α variants with Gly/Gly at 482nd amino acid may impair the Tfam transcription, a regulatory function of mitochondrial biogenesis, resulting in dysfunctional mtDNA replication

  19. Susceptibility effects of GABA receptor subunit alpha-2 (GABRA2) variants and parental monitoring on externalizing behavior trajectories: Risk and protection conveyed by the minor allele.

    Science.gov (United States)

    Trucco, Elisa M; Villafuerte, Sandra; Heitzeg, Mary M; Burmeister, Margit; Zucker, Robert A

    2016-02-01

    Understanding factors increasing susceptibility to social contexts and predicting psychopathology can help identify targets for prevention. Persistently high externalizing behavior in adolescence is predictive of psychopathology in adulthood. Parental monitoring predicts low externalizing behavior, yet youth likely vary in the degree to which they are affected by parents. Genetic variants of GABA receptor subunit alpha-2 (GABRA2) may increase susceptibility to parental monitoring, thus impacting externalizing trajectories. We had several objectives: (a) to determine whether GABRA2 (rs279827, rs279826, rs279858) moderates the relationship between a component of parental monitoring, parental knowledge, and externalizing trajectories; (b) to test the form of this interaction to assess whether GABRA2 variants reflect risk (diathesis-stress) or susceptibility (differential susceptibility) factors; and (c) to clarify GABRA2 associations on the development of problem behavior. This prospective study (N = 504) identified three externalizing trajectory classes (i.e., low, decreasing, and high) across adolescence. A GABRA2 × Parental Monitoring effect on class membership was observed, such that A-carriers were largely unaffected by parental monitoring, whereas class membership for those with the GG genotype was affected by parental monitoring. Findings support differential susceptibility in GABRA2. PMID:25797587

  20. Combination of carmustine and selenite effectively inhibits tumor growth by targeting androgen receptor, androgen receptor-variants, and Akt in preclinical models: New hope for patients with castration resistant prostate cancer.

    Science.gov (United States)

    Thamilselvan, Vijayalakshmi; Menon, Mani; Thamilselvan, Sivagnanam

    2016-10-01

    Despite established androgen receptor (AR) antagonists, AR/AR-variants signaling remain a major obstacle for the successful treatment of castration resistant prostate cancer (CRPC). In addition, CRPC cells adapt to survive via AR-independent pathways to escape next generation therapies. Therefore, there is an urgent need for drugs that can target these signaling pathways in CRPC. In this study, we sought to determine whether carmustine and selenite in combination could induce apoptosis and inhibit growth of CRPC in-vitro and in-vivo. CRPC (22Rv1, VCaP, and PC-3) cell lines in culture and xenograft mouse were used. Combination of carmustine and selenite treatment significantly increased reactive oxygen species, apoptosis and growth inhibition in CRPC cells with down regulation of anti-apoptotic (Bcl-2 and Mcl-1) and proliferative proteins (c-Myc and cyclin-D1). This effect was associated with complete reduction of AR/AR-variants, AR-V7, PSA and significant induction of p27Kip1. Combination treatment substantially abolished phospho-Akt, phospho-GSK-3β, and anchorage-independent growth in AR-positive and AR-negative cells. Consistent with in-vitro results, combination treatment effectively induced apoptosis and completely inhibited xenograft tumor growth and markedly reduced AR/AR-variants, AR-V7, PSA, and Bcl-2 in xenograft tumors without causing genotoxicity in host mice. Individual agent treatment showed only partial effect. The combination treatment showed a significant synergistic effect. The present study is the first to demonstrate that the combination of carmustine and selenite treatment completely suppressed CRPC tumor growth by reducing AR/AR-variants and Akt signaling. Our findings suggest that the combination of carmustine and selenite could constitute a promising next-generation therapy for successful treatment of patients with CRPC. PMID:27198552

  1. A Variant of Fibroblast Growth Factor Receptor 2 (Fgfr2) Regulates Left-Right Asymmetry in Zebrafish

    OpenAIRE

    Liu, Da-Wei; Hsu, Chia-Hao; Tsai, Su-Mei; Hsiao, Chung-Der; Wang, Wen-Pin

    2011-01-01

    Many organs in vertebrates are left-right asymmetrical located. For example, liver is at the right side and stomach is at the left side in human. Fibroblast growth factor (Fgf) signaling is important for left-right asymmetry. To investigate the roles of Fgfr2 signaling in zebrafish left-right asymmetry, we used splicing blocking morpholinos to specifically block the splicing of fgfr2b and fgfr2c variants, respectively. We found that the relative position of the liver and the pancreas were dis...

  2. Prevalence of mutations and functional analyses of melanocortin 4 receptor variants identified among 750 men with juvenile-onset obesity

    DEFF Research Database (Denmark)

    Larsen, Lesli H; Echwald, Søren Morgenthaler; Sørensen, Thorkild I A;

    2005-01-01

    Mutations in the gene encoding the melanocortin 4 receptor (MC4R) are associated with the most common monogenic form of obesity. We examined 750 Danish men with juvenile-onset obesity (body mass index 33.3 +/- 2.4 kg/m(2)) and 706 control subjects (body mass index 21.4 +/- 2.1 kg/m(2)) for...

  3. Inducible production of recombinant human Flt3 ectodomain variants in mammalian cells and preliminary crystallographic analysis of Flt3 ligand–receptor complexes

    International Nuclear Information System (INIS)

    The preparative purification and crystallization of Flt3 receptor–ligand complexes are described. The extracellular complex between the haematopoietic receptor Flt3 and its cytokine ligand (FL) is the cornerstone of signalling cascades that are central to early haematopoiesis and the immune system. Here, efficient protocols for the production of two ectodomain variants of human Flt3 receptor, Flt3D1–D5 and Flt3D1–D4, for structural studies are reported based on tetracycline-inducible stable cell lines in HEK293S cells deficient in N-acetylglycosaminyltransferase I (GnTI−/−) that can secrete the target proteins with limited and homogeneous N-linked glycosylation to milligram amounts. The ensuing preparative purification of Flt3 receptor–ligand complexes yielded monodisperse complex preparations that were amenable to crystallization. Crystals of the Flt3D1–D4–FL and Flt3D1–D5–FL complexes diffracted to 4.3 and 7.8 Å resolution, respectively, and exhibited variable diffraction quality even within the same crystal. The resulting data led to the successful structure determination of Flt3D1–D4–FL via a combination of molecular-replacement and density-modification protocols exploiting the noncrystallographic symmetry and high solvent content of the crystals

  4. Synthesis and evaluation of aryl-naloxamide opiate analgesics targeting truncated exon 11-associated mu opioid receptor (MOR-1) splice variants

    Science.gov (United States)

    Majumdar, Susruta; Subrath, Joan; Le Rouzic, Valerie; Polikar, Lisa; Burgman, Maxim; Nagakura, Kuni; Ocampo, Julie; Haselton, Nathan; Pasternak, Anna R.; Grinnell, Steven; Pan, Ying-Xian; Pasternak, Gavril W.

    2012-01-01

    3-Iodobenzoylnaltrexamide 1 (IBNtxA) is a potent analgesic acting through a novel receptor target that lack many side-effects of traditional opiates composed, in part, of exon 11-associated truncated six transmembrane domain MOR-1 (6TM/E11) splice variants. To better understand the SAR of this drug target, a number of 4,5-epoxymorphinan analogs were synthesized. Results show the importance of a free 3-phenolic group, a phenyl ring at the 6 position, an iodine at the 3′ or 4′ position of the phenyl ring and an N-allyl or c-propylmethyl group to maintain high 6TM/E11 affinity and activity. 3-Iodobenzoylnaloxamide 15 (IBNalA) with a N-allyl group displayed lower delta opioid receptor affinity than its naltrexamine analog, was 10-fold more potent an analgesic than morphine, elicited no respiratory depression or physical dependence and only limited inhibition of gastrointestinal transit. Thus, the aryl-naloxamide scaffold can generate a potent analgesic acting through the 6TM/E11 sites with advantageous side-effect profile and greater selectivity. PMID:22734622

  5. Synthesis and evaluation of aryl-naloxamide opiate analgesics targeting truncated exon 11-associated μ opioid receptor (MOR-1) splice variants.

    Science.gov (United States)

    Majumdar, Susruta; Subrath, Joan; Le Rouzic, Valerie; Polikar, Lisa; Burgman, Maxim; Nagakura, Kuni; Ocampo, Julie; Haselton, Nathan; Pasternak, Anna R; Grinnell, Steven; Pan, Ying-Xian; Pasternak, Gavril W

    2012-07-26

    3-Iodobenzoylnaltrexamide 1 (IBNtxA) is a potent analgesic acting through a novel receptor target that lack many side-effects of traditional opiates composed, in part, of exon 11-associated truncated six transmembrane domain MOR-1 (6TM/E11) splice variants. To better understand the SAR of this drug target, a number of 4,5-epoxymorphinan analogues were synthesized. Results show the importance of a free 3-phenolic group, a phenyl ring at the 6 position, an iodine at the 3'or 4' position of the phenyl ring, and an N-allyl or c-propylmethyl group to maintain high 6TM/E11 affinity and activity. 3-Iodobenzoylnaloxamide 15 (IBNalA) with a N-allyl group displayed lower δ opioid receptor affinity than its naltrexamine analogue, was 10-fold more potent an analgesic than morphine, elicited no respiratory depression or physical dependence, and only limited inhibition of gastrointestinal transit. Thus, the aryl-naloxamide scaffold can generate a potent analgesic acting through the 6TM/E11 sites with advantageous side-effect profile and greater selectivity. PMID:22734622

  6. Identification and Characterization of the Corazonin Receptor and Possible Physiological Roles of the Corazonin-Signaling Pathway in Rhodnius prolixus.

    Science.gov (United States)

    Hamoudi, Zina; Lange, Angela B; Orchard, Ian

    2016-01-01

    Neuropeptides control many physiological and endocrinological processes in animals, acting as neuroactive chemicals within the central and peripheral nervous systems. Corazonin (CRZ) is one such neuropeptide that has a variety of physiological roles associated with control of heartbeat, ecdysis behavior initiation, and cuticle coloration. These physiological effects are mediated by the CRZ receptor (CRZR). In order to understand the role of the CRZ-signaling pathway in Rhodnius prolixus, the cDNA sequence encoding the Rhopr-CRZR was isolated and cloned revealing two splice variants (Rhopr-CRZR-α and β). Sequence analysis revealed characteristics of rhodopsin-like GPCRs. Rhopr-CRZR-α and β were dose-dependently activated by Rhopr-CRZ with EC50 values of 2.7 and 1 nM, respectively, when tested in a functional receptor assay using CHOKI-aeq cells. Neither receptors were activated by the evolutionarily-related peptides, Rhopr-AKH, or Rhopr-ACP. For 5th instars, qPCR revealed expression of Rhopr-CRZR transcript in the CNS, the dorsal vessel, abdominal dorsal epidermis, and prothoracic glands with associated fat body. Interestingly, transcript expression was also found in the female and male reproductive tissues. Rhopr-CRZR transcript was reduced after injection of dsCRZR into adult R. prolixus. In these insects, the basal heartbeat rate was reduced in vivo, and the increase in heartbeat frequency normally produced by CRZ on dorsal vessel in vitro was much reduced. No effect of dsCRZR injection was seen on ecdysis or coloration of the cuticle. PMID:27536213

  7. Conserved Expression of the Glutamate NMDA Receptor 1 Subunit Splice Variants during the Development of the Siberian Hamster Suprachiasmatic Nucleus

    OpenAIRE

    Duffield, Giles E.; Jens D Mikkelsen; Ebling, Francis J. P.

    2012-01-01

    Glutamate neurotransmission and the N-methyl-D-aspartate receptor (NMDAR) are central to photic signaling to the master circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). NMDARs also play important roles in brain development including visual input circuits. The functional NMDAR is comprised of multiple subunits, but each requiring the NR1 subunit for normal activity. The NR1 can be alternatively spliced to produce isoforms that confer different functional propertie...

  8. Identification of Genetic Variants Within Androgen Receptor Gene of Sika Deer and its Association with Antler Production

    OpenAIRE

    Liguo Yang; Shujun Zhang; Lijun Huo; Pu Zhang; Bin Fan; Lei Shen; Guohua Hua; Feifei Yang; Jiajun Xiong

    2012-01-01

    Antler production is one of the most important economical traits of Sika deer. However, the genetic mechanism of antler growth and genetic markers associated with antler yield remain unclear. In the present study Androgen Receptor (AR) gene has been considered as a candidate gene to identify the polymorphisms. Besides, its effect on antler production was investigated in Chinese Sika deer. Genomic sequences of exons1-7 of Sika deer have been successfully obtained and showed high homogeneity wi...

  9. Agonist-dependence of functional properties for common nonsynonymous variants of human transient receptor potential vanilloid 1.

    Science.gov (United States)

    Wang, Sen; Joseph, John; Diatchenko, Luda; Ro, Jin Y; Chung, Man-Kyo

    2016-07-01

    Transient receptor potential vanilloid 1 (TRPV1) is a polymodal receptor activated by capsaicin, heat, and acid, which plays critical roles in thermosensation and pain. In addition, TRPV1 also contributes to multiple pathophysiological states in respiratory, cardiovascular, metabolic, and renal systems. These contributions are further supported by evidence that variations in the human TRPV1 (hTRPV1) gene are associated with various physiological and pathological phenotypes. However, it is not well understood how the variations in hTRPV1 affect channel functions. In this study, we examined functional consequences of amino acid variations of hTRPV1 induced by 5 nonsynonymous single-nucleotide polymorphisms (SNPs) that most commonly exist in the human population. Using electrophysiological assays in HEK293 cells, we examined 9 parameters: activation, Ca permeation, and desensitization after activation by capsaicin, acid, and heat. Our results demonstrated that the 5 SNPs differentially affected functional properties of hTRPV1 in an agonist-dependent manner. Based upon the directionality of change of each phenotype and cumulative changes in each SNP, we classified the 5 SNPs into 3 presumptive functional categories: gain of function (hTRPV1 Q85R, P91S, and T469I), loss of function (I585V), and mixed (M315I). These results reveal a spectrum of functional variation among common hTRPV1 polymorphisms in humans and may aid mechanistic interpretation of phenotypes associated with nonsynonymous hTRPV1 SNPs under pathophysiological conditions. PMID:26967694

  10. Effects of Sorafenib on C-Terminally Truncated Androgen Receptor Variants in Human Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Mark Schrader

    2012-09-01

    Full Text Available Recent evidence suggests that the development of castration resistant prostate cancer (CRPCa is commonly associated with an aberrant, ligand-independent activation of the androgen receptor (AR. A putative mechanism allowing prostate cancer (PCa cells to grow under low levels of androgens, is the expression of constitutively active, C-terminally truncated AR lacking the AR-ligand binding domain (LBD. Due to the absence of a LBD, these receptors, termed ARΔLBD, are unable to respond to any form of anti-hormonal therapies. In this study we demonstrate that the multikinase inhibitor sorafenib inhibits AR as well as ARΔLBD-signalling in CRPCa cells. This inhibition was paralleled by proteasomal degradation of the AR- and ARΔLBD-molecules. In line with these observations, maximal antiproliferative effects of sorafenib were achieved in AR and ARΔLBD-positive PCa cells. The present findings warrant further investigations on sorafenib as an option for the treatment of advanced AR-positive PCa.

  11. Association of estrogen receptor beta variants and serum levels of estradiol with risk of colorectal cancer: a case control study

    Directory of Open Access Journals (Sweden)

    Wu Huanlei

    2012-07-01

    Full Text Available Abstract Background Endogenous estrogens may play a vital role in colorectal tumorigenesis. Estrogen receptor beta is the predominant subtype which mediates the biological effect of estrogens, while loss of expression of estrogen receptor beta has been indicated as a common step in the development of colorectal cancer (CRC. Epidemiological studies have revealed several functional polymorphisms of estrogen receptor beta (ESR2 for cancer risk, but relevant study in CRC is limited, particularly in men. This study aimed to investigate the association of circulating estradiol and variations of ESR2 with CRC risk in men. Methods We initiated a case–control study consisting of 390 patients with CRC and 445 healthy controls in men only. We genotyped ESR2 single nucleotide polymorphisms (SNPs rs1256049 and rs4986938 and measured serum estradiol concentration using chemilluminescence immunoassay. Multivariable logistic regression model was performed to evaluate the associations between these variables and CRC risk. Results ESR2 rs1256049 CT/TT genotypes were associated with reduced risk of CRC (odds ratio [OR], 0.7, 95% confidence interval [CI], 0.5–1.0, while rs4986938 CT/TT genotypes were associated with increased risk of CRC (OR, 1.5, 95% CI, 1.0–2.1. In addition, the CRC risk increased with the number of risk genotypes of these two SNPs in a dose–response manner (Ptrend, 0.003. Specifically, subjects carrying risk genotypes of both SNPs had the highest risk of CRC (OR, 2.0, 95% CI, 1.3–3.3.. Moreover, serum estradiol concentration alone was associated with risk of CRC in men (OR, 1.2, 95% CI, 1.0–1.3. However, individuals presenting both rs4986938 CT/TT genotypes and high level of serum estradiol had a high risk of CRC (OR, 2.3, 95% CI, 1.4–3.9, compared with those presenting CC genotype and low level of serum estradiol. The similar joint results were not observed for SNP rs1256049. Conclusions These results suggest that endogenous

  12. Targeting of a CCK{sub 2} receptor splice variant with {sup 111}In-labelled cholecystokinin-8 (CCK8) and {sup 111}In-labelled minigastrin

    Energy Technology Data Exchange (ETDEWEB)

    Laverman, Peter; Gotthardt, Martin; Oyen, Wim J.G.; Boerman, Otto C. [Radboud University Nijmegen Medical Center, Department of Nuclear Medicine, PO Box 9101, HB Nijmegen (Netherlands); Roosenburg, Susan [Radboud University Nijmegen Medical Center, Department of Nuclear Medicine, PO Box 9101, HB Nijmegen (Netherlands); Radboud University Nijmegen, Institute for Molecules and Materials, Nijmegen (Netherlands); Park, Jeseong; Hellmich, Mark R. [University of Texas Medical Branch, Department of Surgery and the Sealy Center for Cancer Cell Biology, Galveston, TX (United States); Jong, Marion de [Erasmus Medical Center, Department of Nuclear Medicine, Rotterdam (Netherlands); Rutjes, Floris P.J.T.; Delft, Floris L. van [Radboud University Nijmegen, Institute for Molecules and Materials, Nijmegen (Netherlands)

    2008-02-15

    Radiolabelled cholecystokinin (CCK) and gastrin-derived peptides potentially can be used for peptide receptor radionuclide therapy (PRRT). Recently, a splice variant version of the CCK2R has been identified, designated CCK2i4svR. Constitutive expression of this receptor has been demonstrated in human colorectal cancer and in pancreatic cancer, but not in normal tissue. So far, it has never been shown whether radiolabelled peptides can target the CCK2i4svR in vivo. In this paper, we investigated the potential of sulfated {sup 111}In-labelled DOTA-CCK8 (sCCK8), a pan-CCKR-binding peptide, and [{sup 111}In]DOTA-minigastrin (MG0), a CCK2R selective peptide, for the targeting of the CCK2i4svR. The receptor binding affinity of [{sup 111}In]DOTA-sCCK8 and [{sup 111}In]DOTA-MG0 for the CCK2R and CCK2i4svR was determined using stably transfected HEK293 cell lines, expressing either CCK2R or CCK2i4svR. Tumour targeting was studied in HEK293-CCK2i4svR tumour-bearing athymic mice. [{sup 111}In]DOTA-sCCK8 as well as [{sup 111}In]DOTA-MG0 specifically bound both CCK2R and CCK2i4svR with affinities in the low nanomolar range. In vivo experiments revealed that accumulation of both peptides in CCK2i4svR-positive tumours was similar (3.21 {+-} 0.77 and 3.01 {+-} 0.67%ID/g, sCCK8 and MG0, respectively, 24 h p.i.). Kidney retention of [{sup 111}In]DOTA-MG0 (32.4 {+-} 7.5%ID/g, 24 h p.i.) was markedly higher than that of [{sup 111}In]DOTA-sCCK8 (2.75 {+-} 0.31%ID/g, 24 h p.i.). We demonstrated that the CCK2i4svR is a potential target for PRRT using a radiolabelled sulfated CCK8 peptide. As this receptor is expressed on colorectal and pancreatic tumours, but not in normal tissue, these tumours are potentially new targets for PRRT with CCK8 and gastrin analogs. (orig.)

  13. Targeting of a CCK2 receptor splice variant with 111In-labelled cholecystokinin-8 (CCK8) and 111In-labelled minigastrin

    International Nuclear Information System (INIS)

    Radiolabelled cholecystokinin (CCK) and gastrin-derived peptides potentially can be used for peptide receptor radionuclide therapy (PRRT). Recently, a splice variant version of the CCK2R has been identified, designated CCK2i4svR. Constitutive expression of this receptor has been demonstrated in human colorectal cancer and in pancreatic cancer, but not in normal tissue. So far, it has never been shown whether radiolabelled peptides can target the CCK2i4svR in vivo. In this paper, we investigated the potential of sulfated 111In-labelled DOTA-CCK8 (sCCK8), a pan-CCKR-binding peptide, and [111In]DOTA-minigastrin (MG0), a CCK2R selective peptide, for the targeting of the CCK2i4svR. The receptor binding affinity of [111In]DOTA-sCCK8 and [111In]DOTA-MG0 for the CCK2R and CCK2i4svR was determined using stably transfected HEK293 cell lines, expressing either CCK2R or CCK2i4svR. Tumour targeting was studied in HEK293-CCK2i4svR tumour-bearing athymic mice. [111In]DOTA-sCCK8 as well as [111In]DOTA-MG0 specifically bound both CCK2R and CCK2i4svR with affinities in the low nanomolar range. In vivo experiments revealed that accumulation of both peptides in CCK2i4svR-positive tumours was similar (3.21 ± 0.77 and 3.01 ± 0.67%ID/g, sCCK8 and MG0, respectively, 24 h p.i.). Kidney retention of [111In]DOTA-MG0 (32.4 ± 7.5%ID/g, 24 h p.i.) was markedly higher than that of [111In]DOTA-sCCK8 (2.75 ± 0.31%ID/g, 24 h p.i.). We demonstrated that the CCK2i4svR is a potential target for PRRT using a radiolabelled sulfated CCK8 peptide. As this receptor is expressed on colorectal and pancreatic tumours, but not in normal tissue, these tumours are potentially new targets for PRRT with CCK8 and gastrin analogs. (orig.)

  14. Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

    DEFF Research Database (Denmark)

    Bown, Matthew J; Jones, Gregory T; Harrison, Seamus C;

    2011-01-01

    additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p <1 × 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low......-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined...

  15. Investigating the Interaction between the Neonatal Fc Receptor and Monoclonal Antibody Variants by Hydrogen/Deuterium Exchange Mass Spectrometry

    DEFF Research Database (Denmark)

    Jensen, Pernille Foged; Larraillet, Vincent; Schlothauer, Tilman; Kettenberger, Hubert; Hilger, Maximiliane; Rand, Kasper D

    2015-01-01

    The recycling of immunoglobulins by the neonatal Fc receptor (FcRn) is of crucial importance in the maintenance of antibody levels in plasma and is responsible for the long half-lives of endogenous and recombinant monoclonal antibodies. From a therapeutic point of view there is great interest in...... understanding and modulating the IgG-FcRn interaction to optimize antibody pharmacokinetics and ultimately improve efficacy and safety. Here we studied the interaction between a full-length human IgG1 and human FcRn via hydrogen/deuterium exchange mass spectrometry and targeted electron transfer dissociation to...... wild-type glycosylated IgG. Our results provide new molecular insight into the IgG-FcRn interaction and illustrate the capability of hydrogen/deuterium exchange mass spectrometry to advance structural proteomics by providing detailed information on the conformation and dynamics of large protein...

  16. Human fear acquisition deficits in relation to genetic variants of the corticotropin releasing hormone receptor 1 and the serotonin transporter.

    Directory of Open Access Journals (Sweden)

    Ivo Heitland

    Full Text Available The ability to identify predictors of aversive events allows organisms to appropriately respond to these events, and failure to acquire these fear contingencies can lead to maladaptive contextual anxiety. Recently, preclinical studies demonstrated that the corticotropin-releasing factor and serotonin systems are interactively involved in adaptive fear acquisition. Here, 150 healthy medication-free human subjects completed a cue and context fear conditioning procedure in a virtual reality environment. Fear potentiation of the eyeblink startle reflex (FPS was measured to assess both uninstructed fear acquisition and instructed fear expression. All participants were genotyped for polymorphisms located within regulatory regions of the corticotropin releasing hormone receptor 1 (CRHR1 - rs878886 and the serotonin transporter (5HTTLPR. These polymorphisms have previously been linked to panic disorder and anxious symptomology and personality, respectively. G-allele carriers of CRHR1 (rs878886 showed no acquisition of fear conditioned responses (FPS to the threat cue in the uninstructed phase, whereas fear acquisition was present in C/C homozygotes. Moreover, carrying the risk alleles of both rs878886 (G-allele and 5HTTLPR (short allele was associated with increased FPS to the threat context during this phase. After explicit instructions regarding the threat contingency were given, the cue FPS and context FPS normalized in all genotype groups. The present results indicate that genetic variability in the corticotropin-releasing hormone receptor 1, especially in interaction with the 5HTTLPR, is involved in the acquisition of fear in humans. This translates prior animal findings to the human realm.

  17. Association analysis between variants of the interleukin-1β and the interleukin-1 receptor antagonist gene and antidepressant treatment response in major depression

    Directory of Open Access Journals (Sweden)

    André Tadic

    2008-03-01

    Full Text Available André Tadic1, Dan Rujescu2, Matthias J Müller3, Ralf Kohnen4, Hans H. Stassen5, Armin Szegedi6, Norbert Dahmen11Department of Psychiatry, University of Mainz, Germany; 2Department of Psychiatry, University of Munich, Germany; 3Clinic for Psychiatry and Psychotherapy, Marburg-Sued, Germany, and Clinic for Psychiatry and Psychotherapy, Giessen, Germany; 4IMEREM, Nuernberg, Germany; 5Department of Psychiatry, University of Zurich, Switzerland; 6Organon, Roseland, NJ, USAAbstract: This study investigated the possible association of the interleukin-1 beta (IL-1β C-511T promoter polymorphism and the interleukin-1 receptor antagonist (IL-1Ra (86bpn variable number of tandem repeats (VNTR polymorphism with antidepressant response to paroxetine and mirtazapine treatment. The study group consisted of 101 patients suffering from DSM-IV major depression participating in a randomized double-blind controlled clinical trial. Patients homozygous for the IL-1β-511T allele had a significantly faster and more pronounced response to paroxetine treatment than IL-1β-511C allele carriers. No association was found for the IL-1β C-511T polymorphism with mirtazapine treatment response. The IL-1Ra VNTR showed neither an association with paroxetine nor with mirtazapine treatment response. Our results provide further suggestive evidence that time course of response and antidepressant efficacy of paroxetine, but not of mirtazapine, is influenced in a clinically relevant manner by the IL-1β C-511T gene variant. Our data do not support the hypothesis that the IL-1Ra (86bpn VNTR affects antidepressant treatment response to paroxetine or mirtazapine. An independent replication of our finding is needed. If replicated, the IL-1β C-511T promoter polymorphism could be considered useful for prospective confirmatory pharmacogenetic trials in patients with major depression.Keywords: major depression, antidepressive agents, treatment outcome, interleukin-1 beta, interleukin-1

  18. Genetic variants in epidermal growth factor receptor pathway genes and risk of esophageal squamous cell carcinoma and gastric cancer in a Chinese population.

    Directory of Open Access Journals (Sweden)

    Wen-Qing Li

    Full Text Available The epidermal growth factor receptor (EGFR signaling pathway regulates cell proliferation, differentiation, and survival, and is frequently dysregulated in esophageal and gastric cancers. Few studies have comprehensively examined the association between germline genetic variants in the EGFR pathway and risk of esophageal and gastric cancers. Based on a genome-wide association study in a Han Chinese population, we examined 3443 SNPs in 127 genes in the EGFR pathway for 1942 esophageal squamous cell carcinomas (ESCCs, 1758 gastric cancers (GCs, and 2111 controls. SNP-level analyses were conducted using logistic regression models. We applied the resampling-based adaptive rank truncated product approach to determine the gene- and pathway-level associations. The EGFR pathway was significantly associated with GC risk (P = 2.16×10(-3. Gene-level analyses found 10 genes to be associated with GC, including FYN, MAPK8, MAP2K4, GNAI3, MAP2K1, TLN1, PRLR, PLCG2, RPS6KB2, and PIK3R3 (P<0.05. For ESCC, we did not observe a significant pathway-level association (P = 0.72, but gene-level analyses suggested associations between GNAI3, CHRNE, PAK4, WASL, and ITCH, and ESCC (P<0.05. Our data suggest an association between specific genes in the EGFR signaling pathway and risk of GC and ESCC. Further studies are warranted to validate these associations and to investigate underlying mechanisms.

  19. A naturally occurring null variant of the NMDA type glutamate receptor NR3B subunit is a risk factor of schizophrenia.

    Directory of Open Access Journals (Sweden)

    Hitomi Matsuno

    Full Text Available Hypofunction of the N-methyl-D-aspartate type glutamate receptor (NMDAR has been implicated in the pathogenesis of schizophrenia. Here, we investigated the significance of a common human genetic variation of the NMDAR NR3B subunit that inserts 4 bases within the coding region (insCGTT in the pathogenesis of schizophrenia. The cDNA carrying this polymorphism generates a truncated protein, which is electrophysiologically non-functional in heterologous expression systems. Among 586 schizophrenia patients and 754 healthy controls, insCGTT was significantly overrepresented in patients compared to controls (odds ratio = 1.37, p = 0.035. Among 121 schizophrenia patients and 372 healthy controls, genetic analyses of normal individuals revealed that those carrying insCGTT have a predisposition to schizotypal personality traits (F1,356 = 4.69, p = 0.031. Furthermore, pre-pulse inhibition, a neurobiological trait disturbed in patients with schizophrenia, was significantly impaired in patients carrying insCGTT compared with those with the major allele (F1,116 = 5.72, p = 0.018, F1,238 = 4.46, p = 0.036, respectively. These results indicate that a naturally occurring null variant in NR3B could be a risk factor of schizophrenia.

  20. A Natural Variant of the T Cell Receptor-Signaling Molecule Vav1 Reduces Both Effector T Cell Functions and Susceptibility to Neuroinflammation

    Science.gov (United States)

    Kassem, Sahar; Bernard, Isabelle; Dejean, Anne S.; Liblau, Roland; Fournié, Gilbert J.; Colacios, Céline

    2016-01-01

    The guanine nucleotide exchange factor Vav1 is essential for transducing T cell antigen receptor signals and therefore plays an important role in T cell development and activation. Our previous genetic studies identified a locus on rat chromosome 9 that controls the susceptibility to neuroinflammation and contains a non-synonymous polymorphism in the major candidate gene Vav1. To formally demonstrate the causal implication of this polymorphism, we generated a knock-in mouse bearing this polymorphism (Vav1R63W). Using this model, we show that Vav1R63W mice display reduced susceptibility to experimental autoimmune encephalomyelitis (EAE) induced by MOG35-55 peptide immunization. This is associated with a lower production of effector cytokines (IFN-γ, IL-17 and GM-CSF) by autoreactive CD4 T cells. Despite increased proportion of Foxp3+ regulatory T cells in Vav1R63W mice, we show that this lowered cytokine production is intrinsic to effector CD4 T cells and that Treg depletion has no impact on EAE development. Finally, we provide a mechanism for the above phenotype by showing that the Vav1R63W variant has normal enzymatic activity but reduced adaptor functions. Together, these data highlight the importance of Vav1 adaptor functions in the production of inflammatory cytokines by effector T cells and in the susceptibility to neuroinflammation. PMID:27438086

  1. Association of the Lipoprotein Receptor SCARB1 Common Missense Variant rs4238001 with Incident Coronary Heart Disease.

    Directory of Open Access Journals (Sweden)

    Ani Manichaikul

    Full Text Available Previous studies in mice and humans have implicated the lipoprotein receptor SCARB1 in association with atherosclerosis and lipid levels. In the current study, we sought to examine association of SCARB1 missense single nucleotide polymorphism (SNP rs4238001 with incident coronary heart disease (CHD.Genotypes for rs4238001 were imputed for 2,319 White, 1,570 African American, and 1,292 Hispanic-American MESA participants using the 1,000 Genomes reference set. Cox proportional hazards models were used to determine association of rs4238001 with incident CHD, with adjustments for age, sex, study site, principal components of ancestry, body mass index, diabetes status, serum creatinine, lipid levels, hypertension status, education and smoking exposure. Meta-analysis across race/ethnic groups within MESA showed statistically significant association of the T allele with higher risk of CHD under a consistent and formally adjudicated definition of CHD events in this contemporary cohort study (hazard ratio [HR] = 1.49, 95% CI [1.04, 2.14], P = 0.028. Analyses combining MESA with additional population-based cohorts expanded our samples in Whites (total n = 11,957 with 871 CHD events and African Americans (total n = 5,962 with 355 CHD events and confirmed an increased risk of CHD overall (HR of 1.19 with 95% CI [1.04, 1.37], P = 0.013, in African Americans (HR of 1.49 with 95% CI [1.07, 2.06], P = 0.019, in males (HR of 1.29 with 95% CI [1.08, 1.54], P = 4.91 x 10(-3 and in White males (HR of 1.24 with 95% CI [1.03, 1.51], P = 0.026.SCARB1 missense rs4238001 is statistically significantly associated with incident CHD across a large population of multiple race/ethnic groups.

  2. Cellulase variants

    Energy Technology Data Exchange (ETDEWEB)

    Blazej, Robert; Toriello, Nicholas; Emrich, Charles; Cohen, Richard N.; Koppel, Nitzan

    2015-07-14

    This invention provides novel variant cellulolytic enzymes having improved activity and/or stability. In certain embodiments the variant cellulotyic enzymes comprise a glycoside hydrolase with or comprising a substitution at one or more positions corresponding to one or more of residues F64, A226, and/or E246 in Thermobifida fusca Cel9A enzyme. In certain embodiments the glycoside hydrolase is a variant of a family 9 glycoside hydrolase. In certain embodiments the glycoside hydrolase is a variant of a theme B family 9 glycoside hydrolase.

  3. Association of the Serotonin Receptor 3E Gene as a Functional Variant in the MicroRNA-510 Target Site with Diarrhea Predominant Irritable Bowel Syndrome in Chinese Women

    OpenAIRE

    Zhang, Yu; Li, Yaoyao; Hao, Zhenfeng; Li, Xiangming; Bo, Ping; Gong, Weijuan

    2016-01-01

    Background/Aims The functional variant (rs56109847) in the 3′-untranslated regions (3′-UTR) of the serotonin receptor 3E (HTR3E) gene is associated with female diarrhea predominant irritable bowel syndrome (IBS-D) in British populations. However, the relationship of the polymorphism both to HTR3E expression in the intestine and to the occurrence of Chinese functional gastrointestinal disorders has yet to be examined. Methods Polymerase chain reaction amplification and restriction fragment len...

  4. The Int7G24A variant of transforming growth factor-beta receptor type I is a risk factor for colorectal cancer in the male Spanish population: a case-control study

    International Nuclear Information System (INIS)

    The Int7G24A variant of transforming growth factor-beta receptor type I (TGFBR1) has been shown to increase the risk for kidney, ovarian, bladder, lung and breast cancers. Its role in colorectal cancer (CRC) has not been established. The aims of this study were to assess the association of TGFBR1*Int7G24A variant with CRC occurrence, patient age, gender, tumour location and stage. We performed a case-control study with 504 cases of sporadic CRC; and 504 non-cancerous age, gender and ethnically matched controls. Genotyping analysis was performed using allelic discrimination assay by real time PCR. The Int7G24A variant was associated with increased CRC incidence in an additive model of inheritance (P for trend = 0.005). No significant differences were found between Int7G24A genotypes and tumour location or stage. Interestingly, the association of the Int7G24A variant with CRC risk was significant in men (odds ratio 4.10 with 95% confidence intervals 1.41-11.85 for homozygous individuals; P for trend = 0.00023), but not in women. We also observed an increase in susceptibility to CRC for individuals aged less than 70 years. Our data suggest that the Int7G24A variant represents a risk factor for CRC in the male Spanish population

  5. Missense splice variant (g.20746A>G, p.Ile183Val) of interferon gamma receptor 1 (IFNGR1) coincidental with mycobacterial osteomyelitis - a screen of osteoarticular lesions.

    Science.gov (United States)

    Bińczak-Kuleta, Agnieszka; Szwed, Aleksander; Walter, Mark R; Kołban, Maciej; Ciechanowicz, Andrzej; Clark, Jeremy S C

    2016-08-01

    Previously, dominant partial interferon-gamma receptor 1 (IFN-g-R1) susceptibility to environmental mycobacteria was found with IFNGR1 deletions or premature stop. Our aim was to search for IFNGR1 variants in patients with mycobacterial osteoarticular lesions. Biopsies from the patients were examined for acid-fast bacilli, inflammatory cell infiltration, and mycobacterial niacin. Mycobacterial rRNA was analyzed using a target-amplified rRNA probe test. Peripheral-blood-leukocyte genomic DNA was isolated from 19 patients using the QIAamp DNA Mini Kit, and all IFNGR1 exons were sequenced using an ABIPRISM 3130 device. After the discovery of an exon 5 variant, a Polish newborn population sample (n = 100) was assayed for the discovered variant. Splice sites and putative amino acid interactions were analyzed. All patients tested were positive for mycobacteria; one was heterozygous for the IFNGR1 exon 5 single-nucleotide-missense substitution (g.20746A>G, p.Ile183Val). No other variant was found. The splice analysis indicated the creation of an exonic splicing silencer, and alternatively, molecular graphics indicated that the p.Ile183Val might alter beta-strand packing (loss of van der Waals contacts; Val183/Pro205), possibly altering the IFN-g-R1/IFN-g-R2 interaction. The probability of non-deleterious variant was estimated as genes affecting Type 1 T-helper-cell-mediated immunity. PMID:27483180

  6. Common gene variants in the tumor necrosis factor (TNF and TNF receptor superfamilies and NF-kB transcription factors and non-Hodgkin lymphoma risk.

    Directory of Open Access Journals (Sweden)

    Sophia S Wang

    Full Text Available BACKGROUND: A promoter polymorphism in the pro-inflammatory cytokine tumor necrosis factor (TNF (TNF G-308A is associated with increased non-Hodgkin lymphoma (NHL risk. The protein product, TNF-alpha, activates the nuclear factor kappa beta (NF-kappaB transcription factor, and is critical for inflammatory and apoptotic responses in cancer progression. We hypothesized that the TNF and NF-kappaB pathways are important for NHL and that gene variations across the pathways may alter NHL risk. METHODOLOGY/PRINCIPAL FINDINGS: We genotyped 500 tag single nucleotide polymorphisms (SNPs from 48 candidate gene regions (defined as 20 kb 5', 10 kb 3' in the TNF and TNF receptor superfamilies and the NF-kappaB and related transcription factors, in 1946 NHL cases and 1808 controls pooled from three independent population-based case-control studies. We obtained a gene region-level summary of association by computing the minimum p-value ("minP test". We used logistic regression to compute odds ratios and 95% confidence intervals for NHL and four major NHL subtypes in relation to SNP genotypes and haplotypes. For NHL, the tail strength statistic supported an overall relationship between the TNF/NF-kappaB pathway and NHL (p = 0.02. We confirmed the association between TNF/LTA on chromosome 6p21.3 with NHL and found the LTA rs2844484 SNP most significantly and specifically associated with the major subtype, diffuse large B-cell lymphoma (DLBCL (p-trend = 0.001. We also implicated for the first time, variants in NFKBIL1 on chromosome 6p21.3, associated with NHL. Other gene regions identified as statistically significantly associated with NHL included FAS, IRF4, TNFSF13B, TANK, TNFSF7 and TNFRSF13C. Accordingly, the single most significant SNPs associated with NHL were FAS rs4934436 (p-trend = 0.0024, IRF4 rs12211228 (p-trend = 0.0026, TNFSF13B rs2582869 (p-trend = 0.0055, TANK rs1921310 (p-trend = 0.0025, TNFSF7 rs16994592 (p-trend = 0.0024, and TNFRSF13C rs6002551

  7. Molecular characterization and tissue distribution of aryl hydrocarbon receptor nuclear translocator isoforms, ARNT1 and ARNT2, and identification of novel splice variants in common cormorant (Phalacrocorax carbo).

    Science.gov (United States)

    Lee, Jin-Seon; Kim, Eun-Young; Iwata, Hisato; Tanabe, Shinsuke

    2007-04-01

    High levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related planar halogenated aromatic hydrocarbons (PHAHs) are accumulated in fish-eating birds including common cormorant (Phalacrocorax carbo). Most of the biochemical and toxic effects of TCDD are mediated by a basic helix-loop-helix and a conserved region among Per, ARNT, and Sim (bHLH/PAS) proteins, aryl hydrocarbon receptor (AHR) and AHR nuclear translocator (ARNT). To study the molecular mechanism of TCDD toxicity in common cormorant as an avian model species, characterization of the AHR/ARNT signaling pathway in this species is necessary. The present study focuses on molecular characterization of ARNT from common cormorant (ccARNT). The cDNA of the ccARNT isoform, ccARNT1 obtained by the screening of hepatic cDNA library contains a 2424-bp open reading frame that encodes 807 amino acids, exhibiting high identities (92%) with chicken ARNT. This isoform contains a unique 22 amino acid residue in 3' end of PAS A domain as is also recognized in chicken ARNT. The ccARNT2 cDNA isolated from brain tissue has a 2151-bp open reading frame. The deduced amino acid sequence of ccARNT2 protein (716 aa) shows a conservation of bHLH and PAS motif in its N-terminal region with high similarities (96% and 78%, respectively) to that of ccARNT1. Using quantitative RT-PCR methods, the tissue distribution profiles of ccARNT1 and ccARNT2 were unveiled. Both ccARNT1 and ccARNT2 mRNAs were ubiquitously expressed in all examined tissues including liver. The expression profile of ccARNT1 was comparable with that of rodent ARNT1, but ccARNT2 was not with rodent ARNT2, implying different roles of ARNT2 between the two species. There was a significant positive correlation between ARNT1 and ARNT2 mRNA expression levels in the liver of wild cormorant population, indicating that their expressions may be enforced by similar transcriptional regulation mechanism. Novel variants of ccARNT1 and ccARNT2 isoforms that were supposed to

  8. Association of the beta-1 adrenergic receptor carboxyl terminal variants with left ventricular hypertrophy among diabetic and non-diabetic survivors of acute myocardial infarction

    Directory of Open Access Journals (Sweden)

    Hakalahti Anna E

    2010-08-01

    Full Text Available Abstract Background The beta-1 adrenergic receptor (β1AR plays a fundamental role in the regulation of cardiovascular functions. It carries a nonsynonymous single nucleotide polymorphism in its carboxyl terminal tail (Arg389Gly, which has been shown to associate with various echocardiographic parameters linked to left ventricular hypertrophy (LVH. Diabetes mellitus (DM, on the other hand, represents a risk factor for LVH. We investigated the possible association between the Arg389Gly polymorphism and LVH among non-diabetic and diabetic acute myocardial infarction (AMI survivors. Methods The study population consisted of 452 AMI survivors, 20.6% of whom had diagnosed DM. Left ventricular parameters were measured with two-dimensional guided M-mode echocardiography 2-7 days after AMI, and the Arg389Gly polymorphism was determined using a polymerase chain reaction-restriction fragment length polymorphism assay. Results The Arg389 homozygotes in the whole study population had a significantly increased left ventricular mass index (LVMI when compared to the Gly389 carriers (either Gly389 homozygotes or Arg389/Gly389 heterozygotes [62.7 vs. 58.4, respectively (p = 0.023]. In particular, the Arg389 homozygotes displayed thicker diastolic interventricular septal (IVSd measures when compared to the Gly389 carriers [13.2 vs. 12.3 mm, respectively (p = 0.004]. When the euglycemic and diabetic patients were analyzed separately, the latter had significantly increased LVMI and diastolic left ventricular posterior wall (LVPWd values compared to the euglycemic patients [LVMI = 69.1 vs. 58.8 (p = 0.001 and LVPWd = 14.2 vs. 12.3 mm (p Conclusions The data suggest an association between the β1AR Arg389Gly polymorphism and LVH, particularly the septal hypertrophy. The Arg389 variant appears to confer a higher risk of developing LVH than the corresponding Gly389 variant among patients who have suffered AMI. This association cannot be considered to be universal

  9. Variant Toll-Like Receptor4 (Asp299Gly and Thr399Ile Alleles and Toll-Like Receptor2 (Arg753Gln and Arg677Trp Alleles in Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Homa Davoodi

    2011-06-01

    Full Text Available The innate immune system recognizes the presence of bacterial products through the expression of a family of membrane receptors known as Toll-like receptors (TLRs. Polymorphisms in TLRs have been shown to be associated with increased susceptibility to diseases such as inflammatory bowel disease.The aim of this study was to determine whether there was a correlation between polymorphisms of TLR4 (Asp299Gly; Thr399Ile and TLR2 (Arg677Trp; Arg753Gln genes and risk of colorectal cancer. DNA from 60 colorectal carcinoma patients from 3 major races in Malaysia  (22  Malays,  20  Chinese  and  18  Indians  and  blood  from  50  apparently  healthy individuals were evaluated. Control group were matched to study group by race and age. The polymorphisms were determined by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP.Genotyping results showed two out of sixty tumor specimens (3.3% harbored both variant TLR4 Asp299Gly and Thr399Ile alleles. In contrast, DNA isolated from blood cells of 50 apparently healthy individuals harbored wild type TLR4. In the case of TLR2 Arg753Gln genotyping, all of the fifty normal and 60 tumors were of the wild type genotype. TLR2 Arg677Trp genotyping showed a heterozygous pattern in all samples. However, this may not be a true polymorphism of the TLR2 gene as it is likely due to a variation of a duplicated (pseudogene region. There was only a low incidence (2/60; 3.3% of TLR4 polymorphism at the Asp299Gly and Thr399Ile alleles in colorectal cancer patients. All normal and tumor samples harbored the wild type TLR2 Arg753 allele.Our study suggests that variant TLR4 (Asp299Gly and Thr399Ile alleles as well as TLR2 (Arg753Gln allele are not associated with risk of colorectal cancer.

  10. Labeling internalizing anti-epidermal growth factor receptor variant III monoclonal antibody with 177Lu: in vitro comparison of acyclic and macrocyclic ligands

    International Nuclear Information System (INIS)

    Introduction: The monoclonal antibody (mAb) L8A4, reactive with the epidermal growth factor receptor variant III (EGFRvIII), internalizes rapidly in glioma cells after receptor binding. Combining this tumor-specific mAb with the low-energy β-emitter 177Lu would be an attractive approach for brain tumor radioimmunotherapy, provided that trapping of the radionuclide in tumor cells after mAb intracellular processing could be maximized. Materials and Methods: L8A4 mAb was labeled with 177Lu using the acyclic ligands [(R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S) -cyclohexane-1,2-diamine-pentaacetic acid (CHX-A''-DTPA), 2-(4-isothiocyanatobenzyl)-diethylenetriaminepenta-acetic acid (pSCN-Bz-DTPA) and 2-(4-isothiocyanatobenzyl)-6-methyldiethylenetriaminepentaacetic acid (1B4M-DTPA), and the macrocyclic ligands S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-tetraacetic acid (C-DOTA) and α-(5-isothiocyanato-2-methoxyphenyl)-1,4,7,10-tetraazacyclododecane-1,4,7, 10-tetraacetic acid (MeO-DOTA). Paired-label internalization and cellular processing assays were performed on EGFRvIII-expressing U87.ΔEGFR glioma cells over 24 h to directly compare 177Lu-labeled L8A4 to L8A4 labeled with 125I using either iodogen or N-succinimidyl 4-guanidinomethyl-3-[125I]iodobenzoate ([125I]SGMIB). In order to facilitate comparison of labeling methods, the primary parameter evaluated was the ratio of 177Lu to 125I activity retained in U87.ΔEGFR cells. Results: All chelates demonstrated higher retention of internalized activity compared with mAb labeled using iodogen, with 177Lu/125I ratios of >20 observed for the three DTPA chelates at 24 h. When compared to L8A4 labeled using SGMIB, except for MeO-DOTA, internalized activity for 125I was higher than 177Lu from 1-8 h with the opposite behavior observed thereafter. At 24 h, 177Lu/125I ratios were between 1.5 and 3, with higher values observed for the three DTPA chelates. Conclusions: The nature of the chelate used to

  11. Corticotrophin-Releasing Hormone Type 1 Receptor Gene (CRHR1 Variants Predict Posttraumatic Stress Disorder Onset and Course in Pediatric Injury Patients

    Directory of Open Access Journals (Sweden)

    Ananda B. Amstadter

    2011-01-01

    Full Text Available Posttraumatic stress disorder (PTSD is a common and disabling anxiety disorder that may occur in the aftermath of exposure to potentially traumatic life events. PTSD is moderately heritable, but few specific molecular variants accounting for this heritability have been identified. Genes regulating the hypothalamic-pituitary-adrenal (HPA axis, such as corticotrophin-releasing hormone type 1 receptor gene (CRHR1, have been implicated in traumatic-stress related phenotypes but have yet to be studied in relation to PTSD. The present study sought to examine the relation between 9 single nucleotide polymorphisms (SNPs in the CRHR1 gene and posttraumatic stress symptoms in a prospective study of pediatric injury patients (n = 103 who were first assessed in the acute aftermath of their injury at the hospital. Results indicated that multiple SNPs were associated with acute symptoms at a univariate level, and after correction for multiple testing, rs12944712 was significantly related to acute PTSD symptoms. Longitudinal latent growth curve analyses suggest that rs12944712 is also related to both acute symptom level and trajectory of symptoms over time. The present study adds support for the role of CRHR1 in the stress response following potentially traumatic event exposure in youth. It should be noted that the sample size in this study was small, and therefore statistical power was low; following, results from this study should be considered preliminary. Although results are not definitive, the findings from this study warrant future replication studies on how variation in this gene relates to response to traumatic event exposure in youth.

  12. A functional variant in the neuropeptide S receptor 1 gene moderates the influence of urban upbringing on stress processing in the amygdala.

    Science.gov (United States)

    Streit, Fabian; Haddad, Leila; Paul, Torsten; Frank, Josef; Schäfer, Axel; Nikitopoulos, Jörg; Akdeniz, Ceren; Lederbogen, Florian; Treutlein, Jens; Witt, Stephanie; Meyer-Lindenberg, Andreas; Rietschel, Marcella; Kirsch, Peter; Wüst, Stefan

    2014-07-01

    We have previously shown that urban upbringing and city living were associated with stress-induced activity in the amygdala and the perigenual anterior cingulate cortex (pACC). This finding might link the epidemiological risk factor "urbanicity" to neurobiological mechanisms of psychiatric disorders. However, given the heritability of stress-related phenotypes, it appears likely that genetic factors can modulate the effect of urbanicity on social stress processing. In the present exploratory study, we investigated if a functional sequence variation in the neuropeptide S receptor gene (NPSR1 rs324981) is associated with brain activation patterns under acute psychosocial stress and if it modulates the link between urbanicity and central stress processing. In animals, neuropeptide S has strong anxiolytic effects and it induces hypothalamus-pituitary-adrenal (HPA) axis activation. In humans, rs324981 was found to be associated with anxiety and stress-related phenotypes. Forty-two subjects were exposed to a psychosocial stress task for scanner environments (ScanSTRESS). While no main effect of rs324981 on amygdala and pACC activity was detected, we found a distinct interaction between rs324981 and urban upbringing modulating right amygdala responses. Moreover, right amygdala responses were significantly higher in subjects who also showed a salivary cortisol response to the stress exposure. The present finding of a gene × environment interaction further supports the view that the brain NPS system is involved in central stress regulation. This study provides first evidence for the assumption that a NPSR1 variant modulates brain activation under stress, interacting with the environmental risk factor urban upbringing. PMID:24800784

  13. Association of genetic variants of the histamine H1 and muscarinic M3 receptors with BMI and HbA1c values in patients on antipsychotic medication

    NARCIS (Netherlands)

    Vehof, Jelle; Risselada, Arne J.; Al Hadithy, Asmar F. Y.; Burger, Huibert; Snieder, Harold; Wilffert, Bob; Arends, Johan; Wunderink, Lex; Knegtering, Henrikus; Wiersma, Durk; Cohen, Dan; Mulder, Hans; Bruggeman, Richard

    2011-01-01

    Antipsychotic affinity for the histamine H1 receptor and the muscarinic M3 receptor have been associated with the side effects weight gain, and development of diabetes, respectively. We investigated polymorphisms of the histamine H1 (HRH1) and muscarinic acetylcholine receptor M3 (CHRM3) receptor ge

  14. Jeep variants

    CERN Document Server

    de Bondt, Michiel

    2010-01-01

    The jeep problem was first solved by O. Helmer and N.J. Fine. But not much later, C.G. Phipps formulated a more general solution. He formulated a so-called convoy or caravan variant of the jeep problem and reduced the original problem to it. The convoy idea of Phipps was refined in [3]. Here we will apply this refined idea to several variants of the jeep problem.

  15. Actions of agonists, fipronil and ivermectin on the predominant in vivo splice and edit variant (RDLbd, I/V of the Drosophila GABA receptor expressed in Xenopus laevis oocytes.

    Directory of Open Access Journals (Sweden)

    Kristin Lees

    Full Text Available Ionotropic GABA receptors are the targets for several classes of insecticides. One of the most widely-studied insect GABA receptors is RDL (resistance to dieldrin, originally isolated from Drosophila melanogaster. RDL undergoes alternative splicing and RNA editing, which influence the potency of GABA. Most work has focussed on minority isoforms. Here, we report the first characterisation of the predominant native splice variant and RNA edit, combining functional characterisation with molecular modelling of the agonist-binding region. The relative order of agonist potency is GABA> muscimol> TACA> β-alanine. The I/V edit does not alter the potency of GABA compared to RDLbd. Docking calculations suggest that these agonists bind and activate RDLbdI/V through a similar binding mode. TACA and β-alanine are predicted to bind with lower affinity than GABA, potentially explaining their lower potency, whereas the lower potency of muscimol and isoguvacine cannot be explained structurally from the docking calculations. The A301S (resistance to dieldrin mutation reduced the potency of antagonists picrotoxin, fipronil and pyrafluprole but the I/V edit had no measurable effect. Ivermectin suppressed responses to GABA of RDLbdI/V, RDLbd and RDLbdI/VA301S. The dieldrin resistant variant also showed reduced sensitivity to Ivermectin. This study of a highly abundant insect GABA receptor isoform will help the design of new insecticides.

  16. Actions of agonists, fipronil and ivermectin on the predominant in vivo splice and edit variant (RDLbd, I/V) of the Drosophila GABA receptor expressed in Xenopus laevis oocytes.

    Science.gov (United States)

    Lees, Kristin; Musgaard, Maria; Suwanmanee, Siros; Buckingham, Steven David; Biggin, Philip; Sattelle, David

    2014-01-01

    Ionotropic GABA receptors are the targets for several classes of insecticides. One of the most widely-studied insect GABA receptors is RDL (resistance to dieldrin), originally isolated from Drosophila melanogaster. RDL undergoes alternative splicing and RNA editing, which influence the potency of GABA. Most work has focussed on minority isoforms. Here, we report the first characterisation of the predominant native splice variant and RNA edit, combining functional characterisation with molecular modelling of the agonist-binding region. The relative order of agonist potency is GABA> muscimol> TACA> β-alanine. The I/V edit does not alter the potency of GABA compared to RDLbd. Docking calculations suggest that these agonists bind and activate RDLbdI/V through a similar binding mode. TACA and β-alanine are predicted to bind with lower affinity than GABA, potentially explaining their lower potency, whereas the lower potency of muscimol and isoguvacine cannot be explained structurally from the docking calculations. The A301S (resistance to dieldrin) mutation reduced the potency of antagonists picrotoxin, fipronil and pyrafluprole but the I/V edit had no measurable effect. Ivermectin suppressed responses to GABA of RDLbdI/V, RDLbd and RDLbdI/VA301S. The dieldrin resistant variant also showed reduced sensitivity to Ivermectin. This study of a highly abundant insect GABA receptor isoform will help the design of new insecticides. PMID:24823815

  17. Presence of sst5TMD4, a truncated splice variant of the somatostatin receptor subtype 5, is associated to features of increased aggressiveness in pancreatic neuroendocrine tumors

    Science.gov (United States)

    Gahete, Manuel D.; Serrano-Somavilla, Ana; Villa-Osaba, Alicia; Adrados, Magdalena; Ibáñez-Costa, Alejandro; Martín-Pérez, Elena; Culler, Michael D.

    2016-01-01

    Purpose Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare and heterogeneous tumors, and their biological behavior is not well known. We studied the presence and potential functional roles of somatostatin receptors (sst1-5), focusing particularly on the truncated variants (sst5TMD4, sst5TMD5) and on their relationships with the angiogenic system (Ang/Tie-2 and VEGF) in human GEP-NETs. Experimental Design We evaluated 42 tumor tissue samples (26 primary/16 metastatic) from 26 patients with GEP-NETs, and 30 non-tumoral tissues (26 from adjacent non-tumor regions and 4 from normal controls) from a single center. Expression of sst1-5, sst5TMD4, sst5TMD5, Ang1-2, Tie-2 and VEGF was analyzed using real-time qPCR, immunofluorescence and immunohistochemistry. Expression levels were associated with tumor characteristics and clinical outcomes. Functional role of sst5TMD4 was analyzed in GEP-NET cell lines. Results sst1 exhibited the highest expression in GEP-NET, whilst sst2 was the most frequently observed sst-subtype (90.2%). Expression levels of sst1, sst2, sst3, sst5TMD4, and sst5TMD5 were significantly higher in tumor tissues compared to their adjacent non-tumoral tissue. Lymph-node metastases expressed higher levels of sst5TMD4 than in its corresponding primary tumor tissue. sst5TMD4 was also significantly higher in intestinal tumor tissues from patients with residual disease of intestinal origin compared to those with non-residual disease. Functional assays demonstrated that the presence of sst5TMD4 was associated to enhanced malignant features in GEP-NET cells. Angiogenic markers correlated positively with sst5TMD4, which was confirmed by immunohistochemical/fluorescence studies. Conclusions sst5TMD4 is overexpressed in GEP-NETs and is associated to enhanced aggressiveness, suggesting its potential value as biomarker and target in GEP-NETs. PMID:26673010

  18. A study on genetic variants of Fibroblast growth factor receptor 2 (FGFR2 and the risk of breast cancer from North India.

    Directory of Open Access Journals (Sweden)

    Sarah Siddiqui

    Full Text Available Genome-Wide Association Studies (GWAS have identified Fibroblast growth factor receptor 2 (FGFR2 as a candidate gene for breast cancer with single nucleotide polymorphisms (SNPs located in intron 2 region as the susceptibility loci strongly associated with the risk. However, replicate studies have often failed to extrapolate the association to diverse ethnic regions. This hints towards the existing heterogeneity among different populations, arising due to differential linkage disequilibrium (LD structures and frequencies of SNPs within the associated regions of the genome. It is therefore important to revisit the previously linked candidates in varied population groups to unravel the extent of heterogeneity. In an attempt to investigate the role of FGFR2 polymorphisms in susceptibility to the risk of breast cancer among North Indian women, we genotyped rs2981582, rs1219648, rs2981578 and rs7895676 polymorphisms in 368 breast cancer patients and 484 healthy controls by Polymerase chain reaction-Restriction fragment length polymorphism (PCR-RFLP assay. We observed a statistically significant association with breast cancer risk for all the four genetic variants (P<0.05. In per-allele model for rs2981582, rs1219648, rs7895676 and in dominant model for rs2981578, association remained significant after bonferroni correction (P<0.0125. On performing stratified analysis, significant correlations with various clinicopathological as well as environmental and lifestyle characteristics were observed. It was evident that rs1219648 and rs2981578 interacted with exogenous hormone use and advanced clinical stage III (after Bonferroni correction, P<0.000694, respectively. Furthermore, combined analysis on these four loci revealed that compared to women with 0-1 risk loci, those with 2-4 risk loci had increased risk (OR = 1.645, 95%CI = 1.152-2.347, P = 0.006. In haplotype analysis, for rs2981578, rs2981582 and rs1219648, risk haplotype (GTG was

  19. A Variant of Human Estrogen Receptor-α, hER-α36 Weakens Docetaxel Drug Efficacy against Human Breast Cancer Cell Line MCF-7

    Institute of Scientific and Technical Information of China (English)

    Li Yu; Peng Shen

    2009-01-01

    Objective: hER-α36 is a variant of estrogen receptor-α, identified and cloned by a team of American. This research is to determine whether hER-α36 can enhance or weaken chemosensitivity to docetaxel in breast cancer cell line MCF-7(ERα66 positive).Methods: RT-PCR was used to detect the expressions of ERα66 and ERα36 in the two human breast cancer cell lines MCF-7(MCF-7/ERα66)and MCF-7 transfected with ERα36(MCF-7/ERα36). The two cell lines were treated with docetaxel(0~100μmol/L), and cell growth and apoptosis were evaluated using MTT (3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyl tetrazolium bromide) assay (using adriamycin (0~50μmol/L)as the control) and flowcytometry. Western blot analysis was used to measure the effect of docetaxel on phosphor-ERK1/2 expression in the two cell lines.Results: The expressions of ERα36 and ERα66 were detectable in both MCF-7/ERα66 and MCF-7/ERα36 cell lines, while the expression of ERα36 in MCF-7/ER36 cells was higher. Both docetaxel and adriamycin inhibited the proliferation of both cells lines in a dose and time dependent manner. In comparison with MCF-7/ERα36 cell line, the MCF-7/ERα66 cells produced greater growth inhibition and apoptosis after treatment with docetaxel, but there was no significant difference in growth inhibition between the two cell lines treated with adriamycin; The MCF-7/ERα36 cell line resulted in a significant activation (phosphorylation) of ERK1/2 after treatment with docetaxel in a dose-dependent manner, but in the MCF-7/ERα66 cell line , a decrease in the level of phosphor- ERK1/2 expression was observed as the dose of docetaxel increased.Conclusion: ERα36 may be an agent that weakens chemosensitivity to docetaxel in breast cancer, probably by activating the expression of ERK1/2.

  20. A Commonly Carried Genetic Variant in the Delta Opioid Receptor Gene, OPRD1, is Associated with Smaller Regional Brain Volumes: Replication in Elderly and Young Populations

    OpenAIRE

    Roussotte, Florence F.; Jahanshad, Neda; Hibar, Derrek P.; Sowell, Elizabeth R.; Kohannim, Omid; Barysheva, Marina; Hansell, Narelle K.; McMahon, Katie L.; de Zubicaray, Greig I.; Montgomery, Grant W.; Martin, Nicholas G.; Wright, Margaret J.; Toga, Arthur W.; Jack, Clifford R.; Weiner, Michael W

    2013-01-01

    Delta opioid receptors are implicated in a variety of psychiatric and neurological disorders. These receptors play a key role in the reinforcing properties of drugs of abuse, and polymorphisms in OPRD1 (the gene encoding delta opioid receptors) are associated with drug addiction. Delta opioid receptors are also involved in protecting neurons against hypoxic and ischemic stress. Here, we first examined a large sample of 738 elderly participants with neuroimaging and genetic data from the Alzhe...

  1. Rs6295 promoter variants of the serotonin type 1A receptor are differentially activated by c-Jun in vitro and correlate to transcript levels in human epileptic brain tissue.

    Science.gov (United States)

    Pernhorst, Katharina; van Loo, Karen M J; von Lehe, Marec; Priebe, Lutz; Cichon, Sven; Herms, Stefan; Hoffmann, Per; Helmstaedter, Christoph; Sander, Thomas; Schoch, Susanne; Becker, Albert J

    2013-03-01

    Many brain disorders, including epilepsy, migraine and depression, manifest with episodic symptoms that may last for various time intervals. Transient alterations of neuronal function such as related to serotonin homeostasis generally underlie this phenomenon. Several nucleotide polymorphisms (SNPs) in gene promoters associated with these diseases have been described. For obvious reasons, their regulatory roles on gene expression particularly in human brain tissue remain largely enigmatic. The rs6295 G-/C-allelic variant is located in the promoter region of the human HTR1a gene, encoding the G-protein-coupled receptor for 5-hydroxytryptamine (5HT1AR). In addition to reported transcriptional repressor binding, our bioinformatic analyses predicted a reduced binding affinity of the transcription factor (TF) c-Jun for the G-allele. In vitro luciferase transfection assays revealed c-Jun to (a) activate the rs6295 C- significantly stronger than the G-allelic variant and (b) antagonize efficiently the repressive effect of Hes5 on the promoter. The G-allele of rs6295 is known to be associated with aspects of major depression and migraine. In order to address a potential role of rs6295 variants in human brain tissue, we have isolated DNA and mRNA from fresh frozen hippocampal tissue of pharmacoresistant temporal lobe epilepsy (TLE) patients (n=140) after epilepsy surgery for seizure control. We carried out SNP genotyping studies and mRNA analyses in order to determine HTR1a mRNA expression in human hippocampal samples stratified according to the rs6295 allelic variant. The mRNA expression of HTR1a was significantly more abundant in hippocampal mRNA of TLE patients homozygous for the rs6295 C-allele as compared to those with the GG-genotype. These data may point to a novel, i.e., rs6295 allelic variant and c-Jun dependent transcriptional 5HT1AR 'receptoropathy'. PMID:23333373

  2. An unusual case of an ACTH-secreting macroadenoma with a germline variant in the aryl hydrocarbon receptor-interacting protein (AIP) gene

    DEFF Research Database (Denmark)

    Dinesen, Pia T; Dal, Jakob; Gabrovska, Plamena; Gaustadnes, Mette; Gravholt, Claus H; Stals, Karen; Denes, Judit; Asa, Sylvia L; Korbonits, Márta; Jørgensen, Jens O L

    2015-01-01

    diagnosed with a large pituitary tumor by magnetic resonance imaging (MRI). His visual fields were intact and he exhibited no features of CD. Owing to an exuberant response to synacthen, an overnight dexamethasone suppression test was performed revealing inadequate suppression of plasma cortisol (419 nmol...... adrenocortical failure. Genetic testing revealed an AIP variant of unknown significance (p.R16H) without loss of the normal AIP allele in the tumor. A literature review showed ten CD patients with AIP gene variants, of whom five (including our case) were p.R16H. CD is occasionally dominated by pituitary tumor...... pituitary tumor growth rather than symptoms of hypersecretion.Resolution of both tumor remnant and hormonal hypersecretion may occur within 2 months after postoperative radiotherapy.The particular AIP gene variant identified in our patient is shared by four other reported cases of CD....

  3. Common Low-Density Lipoprotein Receptor p.G116S Variant Has a Large Effect on Plasma Low-Density Lipoprotein Cholesterol in Circumpolar Inuit Populations

    DEFF Research Database (Denmark)

    Dube, J. B.; Wang, J.; Cao, H.;

    2015-01-01

    10(-49)), which was >3x larger than the largest effect sizes seen with other common variants in other populations. Carriers of p.G116S had a 3.02-fold increased risk of hypercholesterolemia (95% confidence interval, 2.34-3.90; P=1.7x10(-17)), but did not have classical familial hypercholesterolemia...

  4. Association of genetic variants of the histamine H1 and muscarinic M3 receptors with BMI and HbA1c values in patients on antipsychotic medication

    NARCIS (Netherlands)

    J. Vehof (Jelle); A.J. Risselada (Arne); A.F.Y. Al Hadithy (Asmar); H. Burger (Herman); H. Snieder (Harold); B. Wilffert (Bob); J. Arends (Johan); L. Wunderink (Lex); H. Knegtering (Henrikus); D. Wiersma (Durk); D. Cohen (Daniel); H. Mulder (Hans Sipko); R. Bruggeman (Richard)

    2011-01-01

    textabstractRationale: Antipsychotic affinity for the histamine H1 receptor and the muscarinic M3 receptor have been associated with the side effects weight gain, and development of diabetes, respectively. Objectives: We investigated polymorphisms of the histamine H1 (HRH1) and muscarinic acetylchol

  5. Association of the insulin-receptor variant Met-985 with hyperglycemia and non-insulin-dependent diabetes mellitus in the Netherlands : A population-based study

    NARCIS (Netherlands)

    tHart, LM; Stolk, RP; Heine, RJ; Grobbee, DE; vanderDoes, FEE; Maassen, JA

    1996-01-01

    One of the characteristics of non-insulin-dependent diabetes mellitus (NIDDM) is the presence of insulin resistance. Most NIDDM patients have a normal sequence of the insulin receptor, indicating that, if insulin-receptor mutations contribute to the development of NIDDM, they will be present only in

  6. Changes in Insulin Sensitivity in Response to Troglitazone Do Not Differ Between Subjects With and Without the Common, Functional Pro12Ala Peroxisome Proliferator-Activated Receptor-γ2 Gene Variant

    Science.gov (United States)

    Snitker, Soren; Watanabe, Richard M.; Ani, Ifeanyi; Xiang, Anny H.; Marroquin, Aura; Ochoa, Cesar; Goico, Jose; Shuldiner, Alan R.; Buchanan, Thomas A.

    2010-01-01

    OBJECTIVE We have tested whether the Pro12Ala variant of the peroxisome proliferator-activated receptor (PPAR)-γ nuclear receptor involved in thiazolidinedione (TZD) action accounted for the failure of troglitazone to increase insulin sensitivity in nondiabetic Hispanic women with previous gestational diabetes treated in the Troglitazone in Prevention of Diabetes (TRIPOD) study. RESEARCH DESIGN AND METHODS Ninety-three women assigned to troglita-zone had intravenous glucose tolerance tests at randomization and after 3 months of treatment with troglitazone, 400 mg/day, and were genotyped for the Pro12Ala variant of the PPAR-γ gene. Subjects were divided into tertiles based on their change in minimal model insulin sensitivity (Si) during the first 3 months of troglitazone treatment. RESULTS The mean changes in Si in the bottom, middle, and top tertiles of Si response were −0.21 ± 0.57, 0.91 ± 0.26, and 2.58 ± 1.32 min−1 per μU/ml · 10−4, respectively. Frequencies of the Ala/− genotype were 30, 22, and 26% in the same three tertiles (P = 0.77). Analysis of phenotypes by genotype revealed only small differences between the Pro/Pro and Ala/− groups, respectively, in baseline Si (2.76 ± 0.19 vs. 2.33 ± 0.33 × 10−4 min−1 per μU/ml; P = 0.27), the change in Si after 3 months of troglitazone treatment (1.19 ± 0.17 vs. 0.93 ± 0.30; P = 0.46), and the cumulative incidence of diabetes during a median follow-up of 30 months (13 vs. 17%; P = 0.66). CONCLUSIONS Among young Hispanic women at high risk for type 2 diabetes, the Pro12Ala variant of the PPAR-γ receptor gene did not explain the failure of ~1/3 of subjects to increase their insulin sensitivity when placed on troglitazone at a dose of 400 mg/day. PMID:15161789

  7. Ser1369Ala Variant in Sulfonylurea Receptor Gene ABCC8 Is Associated With Antidiabetic Efficacy of Gliclazide in Chinese Type 2 Diabetic Patients

    OpenAIRE

    Feng, Yan; Mao, Guangyun; Ren, Xiaowei; Xing, Houxun; Tang, Genfu; Li, Qiang; Li, Xueqi; SUN, LIRONG; Yang, Jinqui; Ma, Weiqing; Wang, Xiaobin; Xu, Xiping

    2008-01-01

    OBJECTIVE—The purpose of this study was to investigate whether genetic variants could influence the antidiabetic efficacy of gliclazide in type 2 diabetic patients. RESEARCH DESIGN AND METHODS—A total of 1,268 type 2 diabetic patients whose diabetes was diagnosed within the past 5 years and who had no recent hypoglycemic treatment were enrolled from 23 hospitals in China. All of the patients were treated with gliclazide for 8 weeks. Fasting and oral glucose tolerance test 2-h plasma glucose, ...

  8. Variants in the 5' region of the neuropeptide Y receptor Y2 gene (NPY2R) are associated with obesity in 5,971 white subjects

    DEFF Research Database (Denmark)

    Torekov, Signe Sørensen; Larsen, L H; Andersen, G; Albrechtsen, A; Glümer, C; Borch-Johnsen, K; Jørgensen, T; Hansen, T; Pedersen, O

    2006-01-01

    The gene encoding neuropeptide Y receptor Y2 (NPY2R) is widely expressed in the central nervous system, with particularly high abundance in the hypothalamus, which is known to be important for appetite regulation. We tested whether variations in NPY2R are associated with obesity.......The gene encoding neuropeptide Y receptor Y2 (NPY2R) is widely expressed in the central nervous system, with particularly high abundance in the hypothalamus, which is known to be important for appetite regulation. We tested whether variations in NPY2R are associated with obesity....

  9. Circadian and developmental regulation of N-methyl-d-aspartate-receptor 1 mRNA splice variants and N-methyl-d-aspartate-receptor 3 subunit expression within the rat suprachiasmatic nucleus

    DEFF Research Database (Denmark)

    Bendová, Z; Sumová, A; Mikkelsen, Jens D.

    2009-01-01

    ontogenesis, expression of two of the NMDAR1 subunit splice variants, as well as the NMDAR3A and 3B subunits, exhibits developmental loss around the time of eye opening. Moreover, we demonstrate the spatial and developmental characteristics of the expression of the truncated splice form of NMDAR1 subunit NR1...

  10. Cutting edge: dominant effect of Ile50Val variant of the human IL-4 receptor alpha-chain in IgE synthesis.

    Science.gov (United States)

    Mitsuyasu, H; Yanagihara, Y; Mao, X Q; Gao, P S; Arinobu, Y; Ihara, K; Takabayashi, A; Hara, T; Enomoto, T; Sasaki, S; Kawai, M; Hamasaki, N; Shirakawa, T; Hopkin, J M; Izuhara, K

    1999-02-01

    Two variants of the IL-4R alpha-chain (IL-4Ralpha) gene have been recently identified in association with different atopic disorders. To clarify the etiological relationship between the two variants, we analyzed responsiveness to IL-4 of transfectants with four kinds of IL-4Ralpha carrying either Val or Ile at 50 and either Gln or Arg at 551. The substitution of Ile for Val augmented STAT6 activation, proliferation, and transcription activity of the Iepsilon promoter by IL-4, whereas that of Arg for Gln did not change these IL-4 signals. Arg551 was not associated with atopic asthma in the Japanese population. CD23 expression and IgE synthesis by IL-4 were augmented in Ile50-bearing PBMC, compared with those bearing Val50. Taken together, substitution of Arg551 does not enhance the IL-4 signal for generation of germline epsilon transcript, whereas the substitution of Ile50 contributes to enhancement of IgE synthesis. PMID:9973373

  11. Microarray gene expression profiles of fasting induced changes in liver and adipose tissues of pigs expressing the melanocortin-4 receptor D298N variant

    Science.gov (United States)

    Transcriptional profiling was used to identify porcine genes and pathways that respond to a fasting in pigs that express the missense mutation (D298N) in the melanocortin-4 receptor (MC4R) gene, which has been associated with increased growth and feed efficiency. Prepubertal gilts (n=24; 12 wildtype...

  12. Identifying a Neuromedin U Receptor 2 Splice Variant and Determining Its Roles in the Regulation of Signaling and Tumorigenesis In Vitro.

    Science.gov (United States)

    Lin, Ting-Yu; Huang, Wei-Lin; Lee, Wei-Yu; Luo, Ching-Wei

    2015-01-01

    Neuromedin U (NMU) activates two G protein-coupled receptors, NMUR1 and NMUR2; this signaling not only controls many physiological responses but also promotes tumorigenesis in diverse tissues. We recently identified a novel truncated NMUR2 derived by alternative splicing, namely NMUR2S, from human ovarian cancer cDNA. Sequence analysis, cell surface ELISA and immunocytochemical staining using 293T cells indicated that NMUR2S can be expressed well on the cell surface as a six-transmembrane protein. Receptor pull-down and fluorescent resonance energy transfer assays demonstrated that NMUR1, NMUR2 and this newly discovered NMUR2S can not only form homomeric complexes but also heteromeric complexes with each other. Although not activated by NMU itself, functional assay in combination with receptor quantification and radio-ligand binding in 293T cells indicated that NMUR2S does not alter the translocation and stability of NMUR1 or NMUR2, but rather effectively dampens their signaling by blocking their NMU binding capability through receptor heterodimerization. We further demonstrated that NMU signaling is significantly up-regulated in human ovarian cancers, whereas expression of NMUR2S can block endogenous NMU signaling and further lead to suppression of proliferation in SKOV-3 ovarian cancer cells. In contrast, in monocytic THP-1 cells that express comparable levels of NMUR1 and NMUR2S, depletion of NMUR2S restored both the signaling and effect of NMU. Thus, these results not only reveal the presence of previously uncharacterized heteromeric relationships among NMU receptors but also provide NMUR2S as a potential therapeutic target for the future treatment of NMU signaling-mediated cancers. PMID:26317338

  13. Identifying a Neuromedin U Receptor 2 Splice Variant and Determining Its Roles in the Regulation of Signaling and Tumorigenesis In Vitro.

    Directory of Open Access Journals (Sweden)

    Ting-Yu Lin

    Full Text Available Neuromedin U (NMU activates two G protein-coupled receptors, NMUR1 and NMUR2; this signaling not only controls many physiological responses but also promotes tumorigenesis in diverse tissues. We recently identified a novel truncated NMUR2 derived by alternative splicing, namely NMUR2S, from human ovarian cancer cDNA. Sequence analysis, cell surface ELISA and immunocytochemical staining using 293T cells indicated that NMUR2S can be expressed well on the cell surface as a six-transmembrane protein. Receptor pull-down and fluorescent resonance energy transfer assays demonstrated that NMUR1, NMUR2 and this newly discovered NMUR2S can not only form homomeric complexes but also heteromeric complexes with each other. Although not activated by NMU itself, functional assay in combination with receptor quantification and radio-ligand binding in 293T cells indicated that NMUR2S does not alter the translocation and stability of NMUR1 or NMUR2, but rather effectively dampens their signaling by blocking their NMU binding capability through receptor heterodimerization. We further demonstrated that NMU signaling is significantly up-regulated in human ovarian cancers, whereas expression of NMUR2S can block endogenous NMU signaling and further lead to suppression of proliferation in SKOV-3 ovarian cancer cells. In contrast, in monocytic THP-1 cells that express comparable levels of NMUR1 and NMUR2S, depletion of NMUR2S restored both the signaling and effect of NMU. Thus, these results not only reveal the presence of previously uncharacterized heteromeric relationships among NMU receptors but also provide NMUR2S as a potential therapeutic target for the future treatment of NMU signaling-mediated cancers.

  14. Functional polymorphism in exon 5 and variant haplotype of the interleukin-1 receptor-associated kinase 1 gene are associated with susceptibility to and severity of sepsis in the Chinese population

    Institute of Scientific and Technical Information of China (English)

    FANG Yu; ZHANG Lu; ZHOU Gang-qiao; WANG Zhi-fu; ZENG Zhao-shu; LUO Zhi-yi; LI Lei; LIU Bao-chi

    2011-01-01

    Background The interleukin-1 (IL-1) receptor-associated kinase 1 (IRAKI) is believed to play an important role in the pathogenesis of sepsis. Recent studies have suggested that the IRAK1 functional genetic variant could affect the severity of sepsis in Caucasians. In this report, we have investigated whether polymorphisms at the IRAK1 gene are associated with the susceptibility to and severity of sepsis among the Chinese population. Methods Haplotype-tagging single nucleotide polymorphisms (htSNPs) were selected from the HapMap database.They were genotyped in 255 patients with sepsis and 260 control subjects by PCR/restriction fragment length polymorphism (RFLP) analysis. The association between the selected htSNPs and the susceptibility to and severity of sepsis were estimated by Logistic regression with adjustments for age, sex, smoking, drinking, chronic disease status,Acute Physiology and Chronic Health Evaluation (APACHE) Ⅱ score and primary diseases. Results rs1059702 was selected to represent the six linked htSNPs for IRAK1. Genotype frequencies of the htSNPs were in Hardy-Weinberg equilibrium for females, as were allele frequencies for both sex groups. Associations were observed in females between the htSNPs C/C genotype and increased susceptibility to sepsis (odds ratio (OR), 5.46;95% confidence interval (Cl), 1.12-26.67; P=0.018), and such associations were also observed between the IRAK1variant haplotype (CC/C-allele) and increased susceptibility to sepsis (OR, 1.68; 95% Cl, 1.05-2.70; P=0.031) when compared with the T/T + T/C genotype and the wild-type haplotype (TC + TT/T-allele). In the multiple organ dysfunction syndrome (MODS) subgroup, the variant haplotype was also associated with increased severity of sepsis (OR, 2.37; 95%Cl, 1.13-4.94; P=0.02) when compared with the wild haplotype. This association was not significant in male patients. Conclusions The functional polymorphism in exon 5 and the variant haplotype of IRAK1 gene mediate

  15. receptores

    Directory of Open Access Journals (Sweden)

    Salete Regina Daronco Benetti

    2006-01-01

    Full Text Available Se trata de un estudio etnográfico, que tuvo lo objetivo de interpretar el sistema de conocimiento y del significado atribuidos a la sangre referente a la transfusión sanguínea por los donadores y receptores de un banco de sangre. Para la colecta de las informaciones se observaron los participantes y la entrevista etnográfica se realizó el análisis de dominio, taxonómicos y temáticos. Los dominios culturales fueron: la sangre es vida: fuente de vida y alimento valioso; creencias religiosas: fuentes simbólicas de apoyos; donación sanguínea: un gesto colaborador que exige cuidarse, gratifica y trae felicidad; donación sanguínea: fuente simbólica de inseguridad; estar enfermo es una condición para realizar transfusión sanguínea; transfusión sanguínea: esperanza de vida; Creencias populares: transfusión sanguínea como riesgo para la salud; donadores de sangre: personas benditas; donar y recibir sangre: como significado de felicidad. Temática: “líquido precioso que origina, sostiene, modifica la vida, provoca miedo e inseguridad”.

  16. Migraine Variants in Children

    Science.gov (United States)

    ... headaches . Home > Migraine Variants in Children Print Email Migraine Variants in Children ACHE Newsletter Sign up for ... newsletter by entering your e-mail address below. Migraine Variants in Children There are several disorders that ...

  17. DC-SIGN (CD209), pentraxin 3 and vitamin D receptor gene variants associate with pulmonary tuberculosis risk in West Africans

    DEFF Research Database (Denmark)

    Olesen, R; Wejse, C; Velez, D R; Bisseye, C; Sodemann, M; Aaby, P; Rabna, P; Worwui, A; Chapman, H; Diatta, M; Adegbola, R A; Hill, P C; Østergaard, L; Williams, S M; Sirugo, G

    2007-01-01

    We investigated the role of DC-SIGN (CD209), long pentraxin 3 (PTX3) and vitamin D receptor (VDR) gene single nucleotide polymorphisms (SNPs) in susceptibility to pulmonary tuberculosis (TB) in 321 TB cases and 347 healthy controls from Guinea-Bissau. Five additional, functionally relevant SNPs...... within toll-like receptors (TLRs) 2, 4 and 9 were typed but found, when polymorphic, not to affect host vulnerability to pulmonary TB. We did not replicate an association between SNPs in the DC-SIGN promoter and TB. However, we found that two polymorphisms, one in DC-SIGN and one in VDR, were associated...... in a nonadditive model with disease risk when analyzed in combination with ethnicity (P=0.03 for DC-SIGN and P=0.003 for VDR). In addition, PTX3 haplotype frequencies significantly differed in cases compared to controls and a protective effect was found in association with a specific haplotype (OR 0...

  18. Further evidence for association between genetic variants in the cannabinoid receptor 1 (CNR1) gene and cocaine dependence: Confirmation in an independent sample and meta-analysis

    OpenAIRE

    Clarke, Toni-Kim; Bloch, Paul J.; Ambrose-Lanci, Lisa M; Doyle, Glenn A.; Ferraro, Thomas N.; BERRETTINI, WADE H.; Kampman, Kyle M.; Dackis, Charles A.; Pettinati, Helen M.; O’Brien, Charles P.; Oslin, David W.; Lohoff, Falk W.

    2011-01-01

    Genetic research on cocaine dependence may help clarify our understanding of the disorder as well as provide insights for effective treatment. Since endocannabinoid signaling and dopamine neurotransmission have been shown to be involved with drug reward, genes related to these systems are plausible candidates for susceptibility to cocaine dependence. The cannabinoid receptor 1 (CB1) protein regulates both the endocannabinoid and dopaminergic neurobiological systems, and polymorphisms in the c...

  19. A Naturally Occurring Null Variant of the NMDA Type Glutamate Receptor NR3B Subunit Is a Risk Factor of Schizophrenia

    OpenAIRE

    Matsuno, Hitomi; Ohi, Kazutaka; Hashimoto, Ryota; Yamamori, Hidenaga; Yasuda, Yuka; Fujimoto, Michiko; Yano-Umeda, Satomi; Saneyoshi, Takeo; Takeda, Masatoshi; Hayashi, Yasunori

    2015-01-01

    Hypofunction of the N-methyl-D-aspartate type glutamate receptor (NMDAR) has been implicated in the pathogenesis of schizophrenia. Here, we investigated the significance of a common human genetic variation of the NMDAR NR3B subunit that inserts 4 bases within the coding region (insCGTT) in the pathogenesis of schizophrenia. The cDNA carrying this polymorphism generates a truncated protein, which is electrophysiologically non-functional in heterologous expression systems. Among 586 schizophren...

  20. Estrogen receptor beta and truncated variants enhance the expression of transfected MMP-1 promoter constructs in response to specific mechanical loading

    OpenAIRE

    Thaler, John D; Achari, Yamini; Lu, Ting; Shrive, Nigel G; Hart, David A.

    2014-01-01

    Background Joint diseases such as osteoarthritis (OA) predominantly afflict post-menopausal women, suggesting a pertinent role for female hormones. Estrogen receptor beta (ER-β) has been detected in connective tissues of the knee joint suggesting that these tissues are responsive to the hormone estrogen. Matrix metalloproteinase-1 (MMP-1) activity contributes to cartilage degradation, a key factor leading to OA development in synovial joints. Two polymorphic forms of MMP-1 exist due to a dele...

  1. Identification, characterisation, and function of adipokinetic hormones and receptor in the African malaria mosquito, "Anopheles Gambiae" (Diptera)

    OpenAIRE

    Kaufmann, Christian; Betschart, Bruno

    2007-01-01

    En utilisant la bioinformatique et la biologie moléculaire, nous avons pu identifier chez le principal vecteur africain de la malaria, le moustique, Anopheles gambiae deux hormones adipokinétiques (AKHs): l'octapeptide, Anoga-AKH-I (pQLTFTPAWa) et le décapeptide, Anoga-AKH-II, (pQVTFSRDWNAa). La fonction principale des AKHs est d’induire une hyperlipémie (effet d’adipokinétique), ainsi qu’une hypertrehalosémie et une hyperprolinémie. En tant que membres de la famille des AKH, les deux neurope...

  2. Identifying a Neuromedin U Receptor 2 Splice Variant and Determining Its Roles in the Regulation of Signaling and Tumorigenesis In Vitro

    OpenAIRE

    Ting-Yu Lin; Wei-Lin Huang; Wei-Yu Lee; Ching-Wei Luo

    2015-01-01

    Neuromedin U (NMU) activates two G protein-coupled receptors, NMUR1 and NMUR2; this signaling not only controls many physiological responses but also promotes tumorigenesis in diverse tissues. We recently identified a novel truncated NMUR2 derived by alternative splicing, namely NMUR2S, from human ovarian cancer cDNA. Sequence analysis, cell surface ELISA and immunocytochemical staining using 293T cells indicated that NMUR2S can be expressed well on the cell surface as a six-transmembrane pro...

  3. Lifelong reduction of LDL-cholesterol related to a common variant in the LDL-receptor gene decreases the risk of coronary artery disease--a Mendelian Randomisation study.

    Directory of Open Access Journals (Sweden)

    Patrick Linsel-Nitschke

    Full Text Available BACKGROUND: Rare mutations of the low-density lipoprotein receptor gene (LDLR cause familial hypercholesterolemia, which increases the risk for coronary artery disease (CAD. Less is known about the implications of common genetic variation in the LDLR gene regarding the variability of cholesterol levels and risk of CAD. METHODS: Imputed genotype data at the LDLR locus on 1 644 individuals of a population-based sample were explored for association with LDL-C level. Replication of association with LDL-C level was sought for the most significant single nucleotide polymorphism (SNP within the LDLR gene in three European samples comprising 6 642 adults and 533 children. Association of this SNP with CAD was examined in six case-control studies involving more than 15 000 individuals. FINDINGS: Each copy of the minor T allele of SNP rs2228671 within LDLR (frequency 11% was related to a decrease of LDL-C levels by 0.19 mmol/L (95% confidence interval (CI [0.13-0.24] mmol/L, p = 1.5x10(-10. This association with LDL-C was uniformly found in children, men, and women of all samples studied. In parallel, the T allele of rs2228671 was associated with a significantly lower risk of CAD (Odds Ratio per copy of the T allele: 0.82, 95% CI [0.76-0.89], p = 2.1x10(-7. Adjustment for LDL-C levels by logistic regression or Mendelian Randomisation models abolished the significant association between rs2228671 with CAD completely, indicating a functional link between the genetic variant at the LDLR gene locus, change in LDL-C and risk of CAD. CONCLUSION: A common variant at the LDLR gene locus affects LDL-C levels and, thereby, the risk for CAD.

  4. Variant Toll-Like Receptor4 (Asp299Gly and Thr399Ile Alleles) and Toll-Like Receptor2 (Arg753Gln and Arg677Trp Alleles) in Colorectal Cancer

    OpenAIRE

    Homa Davoodi; Fong Seow

    2011-01-01

    The innate immune system recognizes the presence of bacterial products through the expression of a family of membrane receptors known as Toll-like receptors (TLRs). Polymorphisms in TLRs have been shown to be associated with increased susceptibility to diseases such as inflammatory bowel disease.The aim of this study was to determine whether there was a correlation between polymorphisms of TLR4 (Asp299Gly; Thr399Ile) and TLR2 (Arg677Trp; Arg753Gln) genes and risk of colorectal cancer. DNA fro...

  5. Variant Toll-Like Receptor4 (Asp299Gly and Thr399Ile Alleles) and Toll-Like Receptor2 (Arg753Gln and Arg677Trp Alleles) in Colorectal Cancer

    OpenAIRE

    Fong Seow; Homa Davoodi

    2011-01-01

    The innate immune system recognizes the presence of bacterial products through the expression of a family of membrane receptors known as Toll-like receptors (TLRs). Polymorphisms in TLRs have been shown to be associated with increased susceptibility to diseases such as inflammatory bowel disease. The aim of this study was to determine whether there was a correlation between polymorphisms of TLR4 (Asp299Gly; Thr399Ile) and TLR2 (Arg677Trp; Arg753Gln) genes and risk of colorectal cancer. DNA fr...

  6. Vitamin D deficiency in girls from South Brazil: a cross-sectional study on prevalence and association with vitamin D receptor gene variants

    Directory of Open Access Journals (Sweden)

    Santos Betânia R

    2012-06-01

    Full Text Available Abstract Background Vitamin D deficiency has been associated with a multitude of disorders including diabetes, defective insulin secretion as well as rickets and poor bone health. Vitamin D is also a concern during childhood and adolescence and has been reported in girls from South Brazil. We determined the prevalence of vitamin D deficiency in girls from South Brazil and investigated whether the genotypic distribution of the BsmI, ApaI and TaqI polymorphisms of the VDR gene and their haplotypes were associated with vitamin D levels. Methods Cross-sectional study including 234 apparently healthy girls aged 7 to 18 years. Height and weight were measured for calculation of body mass index (BMI percentiles for age. Plasma levels of 25-hydroxyvitamin D [25(OHD] were assessed. Participants were genotyped for ApaI (rs7975232, TaqI (rs731236, and BsmI (rs1544410 SNPs. Results The median and interquartile range (25-75% of BMI percentile was 62.0 (33.3 – 84.9. The frequency of overweight/obesity was 24.9%. Circulating levels of 25(OHD (≥ 30 ng/mL were adequate in 9.4%; insufficient in 54.3% (20–29 ng/mL; and deficient in 36.3% (vs. GA + AA, two-tailed Student’s t-test p vs. GT + TT, two-tailed Student’s t-test p = 0.031 and TaqI (TT vs. TC + CC, two-tailed Student’s t-test p = 0.005 SNPs and the GGT haplotype (two-tailed Student’s t-test p = 0.036 were significantly associated with lower 25(OHD levels. Conclusions 25-hydroxyvitamin D deficiency and insufficiency were highly prevalent in this sample. The BsmI, ApaI and TaqI wild variants of the VDR gene, as well as the GGT haplotype, were associated with lower vitamin D levels, suggesting that VDR gene polymorphisms could be linked to higher susceptibility to vitamin D deficiency in a sub-population of children and adolescents.

  7. Radioimmunotargeting of malignant glioma by monoclonal antibody D2C7 reactive against both wild-type and variant III mutant epidermal growth factor receptors

    International Nuclear Information System (INIS)

    Introduction: Malignant glioma remains a significant therapeutic challenge, and immunotherapeutics might be a beneficial approach for these patients. A monoclonal antibody (MAb) specific for multiple molecular targets could expand the treatable patient population and the fraction of tumor cells targeted, with potentially increased efficacy. This motivated the generation of MAb D2C7, which recognizes both wild-type epidermal growth factor receptor (EGFRwt) and a tumor-specific mutant, EGFRvIII. Methods: D2C7 binding affinity was determined by surface plasmon resonance and its specificity characterized through comparison to EGFRwt-specific EGFR.1 and EGFRvIII-specific L8A4 MAbs by flow cytometry and immunohistochemical analysis. The three MAbs were labeled with 125I or 131I using Iodogen, and paired-label internalization assays and biodistribution experiments in athymic mice with human tumor xenografts were performed. Results: The affinity of D2C7 for EGFRwt and EGFRvIII was 5.2×109 M−1 and 3.6×109 M−1, and cell-surface reactivity with both receptors was documented by flow cytometry. Immunohistochemical analyses revealed D2C7 reactivity with malignant glioma tissue from 90 of 101 patients. Internalization assays performed on EGFRwt-expressing WTT cells and EGFRvIII-expressing NR6M cells indicated a threefold lower degradation of 125I-labeled D2C7 compared with 131I-labeled EGFR.1. Uptake of 125I-labeled D2C7 in NR6M xenografts (52.45±13.97 %ID g−1 on Day 3) was more than twice that of 131I-labeled L8A4; a threefold to fivefold tumor delivery advantage was seen when compared to 131I-labeled EGFR.1 in mice with WTT xenografts. Conclusions: These results suggest that D2C7 warrants further evaluation for the development of MAb-based therapeutics against cancers expressing EGFRwt and EGFRvIII.

  8. A radioligand immunoassay for 1,25-dihydroxyvitamin D3 receptors using monoclonal antibody: detection of a phenotypic receptor variant in vitamin D-dependency rickets (type II) which does not bind hormone

    International Nuclear Information System (INIS)

    Vitamin D-dependency rickets, type II (VDDRII), is a well recognized heritable disorder characterized by peripheral target organ resistance to 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the hormonally active form of the vitamin. Recently, cultured skin fibroblasts obtained from a number of patients with VDDRII have been utilized to characterize the underlying molecular defects associated with this malady. Recently monoclonal antibodies to the vitamin D receptor have been generated, and a radioligand immunoassay (RLIA) for the detection of this molecule has been developed which is independent of its hormone-binding capacity. This report describes the application of the immunoassay in the detection of receptor-like molecules in fibroblasts derived from patients with VDDRII. The results indicate that the molecule is generally present in all patients, and provides a mechanism for individual responsiveness to pharmacologic treatment with vitamin D3 metabolites. 8 refs.; 3 figs.; 1 table

  9. Association Between CHRNA3 and CHRNA5 Nicotine Receptor Subunit Gene Variants and Nicotine Dependence in an Isolated Populationof Kashubians in Poland.

    Science.gov (United States)

    Kita-Milczarska, Karolina; Sieminska, Alicja; Jassem, Ewa

    2016-01-01

    BACKGROUND Genome-wide and allelic association studies have shown the contribution of CHRNA5-A3-B4 nicotinic receptor subunit gene cluster within chromosome 15 to nicotine dependence (ND). While an association between several single-nucleotide polymorphisms (SNPs) at that locus and smoking quantity (cigarettes per day; CPD) has been well recognized, there are some inconsistencies in demonstrating the influence of these SNPs on other ND phenotypes. This uncertainty motivated us to examine the association of 3 selected SNPs (CHRNA3 rs1051730, rs6495308, and CHRNA5 rs55853898) with ND in an isolated population of Kashubians from Poland. MATERIAL AND METHODS The study sample consisted of 788 current daily smokers. ND was assessed by CPD, the Fagerstrom Test for Nicotine Dependence (FTND), its brief version - Heavy Smoking Index (HSI), and time to first cigarette after waking (TTF). The correlation between studied SNPs and dichotomized values of ND measures was assessed in the regression analysis. Bonferroni corrected p-value of 0.017 was set for a type 1 error. RESULTS We found a robust association between risk allele A of rs1051730 and CPD >10 (odds ratio (OR)=1.77, 95% confidence interval (CI): 1.20-2.59, p=0.004), and a weak association, which did not survive correction for multiple testing, with FTND ³4. No associations between studied SNPs and HSI or TTF were demonstrated. CONCLUSIONS Our findings confirm that rs1051730 influences ND phenotype, as defined by CPD. PMID:27127891

  10. Individual response speed is modulated by variants of the gene encoding the alpha 4 sub-unit of the nicotinic acetylcholine receptor (CHRNA4).

    Science.gov (United States)

    Schneider, Katja Kerstin; Schote, Andrea B; Meyer, Jobst; Markett, Sebastian; Reuter, Martin; Frings, Christian

    2015-05-01

    Acetylcholine (ACh) is a known modulator of several domains of cognition, among them attention, memory and learning. The neurotransmitter also influences the speed of information processing, particularly the detection of targets and the selection of suitable responses. We examined the effect of the rs1044396 (C/T) polymorphism of the gene encoding the nicotinic acetylcholine receptor α4-subunit (CHRNA4) on response speed and selective visual attention. To this end, we administered a Stroop task, a Negative priming task and an exogenous Posner-Cuing task to healthy participants (n = 157). We found that the CHRNA4 rs1044396 polymorphism modulated the average reaction times (RTs) across all three tasks. Dependent on the C allele dosage, the RTs linearly increased. Homozygous T allele carriers were always fastest, while homozygous C allele carriers were always slowest. We did not observe effects of this polymorphism on selective attention. In sum, we conclude that naturally occurring variations within the cholinergic system influence an important factor of information processing. This effect might possibly be produced by the neuromodulator system rather than the deterministic system of cortical ACh. PMID:25639542

  11. Detection of exonic variants within the melanocortin 1 receptor (MC1R) gene in Black Silky, White Leghorn and Golden duckwing Araucana chicken.

    Science.gov (United States)

    Yeo, Jungsou; Lee, Yoonseok; Hyeong, KiEun; Ha, Jaejung; Yi, JunKoo; Kim, Byungki; Oh, Dongyep

    2014-08-01

    The melanocortin 1 receptor (MC1R) gene can be considered a candidate functional gene for the pigmentation of plumage color. The aim of this study was to investigate the association between the genotype frequencies of g.69 T>C, g.376 G>A and g.427 A>G SNPs within the MC1R gene in Black silky (O), Golden duckwing Araucana (GA) and White Leghorn (W). The CC and AA genotype frequencies of g.69 T>C and g.427 A>G SNPs in White Leghorn (W) were both 1.000, and the TT genotype frequency of the g.69 T>C SNP in Golden duckwing Araucana (GA) was also 1.000. The GG and AA genotype frequencies of g.376 G>A and g.427 A>G SNPs in Black silky (O) were both 0.100. When a haplotype is observed using a combination of markers, a Golden duckwing Araucana (GA) can especially be distinguished when it is a TAG, TGG and TAA type in the SNP combination of the MC1R gene. In case of the CAA types, only White Leghorn (W) could specifically be distinguished. Therefore, three SNPs in MC1R may provide identification in chicken breeds. PMID:24830563

  12. Causative Factors for ADHD: Role of Copy Number Variants in ADHD

    OpenAIRE

    J Gordon Millichap; John J Millichap

    2014-01-01

    Investigators from Brazil determined if copy number variants (CNVs) in glutamate metabotropic receptor genes (GRM) were overrepresented in 1038 individuals with ADHD compared to 1057 subjects without ADHD.

  13. A luteinizing hormone receptor intronic variant is significantly associated with decreased risk of Alzheimer's disease in males carrying an apolipoprotein E ε4 allele

    Directory of Open Access Journals (Sweden)

    Gleason Carey E

    2008-04-01

    Full Text Available Abstract Genetic and biochemical studies support the apolipoprotein E (APOE ε4 allele as a major risk factor for late-onset Alzheimer's disease (AD, though ~50% of AD patients do not carry the allele. APOE transports cholesterol for luteinizing hormone (LH-regulated steroidogenesis, and both LH and neurosteroids have been implicated in the etiology of AD. Since polymorphisms of LH beta-subunit (LHB and its receptor (LHCGR have not been tested for their association with AD, we scored AD and age-matched control samples for APOE genotype and 14 polymorphisms of LHB and LHCGR. Thirteen gene-gene interactions between the loci of LHB, LHCGR, and APOE were associated with AD. The most strongly supported of these interactions was between an LHCGR intronic polymorphism (rs4073366; lhcgr2 and APOE in males, which was detected using all three interaction analyses: linkage disequilibrium, multi-dimensionality reduction, and logistic regression. While the APOE ε4 allele carried significant risk of AD in males [p = 0.007, odds ratio (OR = 3.08(95%confidence interval: 1.37, 6.91], ε4-positive males carrying 1 or 2 C-alleles at lhcgr2 exhibited significantly decreased risk of AD [OR = 0.06(0.01, 0.38; p = 0.003]. This suggests that the lhcgr2 C-allele or a closely linked locus greatly reduces the risk of AD in males carrying an APOE ε4 allele. The reversal of risk embodied in this interaction powerfully supports the importance of considering the role gene-gene interactions play in the etiology of complex biological diseases and demonstrates the importance of using multiple analytic methods to detect well-supported gene-gene interactions.

  14. Estrogen receptor α variant ERα46 mediates growth inhibition and apoptosis of human HT-29 colon adenocarcinoma cells in the presence of 17β-oestradiol

    Institute of Scientific and Technical Information of China (English)

    JIANG Hai-ping; TENG Rong-yue; WANG Qi; ZHANG Xing; WANG Hao-hao; CAO Jiang; TENG Li-song

    2008-01-01

    Background Estrogen is involved in suppression of colon cancer development and exerts its function via estrogen receptors α and β (ERα, ERβ). The recently identified ERα46 resulted from exon 1-deletion from the 66-kDa full length form of ERα66 is devoid of the transactivation domain AF-1, whose function remains largely unknown.Methods In this study, we compared the expression of ERα46 mRNA in 32 normal colorectal tissues and their matched colorectal cancer tissues by real-time quantitative polymerase chain reaction (PCR). Human colon adenocarcinoma cell HT-29, that has low endogenous expression of ERα46, was transfected with ERα46-expression vector; methyl thiazolyl tetrazolium (MTT) assay, flow cytometry, DNA fragmentation and TUNEL staining were used to evaluate the proliferation and apoptosis status of the cells in the presence of 17β-oestradiol.Results Higher ERα46 mRNA levels were observed in normal colorectal tissues than in the corresponding cancer tissues. ERα46-transfected cells showed a significantly decreased growth rate than control cells and an accumulation of cells in the G0/1 phase and a reduced proportion of cells in G2/M phase after exposed to 10-8 mol/L 17β-oestradiol. There were also more positive TUNEL stained cells in ERα46-transfected cells than the control cells in the presence of 1713-oestradiol (P<0.05).Conclusions These data suggest that ERα46 may be involved in the development and/or progression of colorectal cancer via mediating growth inhibition and apoptosis of cancer cells in the presence of 17β-oestradiol.

  15. Association of the human CD3-zeta chain with the alpha beta-T cell receptor/CD3 complex. Clues from a T cell variant with a mutated T cell receptor-alpha chain

    DEFF Research Database (Denmark)

    Geisler, C; Schøller, J; Wahi, M A; Rubin, B; Weiss, A

    1990-01-01

    various components of this multimeric protein complex are not fully understood. In this report, a variant of the human leukemic T cell line Jurkat that synthesized all of the known components of the TCR/CD3 complex but fails to express the TCR/CD3 complex at the cell surface is further characterized. This......The TCR for Ag, on the majority of human T cells, is a disulfide-linked heterodimer composed of TCR-alpha and -beta chains noncovalently associated with the monomorphic CD3 complex composed of the CD3-gamma, -delta, -epsilon, and -zeta chains. The interactions involved in the assembly of the......-CD3-gamma delta epsilon zeta 2). Transfecting a wild-type TCR-alpha gene into J79 reconstituted expression of a complete functionally competent TCR/CD3 complex at the cell surface. The results indicate that the TCR-alpha chain plays a crucial role in the assembly of the CD3-zeta homodimer with the...

  16. Fetal bovine serum and human constitutive androstane receptor: Evidence for activation of the SV23 splice variant by artemisinin, artemether, and arteether in a serum-free cell culture system

    Energy Technology Data Exchange (ETDEWEB)

    Lau, Aik Jiang; Chang, Thomas K.H., E-mail: thomas.chang@ubc.ca

    2014-06-01

    The naturally occurring SV23 splice variant of human constitutive androstane receptor (hCAR-SV23) is activated by di-(2-ethylhexyl)phthalate (DEHP), which is detected as a contaminant in fetal bovine serum (FBS). In our initial experiment, we compared the effect of dialyzed FBS, charcoal-stripped, dextran-treated FBS (CS-FBS), and regular FBS on the basal activity and ligand-activation of hCAR-SV23 in a cell-based reporter gene assay. In transfected HepG2 cells cultured in medium supplemented with 10% FBS, basal hCAR-SV23 activity varied with the type of FBS (regular > dialyzed > CS). DEHP increased hCAR-SV23 activity when 10% CS-FBS, but not regular FBS or dialyzed FBS, was used. With increasing concentrations (1–10%) of regular FBS or CS-FBS, hCAR-SV23 basal activity increased, whereas in DEHP-treated cells, hCAR-SV23 activity remained similar (regular FBS) or slightly increased (CS-FBS). Subsequent experiments identified a serum-free culture condition to detect DEHP activation of hCAR-SV23. Under this condition, artemisinin, artemether, and arteether increased hCAR-SV23 activity, whereas they decreased it in cells cultured in medium supplemented with 10% regular FBS. By comparison, FBS increased the basal activity of the wild-type isoform of hCAR (hCAR-WT), whereas it did not affect the basal activity of the SV24 splice variant (hCAR-SV24) or ligand activation of hCAR-SV24 and hCAR-WT by 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO). The use of serum-free culture condition was suitable for detecting CITCO activation of hCAR-WT and hCAR-SV24. In conclusion, FBS leads to erroneous classification of pharmacological ligands of hCAR-SV23 in cell-based assays, but investigations on functional ligands of hCAR isoforms can be conducted in serum-free culture condition. - Highlights: • FBS leads to erroneous pharmacological classification of hCAR-SV23 ligands. • Artemisinin, artemether, and arteether activate h

  17. Fetal bovine serum and human constitutive androstane receptor: Evidence for activation of the SV23 splice variant by artemisinin, artemether, and arteether in a serum-free cell culture system

    International Nuclear Information System (INIS)

    The naturally occurring SV23 splice variant of human constitutive androstane receptor (hCAR-SV23) is activated by di-(2-ethylhexyl)phthalate (DEHP), which is detected as a contaminant in fetal bovine serum (FBS). In our initial experiment, we compared the effect of dialyzed FBS, charcoal-stripped, dextran-treated FBS (CS-FBS), and regular FBS on the basal activity and ligand-activation of hCAR-SV23 in a cell-based reporter gene assay. In transfected HepG2 cells cultured in medium supplemented with 10% FBS, basal hCAR-SV23 activity varied with the type of FBS (regular > dialyzed > CS). DEHP increased hCAR-SV23 activity when 10% CS-FBS, but not regular FBS or dialyzed FBS, was used. With increasing concentrations (1–10%) of regular FBS or CS-FBS, hCAR-SV23 basal activity increased, whereas in DEHP-treated cells, hCAR-SV23 activity remained similar (regular FBS) or slightly increased (CS-FBS). Subsequent experiments identified a serum-free culture condition to detect DEHP activation of hCAR-SV23. Under this condition, artemisinin, artemether, and arteether increased hCAR-SV23 activity, whereas they decreased it in cells cultured in medium supplemented with 10% regular FBS. By comparison, FBS increased the basal activity of the wild-type isoform of hCAR (hCAR-WT), whereas it did not affect the basal activity of the SV24 splice variant (hCAR-SV24) or ligand activation of hCAR-SV24 and hCAR-WT by 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO). The use of serum-free culture condition was suitable for detecting CITCO activation of hCAR-WT and hCAR-SV24. In conclusion, FBS leads to erroneous classification of pharmacological ligands of hCAR-SV23 in cell-based assays, but investigations on functional ligands of hCAR isoforms can be conducted in serum-free culture condition. - Highlights: • FBS leads to erroneous pharmacological classification of hCAR-SV23 ligands. • Artemisinin, artemether, and arteether activate h

  18. TRAC Variants Associate with IgA Nephropathy

    OpenAIRE

    Li, Ru; Xue, Chao; Li, Caixia; Lou, Tanqi; Tao, Yu; Li, Youji; Huang, Weijun; Zhang, Jun; Leung, Joseph C. K.; Lam, Man F.; Vyse, Tim J.; Kar N. Lai; Wu, Changyou; Wang, Yiming

    2009-01-01

    The T cell receptor alpha constant gene (TRAC) encodes the constant region of the α chain for the T cell receptor, and the association of its gene variants with IgA nephropathy remains controversial. The authors resequenced the gene in 100 patients with IgA nephropathy and 100 controls, tested its linkage disequilibrium pattern, constructed haplotypes, and performed association and functional studies. First, the association between TRAC variants and IgA nephropathy was tested in 704 patients ...

  19. Species-specific engagement of human nucleotide oligomerization domain 2 (NOD)2 and Toll-like receptor (TLR) signalling upon intracellular bacterial infection: role of Crohn's associated NOD2 gene variants.

    Science.gov (United States)

    Salem, M; Seidelin, J B; Eickhardt, S; Alhede, M; Rogler, G; Nielsen, O H

    2015-03-01

    Recognition of bacterial peptidoglycan-derived muramyl-dipeptide (MDP) by nucleotide oligomerization domain 2 (NOD2) induces crucial innate immune responses. Most bacteria carry the N-acetylated form of MDP (A-MDP) in their cell membranes, whereas N-glycolyl MDP (G-MDP) is typical for mycobacteria. Experimental murine studies have reported G-MDP to have a greater NOD2-stimulating capacity than A-MDP. As NOD2 polymorphisms are associated with Crohn's disease (CD), a link has been suggested between mycobacterial infections and CD. Thus, the aim was to investigate if NOD2 responses are dependent upon type of MDP and further to determine the role of NOD2 gene variants for the bacterial recognition in CD. The response pattern to A-MDP, G-MDP, Mycobacterium segmatis (expressing mainly G-MDP) and M. segmatisΔnamH (expressing A-MDP), Listeria monocytogenes (LM) (an A-MDP-containing bacteria) and M. avium paratuberculosis (MAP) (a G-MDP-containing bacteria associated with CD) was investigated in human peripheral blood mononuclear cells (PBMCs). A-MDP and M. segmatisΔnamH induced significantly higher tumour necrosis factor (TNF)-α protein levels in healthy wild-type NOD2 PBMCs compared with G-MDP and M. segmatis. NOD2 mutations resulted in a low tumour necrosis factor (TNF)-α protein secretion following stimulation with LM. Contrary to this, TNF-α levels were unchanged upon MAP stimulation regardless of NOD2 genotype and MAP solely activated NOD2- and Toll-like receptor (TLRs)-pathway with an enhanced production of interleukin (IL)-1β and IL-10. In conclusion, the results indicate that CD-associated NOD2 deficiencies might affect the response towards a broader array of commensal and pathogenic bacteria expressing A-MDP, whereas they attenuate the role of mycobacteria in the pathogenesis of CD. PMID:25335775

  20. Alternative splicing of human and mouse NPFF2 receptor genes: Implications to receptor expression.

    Science.gov (United States)

    Ankö, Minna-Liisa; Ostergård, Maria; Lintunen, Minnamaija; Panula, Pertti

    2006-12-22

    Alternative splicing has an important role in the tissue-specific regulation of gene expression. Here we report that similar to the human NPFF2 receptor, the mouse NPFF2 receptor is alternatively spliced. In human the presence of three alternatively spliced receptor variants were verified, whereas two NPFF2 receptor variants were identified in mouse. The alternative splicing affected the 5' untranslated region of the mouse receptor and the variants in mouse were differently distributed. The mouse NPFF system may also have species-specific features since the NPFF2 receptor mRNA expression differs from that reported for rat. PMID:17157836

  1. Receptor de estrógenos: variantes genéticas del ESR1 y parámetros bioquímicos de riesgo cardiovascular Estrogen Receptor: Polymorphisms of ESR1 and Biochemical Markers of Cardiovascular Risk

    Directory of Open Access Journals (Sweden)

    MB Rauschemberger

    2012-06-01

    Full Text Available El estudio de la asociación entre marcadores genéticos y signos clínicos y/o bioquímicos de determinadas patologías, se ha propuesto para evaluar la posible utilidad clínica de emplear las determinaciones genéticas como predictores de riesgo. La enfermedad cardiovascular es una de las principales causas de muerte en mujeres posmenopáusicas en el mundo occidental, hecho atribuido al descenso de los niveles de estrógenos circulantes. El objetivo de este trabajo fue investigar la existencia de asociaciones entre los polimorfismos del gen del receptor de estrógenos ESR1 (PvuII y XbaI y los marcadores bioquímicos de riesgo cardiovascular en una población local de mujeres sanas fértiles y posmenopáusicas. Se clasificó a ambas poblaciones en subgrupos según el marcador genético 1(P/p, 2(p/p, 3(P/P, A(X/x, B(x/x, C(X/X, donde P/X indica ausencia de corte y p/x indica presencia de corte para PvuII y XbaI respectivamente. En una muestra de sangre periférica, se determinaron parámetros bioquímicos de perfil lipídico, hemostasia e inflamación y se compararon fértiles vs. posmenopáusicas agrupadas según el genotipo. Las mujeres posmenopáusicas con genotipo A presentaron un aumento significativo en los niveles de colesterol total; C-LDL y triglicéridos respecto a las fértiles. En el subgrupo 1 se detectaron cambios solo en CT y C-LDL. En el haplotipo 1A de posmenopáusicas solo se evidenció aumento en colesterol total. Los parámetros de la hemostasia y de inflamación no mostraron cambios significativos entre fértiles y posmenopáusicas en función del marcador genético presente. Los resultados sugieren que, el genotipo A identifica a la población de mujeres posmenopáusicas con un perfil lipídico más desfavorable respecto a las fértiles del mismo subtipo. Los autores declaran no poseer conflictos de interés.In the last few years, the study of the association between genetic markers and clinical or biochemical signs of

  2. The macrophage scavenger receptor CD163

    DEFF Research Database (Denmark)

    Nielsen, Marianne Jensby; Madsen, Mette; Møller, Holger J; Moestrup, Søren K

    2006-01-01

    CD163 is the monocyte/macrophage-specific receptor for haptoglobin-hemoglobin (Hp-Hb) complexes. The cytoplasmic tail of human CD163 exists as a short tail variant and two long tail variants. Reverse transcriptase-polymerase chain reaction analysis indicated that all three CD163 variants are...

  3. Evaluation of 4-[{sup 18}F]fluorobenzoyl-FALGEA-NH{sub 2} as a positron emission tomography tracer for epidermal growth factor receptor mutation variant III imaging in cancer

    Energy Technology Data Exchange (ETDEWEB)

    Lund Denholt, Charlotte, E-mail: charlotte.lund.denholt@rh.regionh.d [Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen O (Denmark); Binderup, Tina [Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen O (Denmark); Cluster for Molecular Imaging, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen N (Denmark); Stockhausen, Marie-Therese; Skovgaard Poulsen, Hans [Department of Radiation Biology, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen O (Denmark); Spang-Thomsen, Mogens [Institute of Molecular Pathology, University of Copenhagen, 2200 Copenhagen N (Denmark); Hansen, Paul Robert [IGM-Bioorganic Chemistry, Faculty of Life Science, University of Copenhagen, 1871 Frederiksberg C (Denmark); Gillings, Nic [Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen O (Denmark); Kjaer, Andreas [Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen O (Denmark); Cluster for Molecular Imaging, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen N (Denmark)

    2011-05-15

    Introduction: This study describes the radiosynthesis, in vitro and in vivo evaluation of the novel small peptide radioligand, 4-[{sup 18}F]fluorobenzoyl-Phe-Ala-Leu-Gly-Glu-Ala-NH{sub 2,} ([{sup 18}F]FBA-FALGEA-NH{sub 2}) as a positron emission tomography (PET) tracer for imaging of the cancer specific epidermal growth factor receptor (EGFR) variant III mutation, EGFRvIII. Methods: For affinity, stability and PET measurements, H-FALGEA-NH{sub 2} was radiolabelled using 4-[{sup 18}F]fluorobenzoic acid ([{sup 18}F]FBA). The binding affinity of ([{sup 18}F]FBA)-FALGEA-NH{sub 2} was measured on EGFRvIII expressing cells, NR6M. Stability studies in vitro and in vivo were carried out in blood plasma from nude mice. PET investigations of [{sup 18}F]FBA-FALGEA-NH{sub 2} were performed on a MicroPET scanner, using seven nude mice xenografted subcutaneously with human glioblastoma multiforme (GBM) tumours, expressing the EGFRvIII in its native form, and five nude mice xenografted subcutaneously with GBM tumours lacking EGFRvIII expression. Images of [{sup 18}F]FDG were also obtained for comparison. The mice were injected with 5-10 MBq of the radiolabelled peptide or [{sup 18}F]FDG. Furthermore, the gene expression of EGFRvIII in the tumours was determined using quantitative real-time PCR. Results: Radiolabelling and purification was achieved within 180 min, with overall radiochemical yields of 2.6-9.8% (decay-corrected) and an average specific radioactivity of 6.4 GBq/{mu}mol. The binding affinity (K{sub d}) of [{sup 18}F]FBA-FALGEA-NH{sub 2} to EGFRvIII expressing cells was determined to be 23 nM. The radiolabelled peptide was moderately stable in the plasma from nude mice where 53% of the peptide was intact after 60 min of incubation in plasma but rapidly degraded in vivo, where no intact peptide was observed in plasma 5 min post-injection. The PET imaging showed that [{sup 18}F]FBA-FALGEA-NH{sub 2} accumulated preferentially in the human GBM xenografts which expressed

  4. Selection and characterization of T-cell variants lacking molecules involved in T-cell activation (T3 T-cell receptor, T44, and T11): analysis of the functional relationship among different pathways of activation

    Energy Technology Data Exchange (ETDEWEB)

    Moretta, A.; Poggi, A.; Olive, D.; Bottino, C.; Fortis, C.; Pantaleo, G.; Moretta, L.

    1987-03-01

    A clone of the interleukin 2-producing Jurkat leukemia cell line termed JA3 (surface phenotype, T3/sup +/, Ti/sup +/, T44/sup +/, T11/sup +/, T40/sup +/) has been used to induce and select cell variants lacking surface molecules involved in T-cell activation. Following 200 rad of ..gamma..-radiation (1 rad = 0.01 Gy), cells were treated with monoclonal antibodies (mAbs) directed to T3, Ti, T44, or T11 antigen and complement. After growth of the residual cells in culture, negative cells were cloned under limiting conditions. Depending on the specificity of the mAb used for the immunoselection, three groups of variants were obtained. (i) The use of mAbs directed to T3 or Ti resulted in cell variants that expressed the T3/sup -/ Ti/sup -/T44/sup +/ Leu1/sup +/ T11/sup +/ T40/sup +/ 4F2/sup +/ HLA class I/sup +/ surface phenotype. (ii) Immunoselection with anti-T44 mAb resulted in 2 variants that shared the T3/sup -/ Ti/sup -/ T44/sup -/ Leu1/sup -/ T11/sup -/ T40/sup -/ 4F2/sup -/ HLA class I/sup +/ phenotype. (iii) Cell treatment with anti-T11 mAb resulted in 15 variants characterized by the lack of T11 antigen expression and of all the other T-cell-specific surface antigens. Therefore, it appears that the different sets of JA3 cell variants, like T cells at discrete stages of intrathymic differentiation, may follow a coordinated expression of surface differentiation antigens. Analysis of the functional responsiveness of the three distinct groups of JA3 cell variants to different stimuli showed that all produced interleukin 2 in response to A23187 calcium ionophore plus phorbol 12-myristate 13-acetate.

  5. Term variants in ontologies

    OpenAIRE

    Aguado de Cea, G.; Montiel-Ponsoda, Elena

    2012-01-01

    Uno de los problemas de la representación de conocimiento en terminología es la variación terminológica, ya que los conceptos se pueden lexicalizar mediante unidades terminológicas diferentes. En esta contribución, tras analizar la tipología de las variantes terminológicas propuestas por diferentes autores, nos centramos en cómo se pueden representar las variantes terminológicas con relación a un modelo conceptual. Este enfoque permite atender por un lado a las variantes que apuntan al mismo ...

  6. Mucopolysaccharidosis: A New Variant?

    Science.gov (United States)

    Primrose, D. A.

    1972-01-01

    Described is a possibly new variant of mucopolysaccharidosis characterized by progressive mental and motor deficiency, bone abnormalities, a generalized skin lesion, and abnormal mucopolysaccharides in the urine as seen in a 20-year-old female. (DB)

  7. Hemoglobin Variants in Mice

    Energy Technology Data Exchange (ETDEWEB)

    Popp, Raymond A.

    1965-04-22

    Variability among mammalian hemoglobins was observed many years ago (35). The chemical basis for differences among hemoglobins from different species of mammals has been studied by several investigators (5, 11, 18, 48). As well as interspecies differences, hemoglobin variants are frequently found within a species of mammals (2, 3, 7, 16) The inheritance of these intraspecies variants can be studied, and pedigrees indicate that the type of hemoglobin synthesized in an individual is genetically controlled (20). Several of the variant human hemoglobins are f'unctionally deficient (7, 16). Such hemoglobin anomalies are of basic interest to man because of the vital role of hemoglobin for transporting oxygen to all tissues of the body.

  8. Association of a complement receptor 1 gene variant with baseline erythrocyte sedimentation rate levels in patients starting anti-TNF therapy in a UK rheumatoid arthritis cohort: results from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate cohort

    OpenAIRE

    Bluett, J; I Ibrahim; Plant, D.; Hyrich, K L; Morgan, A.W.; A G Wilson; Isaacs, J.D.; [...; Gaston, H; Mulherin, D; Price, T; Sheeran, T; Chalam, V; S. Baskar; Emery, P

    2013-01-01

    Eligibility for anti-tumour necrosis factor (TNF) therapy in most European countries is restricted to severe, active rheumatoid arthritis (RA). The DAS28 score is a marker of disease severity and incorporates one of two inflammatory markers, erythrocyte sedimentation rate (ESR) or C-reactive protein. We aimed to determine the relation between genetic variants known to affect ESR and levels of ESR in patients with active RA. DNA samples were genotyped for four single-nucleotide polymorphisms (...

  9. Complementation of the Function of Glycoprotein H of Human Herpesvirus 6 Variant A by Glycoprotein H of Variant B in the Virus Life Cycle

    OpenAIRE

    Oyaizu, Hiroko; Tang, Huamin; Ota, Megumi; Takenaka, Nobuyuki; Ozono, Keiichi; Yamanishi, Koichi; Mori, Yasuko

    2012-01-01

    Human herpesvirus 6 (HHV-6) is a T-cell-tropic betaherpesvirus. HHV-6 can be classified into two variants, HHV-6 variant A (HHV-6A) and HHV-6B, based on genetic, antigenic, and cell tropisms, although the homology of their entire genomic sequences is nearly 90%. The HHV-6A glycoprotein complex gH/gL/gQ1/gQ2 is a viral ligand that binds to the cellular receptor human CD46. Because gH has 94.3% amino acid identity between the variants, here we examined whether gH from one variant could compleme...

  10. Glycolipid binding preferences of Shiga toxin variants.

    Directory of Open Access Journals (Sweden)

    Sayali S Karve

    Full Text Available The major virulence factor of Shiga toxin producing E. coli, is Shiga toxin (Stx, an AB5 toxin that consists of a ribosomal RNA-cleaving A-subunit surrounded by a pentamer of receptor-binding B subunits. The two major isoforms, Stx1 and Stx2, and Stx2 variants (Stx2a-h significantly differ in toxicity. The exact reason for this toxicity difference is unknown, however different receptor binding preferences are speculated to play a role. Previous studies used enzyme linked immunosorbent assay (ELISA to study binding of Stx1 and Stx2a toxoids to glycolipid receptors. Here, we studied binding of holotoxin and B-subunits of Stx1, Stx2a, Stx2b, Stx2c and Stx2d to glycolipid receptors globotriaosylceramide (Gb3 and globotetraosylceramide (Gb4 in the presence of cell membrane components such as phosphatidylcholine (PC, cholesterol (Ch and other neutral glycolipids. In the absence of PC and Ch, holotoxins of Stx2 variants bound to mixtures of Gb3 with other glycolipids but not to Gb3 or Gb4 alone. Binding of all Stx holotoxins significantly increased in the presence of PC and Ch. Previously, Stx2a has been shown to form a less stable B-pentamer compared to Stx1. However, its effect on glycolipid receptor binding is unknown. In this study, we showed that even in the absence of the A-subunit, the B-subunits of both Stx1 and Stx2a were able to bind to the glycolipids and the more stable B-pentamer formed by Stx1 bound better than the less stable pentamer of Stx2a. B-subunit mutant of Stx1 L41Q, which shows similar stability as Stx2a B-subunits, lacked glycolipid binding, suggesting that pentamerization is more critical for binding of Stx1 than Stx2a.

  11. Discovery of a novel insect neuropeptide signaling system closely related to the insect adipokinetic hormone and corazonin hormonal systems

    DEFF Research Database (Denmark)

    Hansen, Karina Kiilerich; Stafflinger, Elisabeth; Schneider, Martina;

    2010-01-01

    structurally related to the AKHs but represent a different neuropeptide signaling system. We have previously cloned an orphan GPCR from the malaria mosquito Anopheles gambiae that was structurally intermediate between the A. gambiae AKH and corazonin GPCRs. Using functional expression of the receptor in cells...... in cell culture, we have now identified the ligand for this orphan receptor as being pQVTFSRDWNAamide, a neuropeptide that is structurally intermediate between AKH and corazonin and that we therefore named ACP (AKH/corazonin-related peptide). ACP does not activate the A. gambiae AKH and corazonin...

  12. Antigenic variants of rabies virus

    OpenAIRE

    Wiktor, TJ; Koprowski, H

    1980-01-01

    Antigenic variants of CVS-11 strain of rabies virus were selected after treatment of virus populations with monoclonal antibodies directed against the glycoprotein antigen of the virus. These variants resisted neutralization by the hybridoma antibody used for their selection. Two independently mutating antigenic sites could be distinguished when five variants were tested with nine hybridoma antibodies. The frequency of single epitope variants in a cloned rabies virus seed was approximately 1:...

  13. Frequency of the allelic variant c.1150T > C in exon 10 of the fibroblast growth factor receptor 3 (FGFR3 gene is not increased in patients with pathogenic mutations and related chondrodysplasia phenotypes

    Directory of Open Access Journals (Sweden)

    Thatiane Yoshie Kanazawa

    2014-12-01

    Full Text Available Mutations in the FGFR3 gene cause the phenotypic spectrum of FGFR3 chondrodysplasias ranging from lethal forms to the milder phenotype seen in hypochondroplasia (Hch. The p.N540K mutation in the FGFR3 gene occurs in ~70% of individuals with Hch, and nearly 30% of individuals with the Hch phenotype have no mutations in the FGFR3, which suggests genetic heterogeneity. The identification of a severe case of Hch associated with the typical mutation c.1620C > A and the occurrence of a c.1150T > C change that resulted in a p.F384L in exon 10, together with the suspicion that this second change could be a modulator of the phenotype, prompted us to investigate this hypothesis in a cohort of patients. An analysis of 48 patients with FGFR3 chondrodysplasia phenotypes and 330 healthy (control individuals revealed no significant difference in the frequency of the C allele at the c.1150 position (p = 0.34. One patient carrying the combination `pathogenic mutation plus the allelic variant c.1150T > C' had a typical achondroplasia (Ach phenotype. In addition, three other patients with atypical phenotypes showed no association with the allelic variant. Together, these results do not support the hypothesis of a modulatory role for the c.1150T > C change in the FGFR3 gene.

  14. Metabotropic glutamate receptor 1 splice variants mGluR1a and mGluR1b combine in mGluR1a/b dimers in vivo

    Czech Academy of Sciences Publication Activity Database

    Techlovská, Šárka; Chambers, Jayne Nicole; Dvořáková, Michaela; Petralia, R.S.; Wang, Y.X.; Hájková, Alena; Franková, Daniela; Prezeau, L.; Blahoš, Jaroslav

    2014-01-01

    Roč. 86, November (2014), s. 329-326. ISSN 0028-3908 R&D Projects: GA ČR GAP303/12/2408 Institutional support: RVO:68378050 Keywords : Glutamate receptors * GPCR * alternative splicing Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.106, year: 2014

  15. The serotonin transporter (5-HTTLPR) but not serotonin receptor (5-HT2C Cys23Ser) variant is associated with bipolar I disorder in Kurdish population from Western Iran.

    Science.gov (United States)

    Mohammadi, Sahar; Khazaie, Habibolah; Rahimi, Ziba; Vaisi-Raygani, Asad; Zargooshi, Newsha; Rahimi, Zohreh

    2015-03-17

    The role of 5-HTTLPR and 5-HT2C Cys23Ser polymorphisms in the psychopathology of mood disorders and suicide behavior is controversial. The aim of present study was to investigate the association between 5-HTTLPR and 5-HT2C Cys23Ser variants and susceptibility to bipolar I disorder (BID). The 5-HT2C genotypes were studied in 152 patients with BID and 173 gender- and age-matched healthy individuals with Kurds ethnic background from Western Iran using PCR and PCR-RFLP methods. In recessive model (SS vs. LL+LS) the SS genotype was associated with 1.79-fold increased risk of BID (p=0.018). Also, the presence of S allele increased the risk of adult-onset BID by 1.76-fold (p=0.027). No association was detected between 5-HTTLPR genotypes and alleles with suicide attempt. The frequency of 5-HT2C Ser allele in patients and controls were 12.3 and 12.5%, respectively. Mutant allele of HT2C Ser had higher frequency in female (14.7%) than male (10.5%, p=0.27) patients. The frequency of HT2C Ser allele in patients with a family history of BID tended to be higher (15.7%) than those without a family history of the disease (11.8%). The frequency of HT2C Ser allele in suicide attempter women was higher (16.7%) than those without a suicide attempt (14.3%). Our findings demonstrate 5-HTTLPR polymorphism might be a risk factor for BID and adult-onset BID in Kurds population. However, we found the lack of an association between 5-HT2C Cys/Ser variants and the risk of BID. PMID:25596490

  16. A Panel of IgG1 b12 Variants with Selectively Diminished or Enhanced Affinity for Fcγ Receptors To Define the Role of Effector Functions in Protection against HIV ▿

    OpenAIRE

    Moldt, Brian; Schultz, Niccole; Dunlop, D. Cameron; Alpert, Michael D.; Harvey, Jackson D.; Evans, David T.; Poignard, Pascal; Hessell, Ann J.; Burton, Dennis R.

    2011-01-01

    Passive transfer of neutralizing antibodies is effective in protecting rhesus macaques against simian/human immunodeficiency virus (SHIV) challenge. In addition to neutralization, effector functions of the crystallizable fragment (Fc) of antibodies are involved in antibody-mediated protection against a number of viruses. We recently showed that interaction between the Fc fragment of the broadly neutralizing antibody IgG1 b12 and cellular Fcγ receptors (FcγRs) plays an important role in protec...

  17. Adipokinetic hormones (AKHs) of sphingid Lepidoptera, including the identification of a second M. sexta AKH

    Czech Academy of Sciences Publication Activity Database

    Weaver, R. J.; Marco, H. G.; Šimek, Petr; Audsley, N.; Clark, K. D.; Gäde, G.

    2012-01-01

    Roč. 34, č. 1 (2012), s. 44-50. ISSN 0196-9781 R&D Projects: GA ČR GAP206/10/2401 Grant ostatní: NRF - Royal Society UK(GB) NRF GUN 63515; National Research Foundation(ZA) FA2007021300002; National Research Foundation(ZA) IFR2008071500048 Institutional research plan: CEZ:AV0Z50070508 Keywords : Insect * Sphingidae * adipokinetic hormone Subject RIV: ED - Physiology Impact factor: 2.522, year: 2012 http://www.sciencedirect.com/science/article/pii/S0196978112000307

  18. Molecular modeling of Gly80 and Ser80 variants of human group IID phospholipase A2 and their receptor complexes: potential basis for weight loss in chronic obstructive pulmonary disease.

    Science.gov (United States)

    Khan, Mohd Imran; Gupta, Ashish Kumar; Kumar, Domada Ratna; Kumar, Manoj; Ethayathulla, Abdul Samarth; Hariprasad, Gururao

    2016-09-01

    Weight loss is a well known systemic manifestation of chronic obstructive pulmonary disease (COPD). A Gly80Ser mutation on human group IID secretory phospholipase A2 (sPLA2) enhances expression of the cytokines that are responsible for weight loss. In this study, we seek to establish a structural correlation of wild type sPLA2 and the Gly80Ser mutation with function. sPLA2 with glycine and serine at the 80th positions and the M-type receptor were modelled. The enzymes were docked to the receptor and molecular dynamics was carried out to 70 ns. Structural analysis revealed the enzymes to comprise three helices (H1-H3), two short helices (SH1 and SH2), and five loops including a calcium binding loop (L1-L5), and to be stabilized by seven disulfide bonds. The overall backbone folds of the two models are very similar, with main chain RMSD of less than 1 Å. The active site within the substrate binding channel shows a catalytic triad of water-His67-Asp112, showing a hydrogen bonded network. Major structural differences between wild type and mutant enzymes were observed locally at the site of the mutation and in their global conformations. These differences include: (1) loop-L3 between H2 and H3, which bears residue Gly80 in the wild type, is in a closed conformation with respect to the channel opening, while in the mutant enzyme it adopts a relatively open conformation; (2) the mutant enzyme is less compact and has higher solvent accessible surface area; and (3) interfacial binding contact surface area is greater, and the quality of interactions with the receptor is better in the mutant enzyme as compared to the wild type. Therefore, the structural differences delineated in this study are potential biophysical factors that could determine the increased potency of the mutant enzyme with macrophage receptor for cytokine secreting function, resulting in exacerbation of cachexia in COPD. PMID:27585677

  19. The Ensembl Variant Effect Predictor.

    Science.gov (United States)

    McLaren, William; Gil, Laurent; Hunt, Sarah E; Riat, Harpreet Singh; Ritchie, Graham R S; Thormann, Anja; Flicek, Paul; Cunningham, Fiona

    2016-01-01

    The Ensembl Variant Effect Predictor is a powerful toolset for the analysis, annotation, and prioritization of genomic variants in coding and non-coding regions. It provides access to an extensive collection of genomic annotation, with a variety of interfaces to suit different requirements, and simple options for configuring and extending analysis. It is open source, free to use, and supports full reproducibility of results. The Ensembl Variant Effect Predictor can simplify and accelerate variant interpretation in a wide range of study designs. PMID:27268795

  20. Variants of windmill nystagmus.

    Science.gov (United States)

    Choi, Kwang-Dong; Shin, Hae Kyung; Kim, Ji-Soo; Kim, Sung-Hee; Choi, Jae-Hwan; Kim, Hyo-Jung; Zee, David S

    2016-07-01

    Windmill nystagmus is characterized by a clock-like rotation of the beating direction of a jerk nystagmus suggesting separate horizontal and vertical oscillators, usually 90° out of phase. We report oculographic characteristics in three patients with variants of windmill nystagmus in whom the common denominator was profound visual loss due to retinal diseases. Two patients showed a clock-like pattern, while in the third, the nystagmus was largely diagonal (in phase or 180° out of phase) but also periodically changed direction by 180°. We hypothesize that windmill nystagmus is a unique manifestation of "eye movements of the blind." It emerges when the central structures, including the cerebellum, that normally keep eye movements calibrated and gaze steady can no longer perform their task, because they are deprived of the retinal image motion that signals a need for adaptive recalibration. PMID:27159990

  1. CEACAM6 gene variants in inflammatory bowel disease.

    Directory of Open Access Journals (Sweden)

    Jürgen Glas

    Full Text Available BACKGROUND: The carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6 acts as a receptor for adherent-invasive E. coli (AIEC and its ileal expression is increased in patients with Crohn's disease (CD. Given its contribution to the pathogenesis of CD, we aimed to investigate the role of genetic variants in the CEACAM6 region in patients with inflammatory bowel diseases (IBD. METHODOLOGY: In this study, a total of 2,683 genomic DNA samples (including DNA from 858 CD patients, 475 patients with ulcerative colitis (UC, and 1,350 healthy, unrelated controls was analyzed for eight CEACAM6 SNPs (rs10415946, rs1805223 = p.Pro42Pro, rs4803507, rs4803508, rs11548735 = p.Gly239Val, rs7246116 = pHis260His, rs2701, rs10416839. In addition, a detailed haplotype analysis and genotype-phenotype analysis were performed. Overall, our genotype analysis did not reveal any significant association of the investigated CEACAM6 SNPs and haplotypes with CD or UC susceptibility, although certain CEACAM6 SNPs modulated CEACAM6 expression in intestinal epithelial cell lines. Despite its function as receptor of AIEC in ileal CD, we found no association of the CEACAM6 SNPs with ileal or ileocolonic CD. Moreover, there was no evidence of epistasis between the analyzed CEACAM6 variants and the main CD-associated NOD2, IL23R and ATG16L1 variants. CONCLUSIONS: This study represents the first detailed analysis of CEACAM6 variants in IBD patients. Despite its important role in bacterial attachment in ileal CD, we could not demonstrate a role for CEACAM6 variants in IBD susceptibility or regarding an ileal CD phenotype. Further functional studies are required to analyze if these gene variants modulate ileal bacterial attachment.

  2. The conditioning of intervention effects on early adolescent alcohol use by maternal involvement and dopamine receptor D4 (DRD4) and serotonin transporter linked polymorphic region (5-HTTLPR) genetic variants.

    Science.gov (United States)

    Cleveland, H Harrington; Schlomer, Gabriel L; Vandenbergh, David J; Feinberg, Mark; Greenberg, Mark; Spoth, Richard; Redmond, Cleve; Shriver, Mark D; Zaidi, Arslan A; Hair, Kerry L

    2015-02-01

    Data drawn from the in-home subsample of the PROSPER intervention dissemination trial were used to investigate the moderation of intervention effects on underage alcohol use by maternal involvement and candidate genes. The primary gene examined was dopamine receptor D4 (DRD4). Variation in this gene and maternal involvement were hypothesized to moderate the influence of intervention status on alcohol use. The PROSPER data used were drawn from 28 communities randomly assigned to intervention or comparison conditions. Participating youth were assessed in five in-home interviews from sixth to ninth grades. A main effect of sixth-grade pretest maternal involvement on ninth-grade alcohol use was found. Neither intervention status nor DRD4 variation was unconditionally linked to ninth-grade drinking. However, moderation analyses revealed a significant three-way interaction among DRD4 status, maternal involvement, and intervention condition. Follow-up analyses revealed that prevention reduced drinking risk, but only for youth with at least one DRD4 seven-repeat allele who reported average or greater pretest levels of maternal involvement. To determine if this conditional pattern was limited to the DRD4 gene, we repeated analyses using the serotonin transporter linked polymorphic region site near the serotonin transporter gene. The results for this supplemental analysis revealed a significant three-way interaction similar but not identical to that found for DRD4. PMID:25640830

  3. Vitamin D3 receptor ( VDR gene rs2228570 (Fok1 and rs731236 (Taq1 variants are not associated with the risk for multiple sclerosis: results of a new study and a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Elena García-Martín

    Full Text Available BACKGROUND: Some epidemiological, genetic, and experimental data suggest a possible role of vitamin D in the pathogenesis of multiple sclerosis (MS and in experimental autoimmune encephalomyelitis. Data on the possible contribution of several single nucleotide polymorphisms (SNP in the vitamin D receptor (VDR gene to the risk for MS are controversial. Several studies suggested an interaction between some SNPs in the VDR gene and HLADRB1*1501 in the risk for MS. OBJECTIVES: The aim of this study was to investigate a possible influence of the SNPs rs2228570 and rs731236 in the VDR gene in the risk for MS. A secondary objective was to address the possible interactions between VDR genes and HLADRB1*1501. METHODS: We analyzed the allelic and genotype frequency of VDR rs2228570, rs731236, and HLADRB1*1501 (rs3135388 in 303 patients with MS and 310 healthy controls, using TaqMan Assays. We also conducted a meta-analysis, that was carried out by using the software Meta-Disc 1.1.1 (http://www.hrc.es/investigacion/metadisc.html; Unit of Clinical Statistics, Hospital Ramón y Cajal, Madrid, Spain. Heterogeneity between studies in terms of degree of association was tested using the Q-statistic. RESULTS: VDR rs2228570 and rs731236 allelic and genotype frequencies did not differ significantly between MS patients and controls, and were unrelated with the age of onset of MS, gender, and course of MS. HLADRB1*1501 showed a high association with the risk of developing MS 4.76(95% C.I.  = 3.14-7.27; p<0.0001. The meta-analysis, after excluding data of one study that was responsible of heterogeneity for rs731236 polymorphism, showed lack of relation of both SNPs with the risk for MS. HLADRB1*1501 showed lack of interaction with VDR rs2228570 and rs731236 in increasing MS risk. CONCLUSIONS: These results suggest that VDR rs2228570 and rs731236 polymorphisms are not related with the risk for MS, and did not confirm interaction between these VDR SNPs and HLADRB1

  4. Tsh receptor

    OpenAIRE

    Frauman, Albert

    2013-01-01

    The TSH receptor is a member of the G protein-coupled receptor(GPCR)family. It is one of the glycoprotein hormone receptors, which also includes the FSH and LH/CG receptors. The TSH receptor mediates the action of the pituitary-derived glycoprotein, TSH (thyroid stimulating hormone, thyrotropin or thyrotrophin). TSH binds to the TSH receptor which is located on thyroid follicular cells (but is also expressed in extrathyroidal sites). Glycosylation of the TSH receptor occurs, as does cleavage ...

  5. Data-variant kernel analysis

    CERN Document Server

    Motai, Yuichi

    2015-01-01

    Describes and discusses the variants of kernel analysis methods for data types that have been intensely studied in recent years This book covers kernel analysis topics ranging from the fundamental theory of kernel functions to its applications. The book surveys the current status, popular trends, and developments in kernel analysis studies. The author discusses multiple kernel learning algorithms and how to choose the appropriate kernels during the learning phase. Data-Variant Kernel Analysis is a new pattern analysis framework for different types of data configurations. The chapters include

  6. Host Genetic Variants in the Pathogenesis of Hepatitis C

    Directory of Open Access Journals (Sweden)

    Monika Rau

    2012-11-01

    Full Text Available Direct-acting antiviral drugs (DAAs are currently replacing antiviral therapy for Hepatitis C infection. Treatment related side effects are even worse and the emergence of resistant viruses must be avoided because of the direct-antiviral action. Altogether it remains a challenge to take treatment decisions in a clinical setting with cost restrictions. Genetic host factors are hereby essential to implement an individualized treatment concept. In recent years results on different genetic variants have been published with a strong association with therapy response, fibrosis and treatment-related side effects. Polymorphisms of the IL28B gene were identified as accurate predictors for therapy response and spontaneous clearance of HCV infection and are already used for diagnostic decisions. For RBV-induced side effects, such as hemolytic anemia, associations to genetic variants of inosine triphosphatase (ITPA were described and different SLC28 transporters for RBV-uptake have been successfully analyzed. Fibrosis progression has been associated with variants of Vitamin D receptor (VDR and ABCB11 (bile salt export pump. Cirrhotic patients especially have a high treatment risk and low therapy response, so that personalized antiviral treatment is mandatory. This review focuses on different host genetic variants in the pathogenesis of Hepatitis C at the beginning of a new area of treatment.

  7. Two new splice variants in porcine PPARGC1A

    Directory of Open Access Journals (Sweden)

    Peelman Luc J

    2008-12-01

    Full Text Available Abstract Background Peroxisome proliferator-activated receptor γ coactivator 1α (PPARGC1A is a coactivator with a vital and central role in fat and energy metabolism. It is considered to be a candidate gene for meat quality in pigs and is involved in the development of obesity and diabetes in humans. How its many functions are regulated, is however still largely unclear. Therefore a transcription profile of PPARGC1A in 32 tissues and 4 embryonic developmental stages in the pig was constructed by screening its cDNA for possible splice variants with exon-spanning primers. Findings This led to the discovery of 2 new splice variants in the pig, which were subsequently also detected in human tissues. In these variants, exon 8 was either completely or partly (the last 66 bp were conserved spliced out, potentially coding for a much shorter protein of respectively 337 and 359 amino acids (aa, of which the first 291 aa would be the same compared to the complete protein (796 aa. Conclusion Considering the functional domains of the PPARGC1A protein, it is very likely these splice variants considerably affect the function of the protein and alternative splicing could be one of the mechanisms by which the diverse functions of PPARGC1A are regulated.

  8. A PYY Q62P variant linked to human obesity

    Energy Technology Data Exchange (ETDEWEB)

    Ahituv, Nadav; Kavaslar, Nihan; Schackwitz, Wendy; Ustaszewska,Anna; Collier, John Michael; Hebert, Sybil; Doelle, Heather; Dent,Robert; Pennacchio, Len A.; McPherson, Ruth

    2005-06-27

    Members of the pancreatic polypeptide family and the irreceptors have been implicated in the control of food intake in rodents and humans. To investigate whether nucleotide changes in these candidate genes result in abnormal weight in humans, we sequenced the coding exons and splice sites of seven family members (NPY, PYY, PPY, NPY1R, NPY2R, NPY4R, and NPY5R) in a large cohort of extremely obese (n=379) and lean (n=378) individuals. In total we found eleven rare non-synonymous variants, four of which exhibited familial segregation, NPY1R L53P and PPY P63L with leanness and NPY2R D42G and PYY Q62P with obesity. Functional analysis of the obese variants revealed NPY2R D42G to have reduced cell surface expression, while previous cell culture based studies indicated variant PYY Q62P to have altered receptor binding selectivity and we show that it fails to reduce food intake through mouse peptide injection experiments. These results support that rare non-synonymous variants within these genes can alter susceptibility to human body mass index extremes.

  9. Ionotropic crustacean olfactory receptors.

    Directory of Open Access Journals (Sweden)

    Elizabeth A Corey

    Full Text Available The nature of the olfactory receptor in crustaceans, a major group of arthropods, has remained elusive. We report that spiny lobsters, Panulirus argus, express ionotropic receptors (IRs, the insect chemosensory variants of ionotropic glutamate receptors. Unlike insects IRs, which are expressed in a specific subset of olfactory cells, two lobster IR subunits are expressed in most, if not all, lobster olfactory receptor neurons (ORNs, as confirmed by antibody labeling and in situ hybridization. Ligand-specific ORN responses visualized by calcium imaging are consistent with a restricted expression pattern found for other potential subunits, suggesting that cell-specific expression of uncommon IR subunits determines the ligand sensitivity of individual cells. IRs are the only type of olfactory receptor that we have detected in spiny lobster olfactory tissue, suggesting that they likely mediate olfactory signaling. Given long-standing evidence for G protein-mediated signaling in activation of lobster ORNs, this finding raises the interesting specter that IRs act in concert with second messenger-mediated signaling.

  10. Variant supercurrents and linearized supergravity

    Energy Technology Data Exchange (ETDEWEB)

    Zheng Sibo [Department of Physics, Chongqing University, Chongqing 400030 (China); Huang Jiahui, E-mail: sibozheng.zju@gmail.com [Center of Mathematical Science, Zhejiang University, Hangzhou 310027 (China)

    2011-04-07

    In this paper, the variant supercurrents based on consistency and completion in off-shell N=1 supergravity are studied. We formulate the embedding relations for supersymmetric current and energy tensor into a supercurrent multiplet. Corresponding linearized supergravity is obtained with an appropriate choice of the Wess-Zumino gauge in each gravity supermultiplet.

  11. Variant supercurrents and linearized supergravity

    International Nuclear Information System (INIS)

    In this paper, the variant supercurrents based on consistency and completion in off-shell N=1 supergravity are studied. We formulate the embedding relations for supersymmetric current and energy tensor into a supercurrent multiplet. Corresponding linearized supergravity is obtained with an appropriate choice of the Wess-Zumino gauge in each gravity supermultiplet.

  12. Variant Supercurrents and Linearized Supergravity

    CERN Document Server

    Zheng, Sibo

    2010-01-01

    In this paper the variant supercurrents based on consistency and completion in off-shell $N=1$ supergravity are studied. We formulate the embedding relations for supersymmetric current and energy tensor into supercurrent multiplet. Corresponding linearized supergravity is obtained with appropriate choice of Wess-Zumino gauge in each gravity supermultiplet.

  13. Variant Supercurrents and Linearized Supergravity

    OpenAIRE

    Zheng, Sibo; Huang, Jia-Hui

    2010-01-01

    In this paper the variant supercurrents based on consistency and completion in off-shell N=1 supergravity are studied. We formulate the embedding relations for supersymmetric current and energy tensor into supercurrent multiplet. Corresponding linearized supergravity is obtained with appropriate choice of Wess-Zumino gauge in each gravity supermultiplet.

  14. GCPII Variants, Paralogs and Orthologs

    Czech Academy of Sciences Publication Activity Database

    Hlouchová, Klára; Navrátil, Václav; Tykvart, Jan; Šácha, Pavel; Konvalinka, Jan

    2012-01-01

    Roč. 19, č. 9 (2012), s. 1316-1322. ISSN 0929-8673 R&D Projects: GA ČR GAP304/12/0847 Institutional research plan: CEZ:AV0Z40550506 Keywords : PSMA * GCPIII * NAALADase L * splice variants * homologs * PSMAL Subject RIV: CE - Biochemistry Impact factor: 4.070, year: 2012

  15. A genetic variant near olfactory receptor genes influences cilantro preference

    OpenAIRE

    Eriksson, Nicholas; Wu, Shirley; Do, Chuong B.; Kiefer, Amy K.; Joyce Y Tung; Joanna L Mountain; Hinds, David A; Francke, Uta

    2012-01-01

    The leaves of the Coriandrum sativum plant, known as cilantro or coriander, are widely used in many cuisines around the world. However, far from being a benign culinary herb, cilantro can be polarizing---many people love it while others claim that it tastes or smells foul, often like soap or dirt. This soapy or pungent aroma is largely attributed to several aldehydes present in cilantro. Cilantro preference is suspected to have a genetic component, yet to date nothing is known about specific ...

  16. Glucocorticoid Receptor Variants Modulate the Sensitivity to Cortisol

    NARCIS (Netherlands)

    H. Russcher (Henk)

    2006-01-01

    textabstractSynthetic glucocorticoids are used therapeutically for numerous indications. However, due to their broad physiological effects across many systems, side effects of GC therapy can be extensive and limit the clinical utility of GCs as a drug. One of the main urgent questions at this mo

  17. Identification and characterisation of alternative transcriptional variants of PDGFRL in two lines of commercial poultry.

    Science.gov (United States)

    McDerment, N A; Hocking, P M; Dunn, I C

    2015-10-01

    The platelet-derived growth factor (PDGF) family of genes and their receptors are involved in angiogenesis and steroid hormone production. A putative member of the family, platelet-derived growth factor receptor-like (PDGFRL), has been implicated in steroid-based feedback mechanisms within the chicken reproductive system. Three potential variants of PDGFRL were identified in the chicken, supported by in silico prediction and EST sequencing. The three potential transcripts have been further verified and the 5' terminal regions sequenced in this research. The sum of expression of all three transcripts in broiler breeders (the parents of broiler chickens) has been shown to be consistent with total expression of the gene. However, cumulative expression of the three transcripts in a range of tissues in egg layers was significantly short of total expression, indicating the existence of potential additional variants. Two additional variants were subsequently identified in egg layer cerebellum tissue and the 5' terminal regions sequenced. Sequence analysis of the three initial variants suggests that only one variant, which was the most abundant in broiler breeders and the majority of egg layer tissues, had a functional signal peptide. Although 5' RACE identified two additional transcripts in egg layers, the most likely protein translations indicated that these variants possessed no functional signal peptide, suggesting that, if they have a function, it is not a traditional one. PMID:26202218

  18. Melanocortin 1 receptor genotype: an important determinant of the damage response of melanocytes to ultraviolet radiation

    OpenAIRE

    Kadekaro, Ana Luisa; Leachman, Sancy; Kavanagh, Renny J.; Swope, Viki; Cassidy, Pamela; Supp, Dorothy; Sartor, Maureen; Schwemberger, Sandy; Babcock, George; Wakamatsu, Kazumasa; Ito, Shosuke; Koshoffer, Amy; Boissy, Raymond E.; Manga, Prashiela; Sturm, Richard A.

    2010-01-01

    The melanocortin 1 receptor gene is a main determinant of human pigmentation, and a melanoma susceptibility gene, because its variants that are strongly associated with red hair color increase melanoma risk. To test experimentally the association between melanocortin 1 receptor genotype and melanoma susceptibility, we compared the responses of primary human melanocyte cultures naturally expressing different melanocortin 1 receptor variants to α-melanocortin and ultraviolet radiation. We found...

  19. Variant (Swine Origin) Influenza Viruses in Humans

    Science.gov (United States)

    ... Past Newsletters Variant (Swine Origin) Influenza Viruses in Humans Language: English Español Recommend on Facebook Tweet ... Page Background Reporting Additional Information Key Facts about Human Infections with Variant Viruses (Swine Origin Influenza Viruses ...

  20. Swine Influenza/Variant Influenza Viruses

    Science.gov (United States)

    ... Documents (General) Workers Employed at Commercial Swine Farms Influenza Types Seasonal Avian Swine Variant Pandemic Other Get ... this? Submit Button Past Newsletters Information on Swine Influenza/Variant Influenza Viruses Language: English Español Recommend ...

  1. MTNR1B G24E variant associates With BMI and fasting plasma glucose in the general population in studies of 22,142 Europeans

    DEFF Research Database (Denmark)

    Andersson, Ehm A; Holst, Birgitte; Sparsø, Thomas; Grarup, Niels; Banasik, Karina; Holmkvist, Johan; Jørgensen, Torben; Borch-Johnsen, Knut; Egerod, Kristoffer L; Lauritzen, Torsten; Sørensen, Thorkild I A; Bonnefond, Amélie; Meyre, David; Froguel, Philippe; Schwartz, Thue W; Pedersen, Oluf; Hansen, Torben

    2010-01-01

    OBJECTIVE: Common variants in the melatonin receptor type 1B (MTNR1B) locus have been shown to increase fasting plasma glucose (FPG) and the risk of type 2 diabetes. The aims of this study were to evaluate whether nonsynonymous variants in MTNR1B associate with monogenic forms of hyperglycemia, t...

  2. The Duffy-Binding-Like β domain (DBLβ) of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) variant, PFD1235w, binds ICAM1

    DEFF Research Database (Denmark)

    Andersen, M. A.; Bengtsson, A.; Rask, Thomas Salhøj;

    2012-01-01

    Plasmodium falciparum is by far the most virulent human malaria parasite. P. falciparum variant erythrocyte surface antigens, known as PfEMP1, play a crucial role in malaria pathogenesis as they mediate adhesion to host endothelial receptors. The PfEMP1 variant, PFD1235w, encoded by the 3D7 group...

  3. Evidence that multiple genetic variants of MC4R play a functional role in the regulation of energy expenditure and appetite in Hispanic children

    Science.gov (United States)

    Melanocortin-4-receptor (MC4R) haploinsufficiency is the most common form of monogenic obesity; however, the frequency of MC4R variants and their functional effects in general populations remain uncertain. The aim of this study was to identify and characterize the effects of MC4R variants in Hispani...

  4. Group Selection and Contribution of Minority Variants during Virus Adaptation Determines Virus Fitness and Phenotype.

    Directory of Open Access Journals (Sweden)

    Antonio V Bordería

    2015-05-01

    Full Text Available Understanding how a pathogen colonizes and adapts to a new host environment is a primary aim in studying emerging infectious diseases. Adaptive mutations arise among the thousands of variants generated during RNA virus infection, and identifying these variants will shed light onto how changes in tropism and species jumps can occur. Here, we adapted Coxsackie virus B3 to a highly permissive and less permissive environment. Using deep sequencing and bioinformatics, we identified a multi-step adaptive process to adaptation involving residues in the receptor footprints that correlated with receptor availability and with increase in virus fitness in an environment-specific manner. We show that adaptation occurs by selection of a dominant mutation followed by group selection of minority variants that together, confer the fitness increase observed in the population, rather than selection of a single dominant genotype.

  5. Distinct expression and ligand-binding profiles of two constitutively active GPR17 splice variants

    DEFF Research Database (Denmark)

    Benned-Jensen, Tau; Rosenkilde, M M

    2010-01-01

    In humans and non-human primates, the 7TM receptor GPR17 exists in two isoforms differing only by the length of the N-terminus. Of these, only the short isoform has previously been characterized. Hence, we investigated gene expression and ligand-binding profiles of both splice variants and furthe...

  6. Association of MC4R variants with obesity-related traits in Hispanic children

    Science.gov (United States)

    Melanocortin 4 receptor (MC4R) has been implicated in the regulation of appetite and energy expenditure. In children, MC4R mutations have been associated with severe obesity. The main objective of this study was to investigate the potential functional effects of variants in MC4R gene on the variatio...

  7. Variants of lumbosacral elastic band.

    Directory of Open Access Journals (Sweden)

    Carlos Cesar Santín Alfaro

    2011-06-01

    Full Text Available It is made an intervention research, qualitative and quantitative of two variants of lumbosacral elastic bands used in Provincial Laboratory of Technical Orthopedics in Sancti Spiritus Province, taking into account the high demand for this device and that the laboratory do not often count with the raw material needed for the original lumbosacral belt made by denim cloth which is the conventional belt. The main goal of this research is to explain the technological process and to compare the cost of production of both elastic variants with lumbosacral belt made by cloth which are offer to patients who look for this service , giving them a rapid solution so that they can feel comfortable.

  8. Genetic Load of Loss-of-Function Polymorphic Variants in Great Apes.

    Science.gov (United States)

    de Valles-Ibáñez, Guillem; Hernandez-Rodriguez, Jessica; Prado-Martinez, Javier; Luisi, Pierre; Marquès-Bonet, Tomàs; Casals, Ferran

    2016-03-01

    Loss of function (LoF) genetic variants are predicted to disrupt gene function, and are therefore expected to substantially reduce individual's viability. Knowing the genetic burden of LoF variants in endangered species is of interest for a better understanding of the effects of declining population sizes on species viability. In this study, we have estimated the number of LoF polymorphic variants in six great ape populations, based on whole-genome sequencing data in 79 individuals. Our results show that although the number of functional variants per individual is conditioned by the effective population size, the number of variants with a drastic phenotypic effect is very similar across species. We hypothesize that for those variants with high selection coefficients, differences in effective population size are not important enough to affect the efficiency of natural selection to remove them. We also describe that mostly CpG LoF mutations are shared across species, and an accumulation of LoF variants at olfactory receptor genes in agreement with its pseudogenization in humans and other primate species. PMID:26912403

  9. Unnatural agrochemical ligands for engineered abscisic acid receptors.

    Science.gov (United States)

    Rodriguez, Pedro L; Lozano-Juste, Jorge

    2015-06-01

    Existing agrochemicals can be endowed with new applications through protein engineering of plant receptors. A recent study shows an engineered PYR1 ABA receptor can be activated by mandipropamid. Plants engineered with such PYR1 variant are responsive to this agrochemical, which confers protection against drought through activation of ABA signaling. PMID:25891067

  10. DETERMINATION OF LEVEL EXPRESSION OF mRNA SPLICING VARIANTS FOR DR3 IN BLOOD CELLS IN INFECTIOUS MONONUCLEOSIS

    Directory of Open Access Journals (Sweden)

    V. D. Cvetkova

    2016-01-01

    Full Text Available The DR3 «death receptor» plays an important role in the initiation of apoptosis, proliferation, or inflammation. This receptor is shown to be involved in various diseases, including infectious conditions. Different variants of mRNA DR3 are formed as a result of alternative splicing. These variant transcripts encode membrane and soluble forms of the receptor which have different functions. Features of their expression and contribution of individual DR3 variants to the immune pathogenesis of infectious mononucleosis (IM are poorely understood.The purpose of this work was to develop, validate and test the techniques of DR3 gene expression assays, as well as to evaluate the DR3 mRNA splice variants by means of real-time RT-PCR and RT-PCR in the IM patients.The original version of real-time RT-PCR allowed to determine relative amounts of DR3 mRNA, DR3 membrane variants (LARD1a + LARD8, and ratios of mRNAs encoding membrane and soluble forms of the receptor. The technique proved to be specific and sensitive (a semi-quantitative detection limit = 34-35 cycles when tested in healthy volunteers and patients with acute infectious mononucleosis (AIM. Lower expression levels were shown for two alternative membrane variants of DR3 mRNA (LARD1b and DR3beta thus regarding these isoforms as minor fractions. The relative levels of total DR3 mRNA expression were decreased in patients with AIM, as compared to healthy volunteers, whereas mRNA expression of membrane receptor variants did not differ between IM and controls.To determine a qualitative contribution of either LARD1a and LARD8 variants into the expression of membrane forms of DR3, a two-step «nested» version of RT-PCR has been developed. It was shown that, in majority of control and IM samples, both main LARD1a, and alternative LARD8 membrane forms are contributing to mRNA expression of membrane DR3 variants.The presented methods for evaluation of expression and occurrence of DR3 mRNA variants allow

  11. Targeted deep resequencing identifies coding variants in the PEAR1 gene that play a role in platelet aggregation.

    Directory of Open Access Journals (Sweden)

    Yoonhee Kim

    Full Text Available Platelet aggregation is heritable, and genome-wide association studies have detected strong associations with a common intronic variant of the platelet endothelial aggregation receptor1 (PEAR1 gene both in African American and European American individuals. In this study, we used a sequencing approach to identify additional exonic variants in PEAR1 that may also determine variability in platelet aggregation in the GeneSTAR Study. A 0.3 Mb targeted region on chromosome 1q23.1 including the entire PEAR1 gene was Sanger sequenced in 104 subjects (45% male, 49% African American, age = 52±13 selected on the basis of hyper- and hypo- aggregation across three different agonists (collagen, epinephrine, and adenosine diphosphate. Single-variant and multi-variant burden tests for association were performed. Of the 235 variants identified through sequencing, 61 were novel, and three of these were missense variants. More rare variants (MAF<5% were noted in African Americans compared to European Americans (108 vs. 45. The common intronic GWAS-identified variant (rs12041331 demonstrated the most significant association signal in African Americans (p = 4.020×10(-4; no association was seen for additional exonic variants in this group. In contrast, multi-variant burden tests indicated that exonic variants play a more significant role in European Americans (p = 0.0099 for the collective coding variants compared to p = 0.0565 for intronic variant rs12041331. Imputation of the individual exonic variants in the rest of the GeneSTAR European American cohort (N = 1,965 supports the results noted in the sequenced discovery sample: p = 3.56×10(-4, 2.27×10(-7, 5.20×10(-5 for coding synonymous variant rs56260937 and collagen, epinephrine and adenosine diphosphate induced platelet aggregation, respectively. Sequencing approaches confirm that a common intronic variant has the strongest association with platelet aggregation in African Americans

  12. Common variants near MC4R in relation to body fat, body fat distribution, metabolic traits and energy expenditure

    DEFF Research Database (Denmark)

    Kring, Sofia Inez Iqbal; Holst, C; Toubro, Søren;

    2010-01-01

    Common variants near melanocortin receptor 4 (MC4R) have been related to fatness and type 2 diabetes. We examined the associations of rs17782313 and rs17700633 in relation to body fat, body fat distribution, metabolic traits, weight development and energy expenditure.......Common variants near melanocortin receptor 4 (MC4R) have been related to fatness and type 2 diabetes. We examined the associations of rs17782313 and rs17700633 in relation to body fat, body fat distribution, metabolic traits, weight development and energy expenditure....

  13. Jupiter und Venus über dem AKH Wien

    OpenAIRE

    Posch, Thomas

    2009-01-01

    Konjunktion (enge Begegnung) der Planeten Jupiter und Venus am Morgen des 1. 2. 2008. Aufgenommen mit einem 85mm-Teleobjektiv in Verbindung mit Canon 20D, Blendenstufe f/4, 1/4 Sekunde belichtet. Aufnahmeort: Wien-Währing.

  14. CT skull base & calvarium normal variant pitfalls

    OpenAIRE

    Lockwood, P

    2013-01-01

    Intended learning outcomes - To recognise the varied neurological appearances of skull based normal variants with the brain. Highlighting the importance of differentiation of normal and variant anatomy from the pitfalls of misdiagnosing a pathological condition Content of Presentation -Pictorial review of 12 common examples of neuroradiological normal variant conditions of skull base and calvarium anatomical areas of the brain, including sutures, asymmetry of bones, benign growths, thicken...

  15. Association of Gamma-Aminobutyric Acid A Receptor α2 Gene (GABRA2) with Alcohol Use Disorder

    OpenAIRE

    Li, Dawei.; Sulovari, Arvis; Cheng, Chao; Zhao, Hongyu; Henry R Kranzler; Gelernter, Joel

    2013-01-01

    Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in mammalian brain. GABA receptor are involved in a number of complex disorders, including substance abuse. No variants of the commonly studied GABA receptor genes that have been associated with substance dependence have been determined to be functional or pathogenic. To reconcile the conflicting associations with substance dependence traits, we performed a meta-analysis of variants in the GABAA receptor genes (GABRB2, GABR...

  16. A rare coding variant in TREM2 increases risk for Alzheimer's disease in Han Chinese.

    Science.gov (United States)

    Jiang, Teng; Tan, Lan; Chen, Qi; Tan, Meng-Shan; Zhou, Jun-Shan; Zhu, Xi-Chen; Lu, Huan; Wang, Hui-Fu; Zhang, Ying-Dong; Yu, Jin-Tai

    2016-06-01

    Two recent studies have identified that a rare coding variant (p.R47H) in exon 2 of triggering receptor expressed on myeloid cells 2 (TREM2) gene is associated with Alzheimer's disease (AD) susceptibility in Caucasians. This association was not successfully replicated in Han Chinese, where this variant was rare or even absent. Previously, we resequenced TREM2 exon 2 to investigate whether additional rare variants conferred risk to AD in our cohort. Although several new variants had been identified, none of them was significantly associated with disease susceptibility. Here, to test whether TREM2 is truly a susceptibility gene of AD in Han Chinese, we extend our previous study by sequencing the other four exons of TREM2 in 988 AD patients and 1,354 healthy controls. We provided the first evidence that a rare coding variant (p.H157Y) in TREM2 exon 3 conferred a considerable risk of AD in our cohort (Pcorrected = 0.02, odds ratio = 11.01, 95% confidence interval: 1.38-88.05). This finding indicates that rare coding variants of TREM2 may play an important role in AD in Han Chinese. PMID:27067662

  17. A Splice Region Variant in LDLR Lowers Non-high Density Lipoprotein Cholesterol and Protects against Coronary Artery Disease.

    Directory of Open Access Journals (Sweden)

    Solveig Gretarsdottir

    2015-09-01

    Full Text Available Through high coverage whole-genome sequencing and imputation of the identified variants into a large fraction of the Icelandic population, we found four independent signals in the low density lipoprotein receptor gene (LDLR that associate with levels of non-high density lipoprotein cholesterol (non-HDL-C and coronary artery disease (CAD. Two signals are novel with respect to association with non-HDL-C and are represented by non-coding low frequency variants (between 2-4% frequency, the splice region variant rs72658867-A in intron 14 and rs17248748-T in intron one. These two novel associations were replicated in three additional populations. Both variants lower non-HDL-C levels (rs72658867-A, non-HDL-C effect = -0.44 mmol/l, Padj = 1.1 × 10⁻⁸⁰ and rs17248748-T, non-HDL-C effect = -0.13 mmol/l, Padj = 1.3 × 10⁻¹² and confer protection against CAD (rs72658867-A, OR = 0.76 and Padj = 2.7 × 10⁻⁸ and rs17248748-T, OR = 0.92 and Padj = 0.022. The LDLR splice region variant, rs72658867-A, located at position +5 in intron 14 (NM_000527:c.2140+5G>A, causes retention of intron 14 during transcription and is expected to produce a truncated LDL receptor lacking domains essential for function of the receptor. About half of the transcripts generated from chromosomes carrying rs72658867-A are characterized by this retention of the intron. The same variant also increases LDLR mRNA expression, however, the wild type transcripts do not exceed levels in non-carriers. This demonstrates that sequence variants that disrupt the LDL receptor can lower non-HDL-C and protect against CAD.

  18. Identification and bioactivity evaluation of the first neuropeptide from the lesser-known insect order Embioptera (webspinner).

    Science.gov (United States)

    Gäde, Gerd; Šimek, Petr; Marco, Heather G

    2016-07-01

    A species of the poorly studied order Embioptera, the webspinner Oligotoma saundersii, is investigated for its complement of neuropeptides of the adipokinetic hormone (AKH) family. A methanolic extract of its corpora cardiaca (CC) is able to effect carbohydrate mobilization in the cockroach, Periplaneta americana, and liquid chromatography coupled to electrospray ionization mass spectrometry clearly identified one decapeptide as a member of the AKH family in the CC of O. saundersii. The primary structure of this peptide, code-named Olisa-AKH, is elucidated as pEVNFSPNWGG amide. It is a novel member of the AKH family and in its synthetic form it has strong hypertrehalosemic activity in the American cockroach. This effect may be explained by its near-identical structure compared with one of the endogenous cockroach AKH peptides. An analog with the reversed order of the proline and asparagine residues, viz. N(6)P(7)-Olisa-AKH, had negligible activity thus, shedding light on the requirements of the cockroach AKH receptor. From reversed-phase high-performance liquid chromatography experiments, we can conclude that the CC from an individual webspinner contains less than one pmol of Olisa-AKH. Comparison of the AKH sequences from the major orders of the Polyneoptera does not point to a close phylogenetic relationship between webspinners and stick insects. PMID:27074720

  19. Mitochondrial DNA variants in obesity.

    Directory of Open Access Journals (Sweden)

    Nadja Knoll

    Full Text Available Heritability estimates for body mass index (BMI variation are high. For mothers and their offspring higher BMI correlations have been described than for fathers. Variation(s in the exclusively maternally inherited mitochondrial DNA (mtDNA might contribute to this parental effect. Thirty-two to 40 mtDNA single nucleotide polymorphisms (SNPs were available from genome-wide association study SNP arrays (Affymetrix 6.0. For discovery, we analyzed association in a case-control (CC sample of 1,158 extremely obese children and adolescents and 435 lean adult controls. For independent confirmation, 7,014 population-based adults were analyzed as CC sample of n = 1,697 obese cases (BMI ≥ 30 kg/m2 and n = 2,373 normal weight and lean controls (BMI<25 kg/m2. SNPs were analyzed as single SNPs and haplogroups determined by HaploGrep. Fisher's two-sided exact test was used for association testing. Moreover, the D-loop was re-sequenced (Sanger in 192 extremely obese children and adolescents and 192 lean adult controls. Association testing of detected variants was performed using Fisher's two-sided exact test. For discovery, nominal association with obesity was found for the frequent allele G of m.8994G/A (rs28358887, p = 0.002 located in ATP6. Haplogroup W was nominally overrepresented in the controls (p = 0.039. These findings could not be confirmed independently. For two of the 252 identified D-loop variants nominal association was detected (m.16292C/T, p = 0.007, m.16189T/C, p = 0.048. Only eight controls carried the m.16292T allele, five of whom belonged to haplogroup W that was initially enriched among these controls. m.16189T/C might create an uninterrupted poly-C tract located near a regulatory element involved in replication of mtDNA. Though follow-up of some D-loop variants still is conceivable, our hypothesis of a contribution of variation in the exclusively maternally inherited mtDNA to the observed larger correlations for BMI between mothers and

  20. Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression.

    Science.gov (United States)

    Fairfax, Benjamin P; Humburg, Peter; Makino, Seiko; Naranbhai, Vivek; Wong, Daniel; Lau, Evelyn; Jostins, Luke; Plant, Katharine; Andrews, Robert; McGee, Chris; Knight, Julian C

    2014-03-01

    To systematically investigate the impact of immune stimulation upon regulatory variant activity, we exposed primary monocytes from 432 healthy Europeans to interferon-γ (IFN-γ) or differing durations of lipopolysaccharide and mapped expression quantitative trait loci (eQTLs). More than half of cis-eQTLs identified, involving hundreds of genes and associated pathways, are detected specifically in stimulated monocytes. Induced innate immune activity reveals multiple master regulatory trans-eQTLs including the major histocompatibility complex (MHC), coding variants altering enzyme and receptor function, an IFN-β cytokine network showing temporal specificity, and an interferon regulatory factor 2 (IRF2) transcription factor-modulated network. Induced eQTL are significantly enriched for genome-wide association study loci, identifying context-specific associations to putative causal genes including CARD9, ATM, and IRF8. Thus, applying pathophysiologically relevant immune stimuli assists resolution of functional genetic variants. PMID:24604202

  1. Local binary patterns new variants and applications

    CERN Document Server

    Jain, Lakhmi; Nanni, Loris; Lumini, Alessandra

    2014-01-01

    This book introduces Local Binary Patterns (LBP), arguably one of the most powerful texture descriptors, and LBP variants. This volume provides the latest reviews of the literature and a presentation of some of the best LBP variants by researchers at the forefront of textual analysis research and research on LBP descriptors and variants. The value of LBP variants is illustrated with reported experiments using many databases representing a diversity of computer vision applications in medicine, biometrics, and other areas. There is also a chapter that provides an excellent theoretical foundation for texture analysis and LBP in particular. A special section focuses on LBP and LBP variants in the area of face recognition, including thermal face recognition. This book will be of value to anyone already in the field as well as to those interested in learning more about this powerful family of texture descriptors.

  2. Relationship between IRS-2G1057D variant and type 2 diabetes mellitus in Han population in Liaoning Province, China

    Institute of Scientific and Technical Information of China (English)

    KONG Ling-fang; QIAN Cong; ZHENG Xiao-min; HOU Yong-sheng; LI Qiang; LIU Guo-liang

    2005-01-01

    @@ The two major pathogeneses of type 2 diabetes mellitus (T2DM) are insulin resistance and insulin secretion deficiency. During recent years, researches on the molecular target sites of insulin resistance and the mechanism of the signal transduction has made great progress: especially, the study of insulin receptor substrate-2 (IRS-2). Human IRS-2 gene is located at 13q8.6. IRS-2G1057D is a replacement of G (glycine) by D (aspartic acid) at site 1057 of insulin receptor substrate-2, which is caused by simple nucleotide polymorphism. The role of this variant is still not clear. We detected IRS-2G1057D variant in Han population in Liaoning Province by measuring body mass index (BMI), waistline/hip ratio (WHR) and other parameters of insulin secretion, as well as insulin action to explore the relationship between IRS-2G1057D variant and T2DM.

  3. A Splice Region Variant in LDLR Lowers Non-high Density Lipoprotein Cholesterol and Protects against Coronary Artery Disease

    NARCIS (Netherlands)

    Gretarsdottir, S.; Helgason, H.; Helgadottir, A.; Sigurdsson, A.; Thorleifsson, G.; Magnusdottir, A.; Oddsson, A.; Steinthorsdottir, V.; Rafnar, T.; Graaf, J. de; Daneshpour, M.S.; Hedayati, M.; Azizi, F.; Grarup, N.; Jorgensen, T.; Vestergaard, H.; Hansen, T.; Eyjolfsson, G.; Sigurdardottir, O.; Olafsson, I.; Kiemeney, B.; Pedersen, O.; Sulem, P.; Thorgeirsson, G.; Gudbjartsson, D.F.; Holm, H.; Thorsteinsdottir, U.; Stefansson, K.

    2015-01-01

    Through high coverage whole-genome sequencing and imputation of the identified variants into a large fraction of the Icelandic population, we found four independent signals in the low density lipoprotein receptor gene (LDLR) that associate with levels of non-high density lipoprotein cholesterol (non

  4. A Splice Region Variant in LDLR Lowers Non-high Density Lipoprotein Cholesterol and Protects against Coronary Artery Disease

    DEFF Research Database (Denmark)

    Gretarsdottir, Solveig; Helgason, Hannes; Helgadottir, Anna;

    2015-01-01

    .7 × 10⁻⁸ and rs17248748-T, OR = 0.92 and Padj = 0.022). The LDLR splice region variant, rs72658867-A, located at position +5 in intron 14 (NM_000527:c.2140+5G>A), causes retention of intron 14 during transcription and is expected to produce a truncated LDL receptor lacking domains essential for function...

  5. Expression of Human CAR Splicing Variants in BAC-Transgenic Mice

    OpenAIRE

    Zhang, Yu-Kun Jennifer; LU, Hong; Klaassen, Curtis D.

    2012-01-01

    The nuclear receptor constitutive androstane receptor (CAR) is a key regulator for drug metabolism in liver. Human CAR (hCAR) transcripts are subjected to alternative splicing. Some hCAR splicing variants (SVs) have been shown to encode functional proteins by reporter assays. However, in vivo research on the activity of these hCAR SVs has been impeded by the absence of a valid model. This study engineered an hCAR-BAC-transgenic (hCAR-TG) mouse model by integrating the 8.5-kbp hCAR gene as wel...

  6. Comparison of atopic cough with cough variant asthma: is atopic cough a precursor of asthma?

    OpenAIRE

    Fujimura, M; Ogawa, H; Nishizawa, Y; Nishi, K

    2003-01-01

    Background: We have described a group of patients who present with isolated chronic bronchodilator resistant non-productive cough with an atopic constitution, eosinophilic tracheobronchitis, and airway cough receptor hypersensitivity without bronchial hyperresponsiveness, which we have termed "atopic cough". Although cough variant asthma (in which the cough responds to bronchodilators) is recognised as a precursor of typical asthma, it is not known whether atopic cough is also a precursor of ...

  7. A variant in ANKK1 modulates acute subjective effects of cocaine: a preliminary study

    OpenAIRE

    Spellicy, Catherine J.; Harding, Mark J.; Hamon, Sara C.; Mahoney, James J.; Reyes, Jennifer A; Thomas R. Kosten; Newton, Thomas F.; De La Garza, Richard; Nielsen, David A.

    2014-01-01

    This study aimed to evaluate whether functional variants in the ankyrin repeat and kinase domain-containing 1 gene (ANKK1) and/or the dopamine receptor D2 gene (DRD2) modulate the subjective effects (reward or non-reward response to a stimulus) produced by cocaine administration. Cocaine-dependent participants (N = 47) were administered 40 mg of cocaine or placebo at time 0, and a subjective effects questionnaire (visual analog scale) was administered 15 minutes prior to cocaine administratio...

  8. Genetic variants in adult liver diseases.

    Science.gov (United States)

    Dröge, C; Häussinger, D; Keitel, V

    2015-12-01

    In the last decades, understanding of genetic variants contributing to liver disease development has considerably improved through novel genotyping techniques. Genetic variants of single genes are known to be decisive for the development of monogenetic liver diseases of varying severity. Identification of genetic variants is an important part of the diagnostic process, e. g. the majority of patients with high iron [Fe] (HFE)-associated hemochromatosis carry the homozygous mutation p.C282Y. Detection of mutations in genes encoding hepatobiliary transport proteins like familial intrahepatic cholestasis 1 (FIC1), bile salt export pump (BSEP), or multidrug resistance protein 3 (MDR3) is the basis to differentiate various forms of intrahepatic cholestasis. Moreover, genetic variants in a variety of genes are known to act as disease modifiers and represent risk factors for disease progression and the development of cirrhosis or even hepatocellular carcinoma. Success of drug treatment or appearance of severe side effects can also be influenced by specific genetic variants. All these aspects underscore the increasing importance of genetic variants, which in the future may help to identify patients at risk for disease progression or help to guide treatment decisions. In the present overview, specific frequent genetic variants are summarized that play roles in monogenetic liver diseases, forms of intrahepatic cholestasis, gallstone development, fatty liver disease, drug-induced liver injury, and liver disease progression as well as hepatocellular carcinoma development. PMID:26666282

  9. Different Variants of Fundamental Portfolio

    Directory of Open Access Journals (Sweden)

    Tarczyński Waldemar

    2014-06-01

    Full Text Available The paper proposes the fundamental portfolio of securities. This portfolio is an alternative for the classic Markowitz model, which combines fundamental analysis with portfolio analysis. The method’s main idea is based on the use of the TMAI1 synthetic measure and, in limiting conditions, the use of risk and the portfolio’s rate of return in the objective function. Different variants of fundamental portfolio have been considered under an empirical study. The effectiveness of the proposed solutions has been related to the classic portfolio constructed with the help of the Markowitz model and the WIG20 market index’s rate of return. All portfolios were constructed with data on rates of return for 2005. Their effectiveness in 2006- 2013 was then evaluated. The studied period comprises the end of the bull market, the 2007-2009 crisis, the 2010 bull market and the 2011 crisis. This allows for the evaluation of the solutions’ flexibility in various extreme situations. For the construction of the fundamental portfolio’s objective function and the TMAI, the study made use of financial and economic data on selected indicators retrieved from Notoria Serwis for 2005.

  10. [Takotsubo cardiomyopathy: origin and variants].

    Science.gov (United States)

    Aronov, D M

    2008-01-01

    This literature review is devoted to the " tako-tsubo " cardiomyopathy - rare type of cardiomyopathy characterized by transient myocardial stunning. In acute phase the disease resembles myocardial infarction. However no involvement of coronary arteries is found at angiography. Echocardiography and ventriculography reveal a- or - hypokinesia of various parts of the left ventricle. Classic (initial) variant of the disease is associated with concomitant apical akinesia and hyperkinesis of basal segments. The heart acquires a distinctive configuration with ballooning apex which resembles device used to trap octopus. The author refers to described by him 11 cases of myocardial damage with infarct-like clinic without changes of coronary arteries in healthy men younger than 35 years (D.M.Aronow, 1968, 1974). These cases occurred during severe physical stress and had in their basis hypercatecholaminemia which led to reversible myocardial damage of the myocardium which corresponded to modern concept of myocardial stunning. During exercise tests these patients had 3 times greater increase of urinal epinephrine excretion compared with 61 patients of the same age with atherosclerotic heart disease. PMID:18991836

  11. Alternative splice variants of the human PD-1 gene

    DEFF Research Database (Denmark)

    Nielsen, Christian; Ohm-Laursen, Line; Barington, Torben;

    2005-01-01

    PD-1 is an immunoregulatory receptor expressed on the surface of activated T cells, B cells, and monocytes. We describe four alternatively spliced PD-1 mRNA transcripts (PD-1Deltaex2, PD-1Deltaex3, PD-1Deltaex2,3, and PD-1Deltaex2,3,4) in addition to the full length isoform. PD-1Deltaex2 and PD-1......Deltaex3 are generated by alternative splicing where exon 2 (extracellular IgV-like domain) and exon 3 (transmembrane domain) respectively are spliced out. PD-1Deltaex3 is therefore likely to encode a soluble form of PD-1. PD-1Deltaex2,3 lacks exon 2 and 3. These three variants have unaffected open...

  12. Development of a Quantitative PCR Assay for Detection of Human Insulin-Like Growth Factor Receptor and Insulin Receptor Isoforms.

    Science.gov (United States)

    Flannery, Clare A; Rowzee, Anne M; Choe, Gina H; Saleh, Farrah L; Radford, Caitlin C; Taylor, Hugh S; Wood, Teresa L

    2016-04-01

    The biological activity of insulin and the insulin-like growth factor (IGF) ligands, IGF-I and IGF-II, is based in part on the relative abundance and distribution of their target receptors: the insulin receptor (IR) splice variants A (IR-A) and B (IR-B) and IGF 1 receptor (IGF-1R). However, the relative quantity of all three receptors in human tissues has never been measured together on the same scale. Due to the high homology between insulin receptor (IR)-A and IR-B proteins and lack of antibodies that discern the two IR splice variants, their mRNA sequence is the most reliable means of distinguishing between the receptors. Hence, highly specific primers for IR-A, IR-B, and IGF-1R mRNA were designed to accurately detect all three receptors by quantitative RT-PCR and enable direct quantification of relative receptor expression levels. A standard concentration curve of cDNA from each receptor was performed. Assay specificity was tested using competition assays and postamplification analysis by gel electrophoresis and cloning. Forward and reverse primer concentrations were optimized to ensure equal efficiencies across primer pairs. This assay enables a specific molecular signature of IGF/insulin signaling receptors to be assayed in different tissues, cell types, or cancers. PMID:26862994

  13. Variante N-621 Potes y Ojedo

    OpenAIRE

    Larrea Gómez, Aitor

    2015-01-01

    RESUMEN: El proyecto que se presenta es una variante de carretera nacional realizada en la Comarca de Liébana, dando servicio a las localidades de Potes y Ojedo y al tráfico circulante entre León y Cantabria a través de la N-621. Se realiza entre los P.K. 147 y 150 enlazándose a esta mediante dos glorietas de dos carriles. El objetivo primordial de esta variante es evitar que el tráfico mencionado circule a través de estas poblaciones y, por tanto, reducir su peligrosidad. La variante pro...

  14. Characterization of form variants of Xenorhabdus luminescens.

    OpenAIRE

    Gerritsen, L.J.M.; Raay, van, C.; Smits, P H

    1992-01-01

    From Xenorhabdus luminescens XE-87.3 four variants were isolated. One, which produced a red pigment and antibiotics, was luminescent, and could take up dye from culture media, was considered the primary form (XE-red). A pink-pigmented variant (XE-pink) differed from the primary form only in pigmentation and uptake of dye. Of the two other variants, one produced a yellow pigment and fewer antibiotics (XE-yellow), while the other did not produce a pigment or antibiotics (XE-white). Both were le...

  15. Vcfanno: fast, flexible annotation of genetic variants.

    Science.gov (United States)

    Pedersen, Brent S; Layer, Ryan M; Quinlan, Aaron R

    2016-01-01

    The integration of genome annotations is critical to the identification of genetic variants that are relevant to studies of disease or other traits. However, comprehensive variant annotation with diverse file formats is difficult with existing methods. Here we describe vcfanno, which flexibly extracts and summarizes attributes from multiple annotation files and integrates the annotations within the INFO column of the original VCF file. By leveraging a parallel "chromosome sweeping" algorithm, we demonstrate substantial performance gains by annotating ~85,000 variants per second with 50 attributes from 17 commonly used genome annotation resources. Vcfanno is available at https://github.com/brentp/vcfanno under the MIT license. PMID:27250555

  16. Renin-Angiotensin System Gene Variants and Type 2 Diabetes Mellitus: Influence of Angiotensinogen

    Directory of Open Access Journals (Sweden)

    Siew Mei Joyce-Tan

    2016-01-01

    Full Text Available Genome-wide association studies (GWAS have been successfully used to call for variants associated with diseases including type 2 diabetes mellitus (T2DM. However, some variants are not included in the GWAS to avoid penalty in multiple hypothetic testing. Thus, candidate gene approach is still useful even at GWAS era. This study attempted to assess whether genetic variations in the renin-angiotensin system (RAS and their gene interactions are associated with T2DM risk. We genotyped 290 T2DM patients and 267 controls using three genes of the RAS, namely, angiotensin converting enzyme (ACE, angiotensinogen (AGT, and angiotensin II type 1 receptor (AGTR1. There were significant differences in allele frequencies between cases and controls for AGT variants (P=0.05 but not for ACE and AGTR1. Haplotype TCG of the AGT was associated with increased risk of T2DM (OR 1.92, 95% CI 1.15–3.20, permuted P=0.012; however, no evidence of significant gene-gene interactions was seen. Nonetheless, our analysis revealed that the associations of the AGT variants with T2DM were independently associated. Thus, this study suggests that genetic variants of the RAS can modestly influence the T2DM risk.

  17. Renin-Angiotensin System Gene Variants and Type 2 Diabetes Mellitus: Influence of Angiotensinogen.

    Science.gov (United States)

    Joyce-Tan, Siew Mei; Zain, Shamsul Mohd; Abdul Sattar, Munavvar Zubaid; Abdullah, Nor Azizan

    2016-01-01

    Genome-wide association studies (GWAS) have been successfully used to call for variants associated with diseases including type 2 diabetes mellitus (T2DM). However, some variants are not included in the GWAS to avoid penalty in multiple hypothetic testing. Thus, candidate gene approach is still useful even at GWAS era. This study attempted to assess whether genetic variations in the renin-angiotensin system (RAS) and their gene interactions are associated with T2DM risk. We genotyped 290 T2DM patients and 267 controls using three genes of the RAS, namely, angiotensin converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II type 1 receptor (AGTR1). There were significant differences in allele frequencies between cases and controls for AGT variants (P = 0.05) but not for ACE and AGTR1. Haplotype TCG of the AGT was associated with increased risk of T2DM (OR 1.92, 95% CI 1.15-3.20, permuted P = 0.012); however, no evidence of significant gene-gene interactions was seen. Nonetheless, our analysis revealed that the associations of the AGT variants with T2DM were independently associated. Thus, this study suggests that genetic variants of the RAS can modestly influence the T2DM risk. PMID:26682227

  18. Annotating Cancer Variants and Anti-Cancer Therapeutics in Reactome

    International Nuclear Information System (INIS)

    Reactome describes biological pathways as chemical reactions that closely mirror the actual physical interactions that occur in the cell. Recent extensions of our data model accommodate the annotation of cancer and other disease processes. First, we have extended our class of protein modifications to accommodate annotation of changes in amino acid sequence and the formation of fusion proteins to describe the proteins involved in disease processes. Second, we have added a disease attribute to reaction, pathway, and physical entity classes that uses disease ontology terms. To support the graphical representation of “cancer” pathways, we have adapted our Pathway Browser to display disease variants and events in a way that allows comparison with the wild type pathway, and shows connections between perturbations in cancer and other biological pathways. The curation of pathways associated with cancer, coupled with our efforts to create other disease-specific pathways, will interoperate with our existing pathway and network analysis tools. Using the Epidermal Growth Factor Receptor (EGFR) signaling pathway as an example, we show how Reactome annotates and presents the altered biological behavior of EGFR variants due to their altered kinase and ligand-binding properties, and the mode of action and specificity of anti-cancer therapeutics

  19. A GABBR2 gene variant modifies pathophysiology in Huntington's disease.

    Science.gov (United States)

    Philpott, April L; Fitzgerald, Paul B; Bailey, Neil W; Churchyard, Andrew; Georgiou-Karistianis, Nellie; Cummins, Tarrant D R

    2016-05-01

    Striatal degeneration in Huntington's disease (HD) causes changes in cortico-subcortical pathways. Transcranial magnetic stimulation (TMS) is a valuable tool for assessing pathophysiology within these pathways, yet has had limited application in HD. As cortico-subcortical pathways are largely mediated by GABA and dopamine receptor genes, understanding how these genes modulate neurophysiology in HD may provide new insights into how underlying pathology maps onto clinical phenotype. Twenty-nine participants with HD underwent motor cortex stimulation, while corticospinal excitability, cortical inhibition and intracortical facilitation were indexed via peripheral electromyography. Single-nucleotide polymorphism mapping was performed across six genes that are known to modulate cortico-subcortical pathways (GABRA2, GABBR1, GABBR2, DRD1, DRD2, DRD4). Genetic associations with six TMS measures and age at onset were investigated. Our hierarchical multiple regression analysis, controlling for CAG and age, revealed that a GABBR2 variant, predicted to be disease-causative, was significantly associated with corticospinal excitability at corrected levels. A subsequent uncorrected exploratory analysis revealed associations between GABBR2, GABRA2 and DRD2 variants with TMS measures of corticospinal excitability and cortical inhibition in HD, as well as with age at onset. Our findings support the notion that uncovering genetic associations with pathophysiological measures and age at onset is an important way forward in terms of generating meaningful biomarkers with diagnostic and prognostic sensitivity, and identifying novel human-validated targets for future clinical trials. PMID:27033668

  20. AMPA receptor pHluorin-GluA2 reports NMDA receptor-induced intracellular acidification in hippocampal neurons

    DEFF Research Database (Denmark)

    Rathje, Mette; Fang, Huaqiang; Bachman, Julia L;

    2013-01-01

    NMDA receptor activation promotes endocytosis of AMPA receptors, which is an important mechanism underlying long-term synaptic depression. The pH-sensitive GFP variant pHluorin fused to the N terminus of GluA2 (pH-GluA2) has been used to assay NMDA-mediated AMPA receptor endocytosis and recycling...... fluorescence recovery was eliminated in the presence of the NHE1 inhibitor zoniporide. Our results indicate that the pH-GluA2 recycling assay is an unreliable assay for studying AMPA receptor trafficking and also suggest a role for PICK1 in regulating intracellular pH via modulation of NHE activity....

  1. Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

    Science.gov (United States)

    Dunning, Alison M; Michailidou, Kyriaki; Kuchenbaecker, Karoline B; Thompson, Deborah; French, Juliet D; Beesley, Jonathan; Healey, Catherine S; Kar, Siddhartha; Pooley, Karen A; Lopez-Knowles, Elena; Dicks, Ed; Barrowdale, Daniel; Sinnott-Armstrong, Nicholas A; Sallari, Richard C; Hillman, Kristine M; Kaufmann, Susanne; Sivakumaran, Haran; Moradi Marjaneh, Mahdi; Lee, Jason S; Hills, Margaret; Jarosz, Monika; Drury, Suzie; Canisius, Sander; Bolla, Manjeet K; Dennis, Joe; Wang, Qin; Hopper, John L; Southey, Melissa C; Broeks, Annegien; Schmidt, Marjanka K; Lophatananon, Artitaya; Muir, Kenneth; Beckmann, Matthias W; Fasching, Peter A; Dos-Santos-Silva, Isabel; Peto, Julian; Sawyer, Elinor J; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E; Flyger, Henrik; González-Neira, Anna; Perez, Jose I A; Anton-Culver, Hoda; Eunjung, Lee; Arndt, Volker; Brenner, Hermann; Meindl, Alfons; Schmutzler, Rita K; Brauch, Hiltrud; Hamann, Ute; Aittomäki, Kristiina; Blomqvist, Carl; Ito, Hidemi; Matsuo, Keitaro; Bogdanova, Natasha; Dörk, Thilo; Lindblom, Annika; Margolin, Sara; Kosma, Veli-Matti; Mannermaa, Arto; Tseng, Chiu-Chen; Wu, Anna H; Lambrechts, Diether; Wildiers, Hans; Chang-Claude, Jenny; Rudolph, Anja; Peterlongo, Paolo; Radice, Paolo; Olson, Janet E; Giles, Graham G; Milne, Roger L; Haiman, Christopher A; Henderson, Brian E; Goldberg, Mark S; Teo, Soo H; Yip, Cheng Har; Nord, Silje; Borresen-Dale, Anne-Lise; Kristensen, Vessela; Long, Jirong; Zheng, Wei; Pylkäs, Katri; Winqvist, Robert; Andrulis, Irene L; Knight, Julia A; Devilee, Peter; Seynaeve, Caroline; Figueroa, Jonine; Sherman, Mark E; Czene, Kamila; Darabi, Hatef; Hollestelle, Antoinette; van den Ouweland, Ans M W; Humphreys, Keith; Gao, Yu-Tang; Shu, Xiao-Ou; Cox, Angela; Cross, Simon S; Blot, William; Cai, Qiuyin; Ghoussaini, Maya; Perkins, Barbara J; Shah, Mitul; Choi, Ji-Yeob; Kang, Daehee; Lee, Soo Chin; Hartman, Mikael; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Brennan, Paul; Sangrajrang, Suleeporn; Ambrosone, Christine B; Toland, Amanda E; Shen, Chen-Yang; Wu, Pei-Ei; Orr, Nick; Swerdlow, Anthony; McGuffog, Lesley; Healey, Sue; Lee, Andrew; Kapuscinski, Miroslav; John, Esther M; Terry, Mary Beth; Daly, Mary B; Goldgar, David E; Buys, Saundra S; Janavicius, Ramunas; Tihomirova, Laima; Tung, Nadine; Dorfling, Cecilia M; van Rensburg, Elizabeth J; Neuhausen, Susan L; Ejlertsen, Bent; Hansen, Thomas V O; Osorio, Ana; Benitez, Javier; Rando, Rachel; Weitzel, Jeffrey N; Bonanni, Bernardo; Peissel, Bernard; Manoukian, Siranoush; Papi, Laura; Ottini, Laura; Konstantopoulou, Irene; Apostolou, Paraskevi; Garber, Judy; Rashid, Muhammad Usman; Frost, Debra; Izatt, Louise; Ellis, Steve; Godwin, Andrew K; Arnold, Norbert; Niederacher, Dieter; Rhiem, Kerstin; Bogdanova-Markov, Nadja; Sagne, Charlotte; Stoppa-Lyonnet, Dominique; Damiola, Francesca; Sinilnikova, Olga M; Mazoyer, Sylvie; Isaacs, Claudine; Claes, Kathleen B M; De Leeneer, Kim; de la Hoya, Miguel; Caldes, Trinidad; Nevanlinna, Heli; Khan, Sofia; Mensenkamp, Arjen R; Hooning, Maartje J; Rookus, Matti A; Kwong, Ava; Olah, Edith; Diez, Orland; Brunet, Joan; Pujana, Miquel Angel; Gronwald, Jacek; Huzarski, Tomasz; Barkardottir, Rosa B; Laframboise, Rachel; Soucy, Penny; Montagna, Marco; Agata, Simona; Teixeira, Manuel R; Park, Sue Kyung; Lindor, Noralane; Couch, Fergus J; Tischkowitz, Marc; Foretova, Lenka; Vijai, Joseph; Offit, Kenneth; Singer, Christian F; Rappaport, Christine; Phelan, Catherine M; Greene, Mark H; Mai, Phuong L; Rennert, Gad; Imyanitov, Evgeny N; Hulick, Peter J; Phillips, Kelly-Anne; Piedmonte, Marion; Mulligan, Anna Marie; Glendon, Gord; Bojesen, Anders; Thomassen, Mads; Caligo, Maria A; Yoon, Sook-Yee; Friedman, Eitan; Laitman, Yael; Borg, Ake; von Wachenfeldt, Anna; Ehrencrona, Hans; Rantala, Johanna; Olopade, Olufunmilayo I; Ganz, Patricia A; Nussbaum, Robert L; Gayther, Simon A; Nathanson, Katherine L; Domchek, Susan M; Arun, Banu K; Mitchell, Gillian; Karlan, Beth Y; Lester, Jenny; Maskarinec, Gertraud; Woolcott, Christy; Scott, Christopher; Stone, Jennifer; Apicella, Carmel; Tamimi, Rulla; Luben, Robert; Khaw, Kay-Tee; Helland, Åslaug; Haakensen, Vilde; Dowsett, Mitch; Pharoah, Paul D P; Simard, Jacques; Hall, Per; García-Closas, Montserrat; Vachon, Celine; Chenevix-Trench, Georgia; Antoniou, Antonis C; Easton, Douglas F; Edwards, Stacey L

    2016-04-01

    We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression. PMID:26928228

  2. Complementation of the Function of Glycoprotein H of Human Herpesvirus 6 Variant A by Glycoprotein H of Variant B in the Virus Life Cycle

    Science.gov (United States)

    Oyaizu, Hiroko; Tang, Huamin; Ota, Megumi; Takenaka, Nobuyuki; Ozono, Keiichi; Yamanishi, Koichi

    2012-01-01

    Human herpesvirus 6 (HHV-6) is a T-cell-tropic betaherpesvirus. HHV-6 can be classified into two variants, HHV-6 variant A (HHV-6A) and HHV-6B, based on genetic, antigenic, and cell tropisms, although the homology of their entire genomic sequences is nearly 90%. The HHV-6A glycoprotein complex gH/gL/gQ1/gQ2 is a viral ligand that binds to the cellular receptor human CD46. Because gH has 94.3% amino acid identity between the variants, here we examined whether gH from one variant could complement its loss in the other. Recently, we successfully reconstituted HHV-6A from its cloned genome in a bacterial artificial chromosome (BAC) (rHHV-6ABAC). Using this system, we constructed HHV-6ABAC DNA containing the HHV-6B gH (BgH) gene instead of the HHV-6A gH (AgH) gene in Escherichia coli. Recombinant HHV-6ABAC expressing BgH (rHHV-6ABAC-BgH) was successfully reconstituted. In addition, a monoclonal antibody that blocks HHV-6B but not HHV-6A infection neutralized rHHV-6ABAC-BgH but not rHHV-6ABAC. These results indicate that HHV-6B gH can complement the function of HHV-6A gH in the viral infectious cycle. PMID:22647694

  3. Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants?

    Science.gov (United States)

    Lovelock, Paul K; Spurdle, Amanda B; Mok, Myth TS; Farrugia, Daniel J; Lakhani, Sunil R; Healey, Sue; Arnold, Stephen; Buchanan, Daniel; Investigators, kConFab; Couch, Fergus J; Henderson, Beric R; Goldgar, David E; Tavtigian, Sean V; Chenevix-Trench, Georgia; Brown, Melissa A

    2007-01-01

    Introduction Many of the DNA sequence variants identified in the breast cancer susceptibility gene BRCA1 remain unclassified in terms of their potential pathogenicity. Both multifactorial likelihood analysis and functional approaches have been proposed as a means to elucidate likely clinical significance of such variants, but analysis of the comparative value of these methods for classifying all sequence variants has been limited. Methods We have compared the results from multifactorial likelihood analysis with those from several functional analyses for the four BRCA1 sequence variants A1708E, G1738R, R1699Q, and A1708V. Results Our results show that multifactorial likelihood analysis, which incorporates sequence conservation, co-inheritance, segregation, and tumour immunohistochemical analysis, may improve classification of variants. For A1708E, previously shown to be functionally compromised, analysis of oestrogen receptor, cytokeratin 5/6, and cytokeratin 14 tumour expression data significantly strengthened the prediction of pathogenicity, giving a posterior probability of pathogenicity of 99%. For G1738R, shown to be functionally defective in this study, immunohistochemistry analysis confirmed previous findings of inconsistent 'BRCA1-like' phenotypes for the two tumours studied, and the posterior probability for this variant was 96%. The posterior probabilities of R1699Q and A1708V were 54% and 69%, respectively, only moderately suggestive of increased risk. Interestingly, results from functional analyses suggest that both of these variants have only partial functional activity. R1699Q was defective in foci formation in response to DNA damage and displayed intermediate transcriptional transactivation activity but showed no evidence for centrosome amplification. In contrast, A1708V displayed an intermediate transcriptional transactivation activity and a normal foci formation response in response to DNA damage but induced centrosome amplification. Conclusion

  4. TCM Differential Treatment of Cough Variant Asthma

    Institute of Scientific and Technical Information of China (English)

    ZHANG Zhong-de; DENG Yi-qi; ZHANG Yu; HAN Yun; LIN Lin; CHAO En-xiang

    2010-01-01

    @@ Cough variant asthma (CVA), also called latent asthma or cough asthma, is a special type of asthma. With gradually deepened understanding of CVA in recent years, good curative effect has been achieved in TCM treatment of CVA.

  5. Splicing variants of porcine synphilin-1

    DEFF Research Database (Denmark)

    Larsen, Knud Erik; Madsen, Lone Bruhn; Farajzadeh, Leila;

    2015-01-01

    (90%) and to mouse (84%) synphilin-1. Three shorter transcript variants of the synphilin-1 gene were identified, all lacking one or more exons. SNCAIP transcripts were detected in most examined organs and tissues and the highest expression was found in brain tissues and lung. Conserved splicing......RNA was investigated by RNAseq. The presented work reports the molecular cloning and characterization of the porcine (Sus scrofa) synphilin-1 cDNA (SNCAIP) and three splice variants hereof. The porcine SNCAIP cDNA codes for a protein (synphilin-1) of 919 amino acids which shows a high similarity to human...... variants and a novel splice form of synhilin-1 were found in this study. All synphilin-1 isoforms encoded by the identified transcript variants lack functional domains important for protein degradation....

  6. OX1 and OX2 orexin/hypocretin receptor pharmacogenetics

    Directory of Open Access Journals (Sweden)

    Miles Douglas Thompson

    2014-05-01

    Full Text Available Orexin/hypocretin peptide mutations are rare in humans. Even though human narcolepsy is associated with orexin deficiency, this is only extremely rarely due to mutations in the gene coding prepro-orexin, the precursor for both orexin peptides. In contrast, coding and non-coding variants of the OX1 and OX2 orexin receptors have been identified in many human populations; sometimes, these have been associated with disease phenotype, although most confer a relatively low risk. In most cases, these studies have been based on a candidate gene hypothesis that predicts involvement of orexins in the relevant pathophysiological processes. In the current review, the known human OX1/HCRTR1 and OX2/HCRTR2 genetic variants/polymorphisms as well as studies concerning their involvement in disorders such as narcolepsy, excessive daytime sleepiness, cluster headache, polydipsia-hyponatremia in schizophrenia, and affective disorders are presented. In most cases, the functional cellular or pharmacological correlates of orexin variants have not been investigated  with the exception of the possible impact of an amino acid 10 Pro/Ser variant of OX2 on orexin potency  leaving conclusions on the nature of the receptor variant effects speculative. Nevertheless, we present perspectives that could shape the basis for further studies. The pharmacology and other properties of the orexin receptor variants are discussed in the context of GPCR signaling. Since orexinergic therapeutics are emerging, the impact of receptor variants on the affinity or potency of ligands deserves consideration. This perspective (pharmacogenetics is also discussed in the review.

  7. Conditionally replicating HIV and SIV variants.

    Science.gov (United States)

    Das, Atze T; Berkhout, Ben

    2016-05-01

    Conditionally replicating human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) variants that can be switched on and off at will are attractive tools for HIV and SIV research. We constructed HIV and SIV variants in which the natural transcription control mechanism was replaced by the doxycycline (dox)-inducible Tet-On gene expression mechanism. These HIV-rtTA and SIV-rtTA variants are fully replication-competent, but replication is critically dependent on dox administration. We here describe how the dox-dependent virus variants may improve the safety of live-attenuated virus vaccines and how they can be used to study the immune responses that correlate with vaccine-induced protection. Furthermore, we review how these variants were initially designed and subsequently optimized by spontaneous viral evolution. These efforts yielded efficiently replicating and tightly dox-controlled HIV-rtTA and SIV-rtTA variants that replicate in a variety of cell and tissue culture systems, and in human immune system (HIS) mice and macaques, respectively. These viruses can be used as a tool in HIV and SIV biology studies and in vaccine research. We review how HIV-rtTA and SIV-rtTA were used to study the role of the viral TAR and Tat elements in virus replication. PMID:25982510

  8. Discovery of rare variants for complex phenotypes.

    Science.gov (United States)

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

    2016-06-01

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

  9. Lipoxin Receptors

    Directory of Open Access Journals (Sweden)

    Mario Romano

    2007-01-01

    Full Text Available Lipoxins (LXs represent a class of arachidonic acid (AA metabolites that carry potent immunoregulatory and anti-inflammatory properties, LXA4 and LXB4 being the main components of this series. LXs are generated by cooperation between 5-lipoxygenase (LO and 12- or 15-LO during cell-cell interactions or by single cell types. LX epimers at carbon 15, the 15-epi-LXs, are formed by aspirin-acetylated cyclooxygenase-2 (COX-2 in cooperation with 5-LO. 15-epi-LXA4 is also termed aspirin-triggered LX (ATL. In vivo studies with stable LX and ATL analogs have established that these eicosanoids possess potent anti-inflammatory activities. A LXA4 receptor has been cloned. It belongs to the family of chemotactic receptors and clusters with formyl peptide receptors on chromosome 19. Therefore, it was initially denominated formyl peptide receptor like 1 (FPRL1. This receptor binds with high affinity and stereoselectivity LXA4 and ATL. It also recognizes a variety of peptides, synthetic, endogenously generated, or disease associated, but with lower affinity compared to LXA4. For this reason, this receptor has been renamed ALX. This review summarizes the current knowledge on ALX expression, signaling, and potential pathophysiological role. The involvement of additional recognition sites in LX bioactions is also discussed.

  10. The Role of Estrogen Receptor β in Prostate Cancer

    OpenAIRE

    Christoforou, Paraskevi; Christopoulos, Panagiotis F; Koutsilieris, Michael

    2014-01-01

    Although androgen receptor (AR) signaling is the main molecular tool regulating growth and function of the prostate gland, estrogen receptor β (ERβ) is involved in the differentiation of prostatic epithelial cells and numerous antiproliferative actions on prostate cancer cells. However, ERβ splice variants have been associated with prostate cancer initiation and progression mechanisms. ERβ is promising as an anticancer therapy and in the prevention of prostate cancer. Herein, we review the re...

  11. The role of Estrogen Receptor Beta in Prostate Cancer.

    OpenAIRE

    Christoforou, Paraskevi; Christopoulos, Panagiotis F; Koutsilieris, Michael

    2014-01-01

    Although androgen receptor (AR) signaling is the main molecular tool regulating growth and function of prostate gland, estrogen receptor beta (ERβ) is involved contributive in the differentiation of prostatic epithelial cells and numerous antiproliferative actions on prostate cancer cells. However, ERβ splice variants have been associated with prostate cancer initiation and progression mechanisms. Nowadays, ERß is a promising target as an anticancer therapy and prevention for prostate cancer....

  12. Autosomal-Recessive Hearing Impairment Due to Rare Missense Variants within S1PR2

    Science.gov (United States)

    Santos-Cortez, Regie Lyn P.; Faridi, Rabia; Rehman, Atteeq U.; Lee, Kwanghyuk; Ansar, Muhammad; Wang, Xin; Morell, Robert J.; Isaacson, Rivka; Belyantseva, Inna A.; Dai, Hang; Acharya, Anushree; Qaiser, Tanveer A.; Muhammad, Dost; Ali, Rana Amjad; Shams, Sulaiman; Hassan, Muhammad Jawad; Shahzad, Shaheen; Raza, Syed Irfan; Bashir, Zil-e-Huma; Smith, Joshua D.; Nickerson, Deborah A.; Bamshad, Michael J.; Riazuddin, Sheikh; Ahmad, Wasim; Friedman, Thomas B.; Leal, Suzanne M.

    2016-01-01

    The sphingosine-1-phosphate receptors (S1PRs) are a well-studied class of transmembrane G protein-coupled sphingolipid receptors that mediate multiple cellular processes. However, S1PRs have not been previously reported to be involved in the genetic etiology of human traits. S1PR2 lies within the autosomal-recessive nonsyndromic hearing impairment (ARNSHI) locus DFNB68 on 19p13.2. From exome sequence data we identified two pathogenic S1PR2 variants, c.323G>C (p.Arg108Pro) and c.419A>G (p.Tyr140Cys). Each of these variants co-segregates with congenital profound hearing impairment in consanguineous Pakistani families with maximum LOD scores of 6.4 for family DEM4154 and 3.3 for family PKDF1400. Neither S1PR2 missense variant was reported among ∼120,000 chromosomes in the Exome Aggregation Consortium database, in 76 unrelated Pakistani exomes, or in 720 Pakistani control chromosomes. Both DNA variants affect highly conserved residues of S1PR2 and are predicted to be damaging by multiple bioinformatics tools. Molecular modeling predicts that these variants affect binding of sphingosine-1-phosphate (p.Arg108Pro) and G protein docking (p.Tyr140Cys). In the previously reported S1pr2−/− mice, stria vascularis abnormalities, organ of Corti degeneration, and profound hearing loss were observed. Additionally, hair cell defects were seen in both knockout mice and morphant zebrafish. Family PKDF1400 presents with ARNSHI, which is consistent with the lack of gross malformations in S1pr2−/− mice, whereas family DEM4154 has lower limb malformations in addition to hearing loss. Our findings suggest the possibility of developing therapies against hair cell damage (e.g., from ototoxic drugs) through targeted stimulation of S1PR2. PMID:26805784

  13. A novel variant in GABRB2 associated with intellectual disability and epilepsy.

    Science.gov (United States)

    Srivastava, Siddharth; Cohen, Julie; Pevsner, Jonathan; Aradhya, Swaroop; McKnight, Dianalee; Butler, Elizabeth; Johnston, Michael; Fatemi, Ali

    2014-11-01

    The γ-aminobutyric acid type A (GABAA ) receptor is one of the three main classes of receptors activated by GABA, the principal inhibitory neurotransmitter in the central nervous system. Mutations in genes encoding various subunits of this receptor (GABRA1, GABRA2, GABRA4, GABRA5, GABRA6, GABRB1, GABRB3, GABRG1, GABRG2, GABRG3, and GABRD) are implicated in a number of neurological and developmental disorders, including epilepsy and autism. To date, no human genetics studies have implicated mutations in GABRB2, encoding the β2 subunit of the GABAA receptor, with neurodevelopmental disorders. Here we present a 12-year-old girl with intellectual disability and epilepsy, who was discovered by whole exome sequencing to have a de novo heterozygous missense variant in exon 4 of GABRB2 (c.236T>C; p.M79T). This variant is likely pathogenic, based on in silico analyses, as well as the fact that it results in the non-conservative substitution of a non-polar amino acid with a polar amino acid at a position that is evolutionarily conserved across multiple species. Our findings underscore the need for further investigation into the mechanisms by which mutations in GABRB2 contribute to neurological and developmental dysfunction. PMID:25124326

  14. Nitrite Reductase Activity in Engineered Azurin Variants.

    Science.gov (United States)

    Berry, Steven M; Strange, Jacob N; Bladholm, Erika L; Khatiwada, Balabhadra; Hedstrom, Christine G; Sauer, Alexandra M

    2016-05-01

    Nitrite reductase (NiR) activity was examined in a series of dicopper P.a. azurin variants in which a surface binding copper site was added through site-directed mutagenesis. Four variants were synthesized with copper binding motifs inspired by the catalytic type 2 copper binding sites found in the native noncoupled dinuclear copper enzymes nitrite reductase and peptidylglycine α-hydroxylating monooxygenase. The four azurin variants, denoted Az-NiR, Az-NiR3His, Az-PHM, and Az-PHM3His, maintained the azurin electron transfer copper center, with the second designed copper site located over 13 Å away and consisting of mutations Asn10His,Gln14Asp,Asn16His-azurin, Asn10His,Gln14His,Asn16His-azurin, Gln8Met,Gln14His,Asn16His-azurin, and Gln8His,Gln14His,Asn16His-azurin, respectively. UV-visible absorption spectroscopy, EPR spectroscopy, and electrochemistry of the sites demonstrate copper binding as well as interaction with small exogenous ligands. The nitrite reduction activity of the variants was determined, including the catalytic Michaelis-Menten parameters. The variants showed activity (0.34-0.59 min(-1)) that was slower than that of native NiRs but comparable to that of other model systems. There were small variations in activity of the four variants that correlated with the number of histidines in the added copper site. Catalysis was found to be reversible, with nitrite produced from NO. Reactions starting with reduced azurin variants demonstrated that electrons from both copper centers were used to reduce nitrite, although steady-state catalysis required the T2 copper center and did not require the T1 center. Finally, experiments separating rates of enzyme reduction from rates of reoxidation by nitrite demonstrated that the reaction with nitrite was rate limiting during catalysis. PMID:27055058

  15. Polymorphisms in the melatonin receptor 1B gene and the risk of delirium

    NARCIS (Netherlands)

    de Jonghe, A; de Rooij, S; Tanck, M W T; Sijbrands, E J G; van Munster, B C V

    2012-01-01

    BACKGROUND/AIMS: A disturbed sleep-wake rhythm cycle can be seen in delirium and as melatonin regulates this cycle via melatonin receptors, genetic variations in these receptors may contribute to susceptibility to delirium. The purpose of this study was to investigate whether genetic variants in the

  16. Heterodimerization and endocytosis of Arabidopsis brassinosteroid receptors BRI1 and AtSERK3 (BAK1)

    DEFF Research Database (Denmark)

    Russinova, Eugenia; Borst, Jan-Willem; Kwaaitaal, Mark Adrianus Cornelis J;

    2004-01-01

    (Saccharomyces cerevisiae) interaction studies suggested that the BRI1-BAK1 receptor complex initiates BR signaling, but the role of the BAK1 receptor is still not clear. Using transient expression in protoplasts of BRI1 and AtSERK3 fused to cyan and yellow fluorescent green fluorescent protein variants allowed...

  17. C-type lectin receptors and RIG-I-like receptors: new points on the oncogenomics map

    International Nuclear Information System (INIS)

    The group of pattern recognition receptors includes families of Toll-like receptors, NOD-like receptors, C-type lectin receptors, and RIG-I-like receptors. They are key sensors for a number of infectious agents, some of which are oncogenic, and they launch an immune response against them, normally promoting their eradication. Inherited variations in genes encoding these receptors and proteins and their signaling pathways may affect their function, possibly modulating cancer risk and features of cancer progression. There are numerous studies investigating the association of single nucleotide polymorphisms within or near genes encoding Toll-like receptors and NOD-like receptors, cancer risk, and features of cancer progression. However, there is an almost total absence of articles analyzing the correlation between polymorphisms of genes encoding C-type lectin receptors and RIG-I-like receptors and cancer risk or progression. Nevertheless, there is some evidence supporting the hypothesis that inherited C-type lectin receptor and RIG-I-like receptor variants can be associated with increased cancer risk. Certain C-type lectin receptors and RIG-I-like receptors recognize pathogen-associated molecular patterns of potentially oncogenic infectious agents, and certain polymorphisms of genes encoding C-type lectin receptors and RIG-I-like receptors may have functional consequences at the molecular level that can lead to association of such single nucleotide polymorphisms with risk or progression of some diseases that may modulate cancer risk, so these gene polymorphisms may affect cancer risk indirectly. Polymorphisms of genes encoding C-type lectin receptors and RIG-I-like receptors thereby may be correlated with a risk of lung, oral, esophageal, gastric, colorectal, and liver cancer, as well as nasopharyngeal carcinoma, glioblastoma, multiple myeloma, and lymphoma. The list of the most promising polymorphisms for oncogenomic investigations may include rs1926736, rs2478577

  18. Modelling Families of Business Process Variants: A Decomposition Driven Method

    OpenAIRE

    Milani, Fredrik; Dumas, Marlon; Ahmed, Naved; Matulevičius, Raimundas

    2013-01-01

    Business processes usually do not exist as singular entities that can be managed in isolation, but rather as families of business process variants. When modelling such families of variants, analysts are confronted with the choice between modelling each variant separately, or modelling multiple or all variants in a single model. Modelling each variant separately leads to a proliferation of models that share common parts, resulting in redundancies and inconsistencies. Meanwhile, modelling all v...

  19. Functional modulation of the glutamate transporter variant GLT1b by the PDZ domain protein PICK1

    DEFF Research Database (Denmark)

    Søgaard, Rikke; Borre, Lars; Braunstein, Thomas H;

    2013-01-01

    The dominant glutamate transporter isoform in the mammalian brain, GLT1, exists as at least three splice variants, GLT1a, GLT1b, and GLT1c. GLT1b interacts with the scaffold protein PICK1 (protein interacting with kinase C1), which is implicated in glutamatergic neurotransmission via its regulatory...... effect on trafficking of AMPA-type glutamate receptors. The 11 extreme C-terminal residues specific for the GLT1b variant are essential for its specific interaction with the PICK1 PDZ domain, but a functional consequence of this interaction has remained unresolved. To identify a functional effect of PICK...

  20. Sequence Variant Descriptions: HGVS Nomenclature and Mutalyzer.

    Science.gov (United States)

    den Dunnen, Johan T

    2016-01-01

    Consistent and unambiguous description of sequence variants is essential to report and exchange information on the analysis of a genome, in particular in DNA diagnostics. The HGVS nomenclature-recommendations for the description of sequence variants as originally proposed by the Human Genome Variation Society-has gradually been accepted as the international standard for variant description. In this unit, we describe the current recommendations (HGVS version 15.11) regarding how to describe variants at the DNA, RNA, and protein level. We explain the rationale and give example descriptions for all variant types: substitution, deletion, duplication, insertion, inversion, conversion, and complex, as well as special types occurring only on the RNA (splicing) or protein level (nonsense, frame shift, extension). Finally, we point users to available support tools and give examples for the use of the freely available Mutalyzer suite. An extensive version of the HGVS recommendations is available online at http://varnomen.hgvs.org/. © 2016 by John Wiley & Sons, Inc. PMID:27367167

  1. Word Variant Identification in Old French

    Directory of Open Access Journals (Sweden)

    Peter Willett

    1997-01-01

    Full Text Available Increasing numbers of historical texts are available in machine-readable form, which retain the original spelling, which can be very different from the modern-day equivalents due to the natural evolution of a language, and because the concept of standardisation in spelling is comparatively modern. Among medieval vernacular writers, the same word could be spelled in different ways and the same author (or scribe might even use several alternative spellings in the same passage. Thus, we do not know,a priori, how many variant forms of a particular word there are in such texts, let alone what these variants might be. Searching on the modern equivalent, or even the commonest historical variant, of a particular word may thus fail to retrieve an appreciable number of occurrences unless the searcher already has an extensive knowledge of the language of the documents. Moreover, even specialist scholars may be unaware of some idiosyncratic variants. Here, we consider the use of computer methods to retrieve variant historical spellings.

  2. MC1R variants increase risk of melanomas harboring BRAF mutations.

    Science.gov (United States)

    Fargnoli, Maria Concetta; Fargnoli, Maria Concetia; Pike, Kris; Pfeiffer, Ruth M; Tsang, Shirley; Rozenblum, Ester; Munroe, David J; Golubeva, Yelena; Calista, Donato; Seidenari, Stefania; Massi, Daniela; Carli, Paolo; Bauer, Juergen; Elder, David E; Bastian, Boris C; Peris, Ketty; Landi, Maria T

    2008-10-01

    Melanocortin-1 receptor (MC1R) variants have been associated with BRAF (v-raf murine sarcoma viral oncogene homolog B1) mutations in non-CSD (chronic solar-damaged) melanomas in an Italian and an American population. We studied an independent Italian population of 330 subjects (165 melanoma patients and 165 controls) to verify and estimate the magnitude of this association and to explore possible effect modifiers. We sequenced MC1R in all subjects and exon 15 of BRAF in 92/165 melanoma patients. Patients with MC1R variants had a high risk of carrying BRAF mutations in melanomas (odds ratio (OR)=7.0, 95% confidence interval (CI)=2.1-23.8) that increased with the number of MC1R variants and variants associated with red hair color. Combining these subjects with the originally reported Italian population (513 subjects overall), MC1R variant carriers had a 5- to 15-fold increased risk of BRAF-mutant melanomas based on carrying one or two variants (P<0.0001, test for trend), and regardless of signs of chronic solar damage. In contrast, no association with BRAF-negative melanomas was found (OR=1.0, 95% CI=0.6-1.6). No characteristics of subjects or melanomas, including age, nevus count, pigmentation, and melanoma thickness or location on chronically or intermittently sun-exposed body sites, substantially modified this association, although results could be affected by the small numbers in some categories. This study confirms that the known MC1R-melanoma risk association is confined to subjects whose melanomas harbor BRAF mutations. PMID:18368129

  3. Scavenger receptor AI/II truncation, lung function and COPD

    DEFF Research Database (Denmark)

    Thomsen, M; Nordestgaard, B G; Tybjaerg-Hansen, A;

    2011-01-01

    The scavenger receptor A-I/II (SRA-I/II) on alveolar macrophages is involved in recognition and clearance of modified lipids and inhaled particulates. A rare variant of the SRA-I/II gene, Arg293X, truncates the distal collagen-like domain, which is essential for ligand recognition. We tested whet...

  4. Scanning for Clues to Better Use Selective Estrogen Receptor Modulators

    OpenAIRE

    Machiela, Mitchell J.; Chanock, Stephen J.

    2013-01-01

    Ingle and colleagues present timely findings identifying genetic variants associated with response to selective estrogen receptor modulator therapy that when substantiated in follow-up may represent an important step towards understanding estrogen-dependent induction of BRCA1 expression and advancing individualized preventive medicine in women at high risk for developing breast cancer.

  5. Screening of GNAL variants in Brazilian patients with isolated dystonia reveals a novel mutation with partial loss of function.

    Science.gov (United States)

    Dos Santos, Camila Oliveira; Masuho, Ikuo; da Silva-Júnior, Francisco Pereira; Barbosa, Egberto Reis; Silva, Sonia Maria Cesar Azevedo; Borges, Vanderci; Ferraz, Henrique Ballalai; Rocha, Maria Sheila Guimarães; Limongi, João Carlos Papaterra; Martemyanov, Kirill A; de Carvalho Aguiar, Patricia

    2016-04-01

    GNAL was identified as a cause of dystonia in patients from North America, Europe and Asia. In this study, we aimed to investigate the prevalence of GNAL variants in Brazilian patients with dystonia. Ninety-one patients with isolated idiopathic dystonia, negative for THAP1 and TOR1A mutations, were screened for GNAL variants by Sanger sequencing. Functional characterization of the Gαolf protein variant was performed using the bioluminescence resonance energy transfer assay. A novel heterozygous nonsynonymous variant (p. F133L) was identified in a patient with cervical and laryngeal dystonia since the third decade of life, with no family history. This variant was not identified in healthy Brazilian controls and was not described in 63,000 exomas of the ExAC database. The F133L mutant exhibited significantly elevated levels of basal BRET and severely diminished amplitude of response elicited by dopamine, that both indicate substantial functional impairment of Gαolf in transducing receptor signals, which could be involved in dystonia pathophysiology. GNAL mutations are not a common cause of dystonia in the Brazilian population and have a lower prevalence than THAP1 and TOR1A mutations. We present a novel variant that results in partial Gαolf loss of function. PMID:26810727

  6. Biophysical analysis of apolipoprotein E3 variants linked with development of type III hyperlipoproteinemia.

    Directory of Open Access Journals (Sweden)

    Dimitra Georgiadou

    Full Text Available BACKGROUND: Apolipoprotein E (apoE is a major protein of the lipoprotein transport system that plays important roles in lipid homeostasis and protection from atherosclerosis. ApoE is characterized by structural plasticity and thermodynamic instability and can undergo significant structural rearrangements as part of its biological function. Mutations in the 136-150 region of the N-terminal domain of apoE, reduce its low density lipoprotein (LDL receptor binding capacity and have been linked with lipoprotein disorders, such as type III hyperlipoproteinemia (HLP in humans. However, the LDL-receptor binding defects for these apoE variants do not correlate well with the severity of dyslipidemia, indicating that these variants may carry additional properties that contribute to their pathogenic potential. METHODOLOGY/PRINCIPAL FINDINGS: In this study we examined whether three type III HLP predisposing apoE3 variants, namely R136S, R145C and K146E affect the biophysical properties of the protein. Circular dichroism (CD spectroscopy revealed that these mutations do not significantly alter the secondary structure of the protein. Thermal and chemical unfolding analysis revealed small thermodynamic alterations in each variant compared to wild-type apoE3, as well as effects in the reversibility of the unfolding transition. All variants were able to remodel multillamelar 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC vesicles, but R136S and R145C had reduced kinetics. Dynamic light scattering analysis indicated that the variant R136S exists in a higher-order oligomerization state in solution. Finally, 1-anilinonaphthalene-8-sulfonic acid (ANS binding suggested that the variant R145C exposes a larger amount of hydrophobic surface to the solvent. CONCLUSIONS/SIGNIFICANCE: Overall, our findings suggest that single amino acid changes in the functionally important region 136-150 of apoE3 can affect the molecule's stability and conformation in solution and may

  7. Fundamental Characteristics of Industrial Variant Specification Systems

    DEFF Research Database (Denmark)

    Hansen, Benjamin Loer; Hvam, Lars

    2004-01-01

    This paper focuses on the operational task of creating customised variants of industrial specifications (e.g. drawings, routings and bill-of-materials). Rooted in a lack of existing literature on the subject the paper describes the nature of variant specification systems. It introduces some...... a set of situational variables (e.g. frequency of orders [low ¡ê high]), a set of functionality variables (e.g. lead time [low ¡ê high]) and a set of structure variables (e.g. level of IT-automation [manual ¡ê IT-automated]) are proposed. Finally, the presented concepts are illustrated through two...... examples. In general the paper discusses an important focus area within mass customization and build-to-order production: the nature of industrial variant specification systems....

  8. Genetics in psychiatry: common variant association studies

    Directory of Open Access Journals (Sweden)

    Buxbaum Joseph D

    2010-03-01

    Full Text Available Abstract Many psychiatric conditions and traits are associated with significant heritability. Genetic risk for psychiatric conditions encompass rare variants, identified due to major effect, as well as common variants, the latter analyzed by association analyses. We review guidelines for common variant association analyses, undertaking after assessing evidence of heritability. We highlight the importance of: suitably large sample sizes; an experimental design that controls for ancestry; careful data cleaning; correction for multiple testing; small P values for positive findings; assessment of effect size for positive findings; and, inclusion of an independent replication sample. We also note the importance of a critical discussion of any prior findings, biological follow-up where possible, and a means of accessing the raw data.

  9. Phenotypic extremes in rare variant study designs.

    Science.gov (United States)

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

    2016-06-01

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

  10. Charge variants in IgG1

    Science.gov (United States)

    Goswami, Sirj; Hutchinson, Ryan; Kwong, Zephania W; Yang, Jihong; Wang, Xiangdan; Yao, Zhenling; Sreedhara, Alavattam; Cano, Tony; Tesar, Devin; Nijem, Ihsan; Allison, David E; Wong, Pin Yee; Kao, Yung-Hsiang; Quan, Cynthia; Joshi, Amita; Harris, Reed J; Motchnik, Paul

    2010-01-01

    Antibody charge variants have gained considerable attention in the biotechnology industry due to their potential influence on stability and biological activity. Subtle differences in the relative proportions of charge variants are often observed during routine biomanufacture or process changes and pose a challenge to demonstrating product comparability. To gain further insights into the impact on biological activity and pharmacokinetics (PK) of monoclonal antibody (mAb) charge heterogeneity, we isolated the major charge forms of a recombinant humanized IgG1 and compared their in vitro properties and in vivo PK. The mAb starting material had a pI range of 8.7–9.1 and was composed of about 20% acidic variants, 12% basic variants and 68% main peak. Cation exchange displacement chromatography was used to isolate the acidic, basic and main peak fractions for animal studies. Detailed analyses were performed on the isolated fractions to identify specific chemical modification contributing to the charge differences and were also characterized for purity and in vitro potency prior to being administered either subcutaneously (SC) or intravenously (IV) in rats. All isolated materials had similar potency and rat FcRn binding relative to the starting material. Following IV or SC administration (10 mg/kg) in rats, no difference in serum PK was observed, indicating that physiochemical modifications and pI differences among charge variants were not sufficient to result in PK changes. Thus, these results provided meaningful information for the comparative evaluation of charge-related heterogeneity of mAbs and suggested that charge variants of IgGs do not affect the in vitro potency, FcRn binding affinity or the PK properties in rats. PMID:20818176

  11. Development of prolactin receptor antagonists with reduced pH-dependence of receptor binding

    DEFF Research Database (Denmark)

    Hansen, Mathilde Johanne Kaas; Olsen, Johan Gotthardt; Bernichtein, Sophie;

    2011-01-01

    H than at physiological pH and since the extracellular environment around solid tumors often is acidic, it is desirable to develop antagonists that have improved binding affinity at low pH. The pK(a) value of a histidine side chain is ~6.8 making histidine residues obvious candidates for examination....... From evaluation of known molecular structures of human prolactin, of the prolactin receptor and of different complexes of the two, three histidine residues in the hormone-receptor binding site 1 were selected for mutational studies. We analyzed 10 variants by circular dichroism spectroscopy, affinity...... and thermodynamic characterization of receptor binding by isothermal titration calorimetry combined with in vitro bioactivity in living cells. Histidine residue 27 was recognized as a central hot spot for pH sensitivity and conservative substitutions at this site resulted in strong receptor binding at...

  12. Identification of the salmon somatolactin receptor, a new member of the cytokine receptor family.

    Science.gov (United States)

    Fukada, Haruhisa; Ozaki, Yuichi; Pierce, Andrew L; Adachi, Shinji; Yamauchi, Kohei; Hara, Akihiko; Swanson, Penny; Dickhoff, Walton W

    2005-05-01

    Somatolactin (SL) is a pituitary hormone of the GH/prolactin (PRL) family that so far has been found only in fish. Compared with GH and PRL, the primary structure of SL is highly conserved among divergent fish species, suggesting it has an important function and a discriminating receptor that constrains structural change. However, SL functions are poorly understood, and receptors for SL have not yet been identified. During cloning of GH receptor cDNA from salmon, we found a variant with relatively high (38-58%) sequence identity to vertebrate GH receptors and low (28-33%) identity to PRL receptors; however, the recombinant protein encoding the extracellular domain showed only weak binding of GH. Ligand binding of the recombinant extracellular domain for this receptor confirmed that the cDNA encoded a specific receptor for SL. The SL receptor (SLR) has common features of a GH receptor including FGEFS motif, six cysteine residues in the extracellular domain, a single transmembrane region, and Box 1 and 2 regions in the intracellular domain. These structural characteristics place the SLR in the cytokine receptor type I homodimeric group, which includes receptors for GH, PRL, erythropoietin, thrombopoietin, granulocyte-colony stimulating factor, and leptin. Transcripts for SLR were found in 11 tissues with highest levels in liver and fat, supporting the notion that a major function of SL is regulation of lipid metabolism. Cloning SLR cDNA opens the way for discovery of new SL functions and target tissues in fish, and perhaps novel members of this receptor family in other vertebrates. PMID:15718271

  13. A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer's disease.

    Science.gov (United States)

    Verheijen, Jan; Van den Bossche, Tobi; van der Zee, Julie; Engelborghs, Sebastiaan; Sanchez-Valle, Raquel; Lladó, Albert; Graff, Caroline; Thonberg, Håkan; Pastor, Pau; Ortega-Cubero, Sara; Pastor, Maria A; Benussi, Luisa; Ghidoni, Roberta; Binetti, Giuliano; Clarimon, Jordi; Lleó, Alberto; Fortea, Juan; de Mendonça, Alexandre; Martins, Madalena; Grau-Rivera, Oriol; Gelpi, Ellen; Bettens, Karolien; Mateiu, Ligia; Dillen, Lubina; Cras, Patrick; De Deyn, Peter P; Van Broeckhoven, Christine; Sleegers, Kristel

    2016-08-01

    The sortilin-related receptor 1 (SORL1) gene has been associated with increased risk for Alzheimer's disease (AD). Rare genetic variants in the SORL1 gene have also been implicated in autosomal dominant early-onset AD (EOAD). Here we report a large-scale investigation of the contribution of genetic variability in SORL1 to EOAD in a European EOAD cohort. We performed massive parallel amplicon-based re-sequencing of the full coding region of SORL1 in 1255 EOAD patients and 1938 age- and origin-matched control individuals in the context of the European Early-Onset Dementia (EOD) consortium, originating from Belgium, Spain, Portugal, Italy, Sweden, Germany, and Czech Republic. We identified six frameshift variants and two nonsense variants that were exclusively present in patients. These mutations are predicted to result in haploinsufficiency through nonsense-mediated mRNA decay, which could be confirmed experimentally for SORL1 p.Gly447Argfs*22 observed in a Belgian EOAD patient. We observed a 1.5-fold enrichment of rare non-synonymous variants in patients (carrier frequency 8.8 %; SkatOMeta p value 0.0001). Of the 84 non-synonymous rare variants detected in the full patient/control cohort, 36 were only detected in patients. Our findings underscore a role of rare SORL1 variants in EOAD, but also show a non-negligible frequency of these variants in healthy individuals, necessitating the need for pathogenicity assays. Premature stop codons due to frameshift and nonsense variants, have so far exclusively been found in patients, and their predicted mode of action corresponds with evidence from in vitro functional studies of SORL1 in AD. PMID:27026413

  14. Glutamate receptors

    DEFF Research Database (Denmark)

    Kristensen, Anders S; Geballe, Matthew T; Snyder, James P;

    2006-01-01

    Fast excitatory synaptic transmission in the CNS relies almost entirely on the neurotransmitter glutamate and its family of ion channel receptors. An appreciation of the coupling between agonist binding and channel opening has advanced rapidly during the past five years, largely as a result of ne...

  15. Somatostatin receptors

    DEFF Research Database (Denmark)

    Møller, Lars Neisig; Stidsen, Carsten Enggaard; Hartmann, Bolette;

    2003-01-01

    In 1972, Brazeau et al. isolated somatostatin (somatotropin release-inhibiting factor, SRIF), a cyclic polypeptide with two biologically active isoforms (SRIF-14 and SRIF-28). This event prompted the successful quest for SRIF receptors. Then, nearly a quarter of a century later, it was announced...

  16. Homozygous FIBP nonsense variant responsible of syndromic overgrowth, with overgrowth, macrocephaly, retinal coloboma and learning disabilities.

    Science.gov (United States)

    Thauvin-Robinet, C; Duplomb-Jego, L; Limoge, F; Picot, D; Masurel, A; Terriat, B; Champilou, C; Minot, D; St-Onge, J; Kuentz, P; Duffourd, Y; Thevenon, J; Rivière, J-B; Faivre, L

    2016-05-01

    The acidic fibroblast growth factor (FGF) intracellular binding protein (FIBP) interacts directly with the fibroblast growth factor FGF1. Although FIBP is known to be implicated in the FGF signaling pathway, its precise function remains unclear. Gain-of-function variants in several FGF receptors (FGFRs) are implicated in a wide spectrum of growth disorders from achondroplasia to overgrowth syndromes. In a unique case from a consanguineous union presenting with overgrowth, macrocephaly, retinal coloboma, large thumbs, severe varicose veins and learning disabilities, exome sequencing identified a homozygous nonsense FIBP variant. The patient's fibroblasts exhibit FIBP cDNA degradation and an increased proliferation capacity compared with controls. The phenotype defines a new multiple congenital abnormalities (MCA) syndrome, overlapping with the heterogeneous group of overgrowth syndromes with macrocephaly. The different clinical features can be explained by the alteration of the FGFR pathway. Taken together, these results suggest the implication of FIBP in a new autosomal recessive MCA. PMID:26660953

  17. Report of a rare anatomic variant

    DEFF Research Database (Denmark)

    De Brucker, Y; Ilsen, B; Muylaert, C;

    2015-01-01

    We report the CT findings in a case of partial anomalous pulmonary venous return (PAPVR) from the left upper lobe in an adult. PAPVR is an anatomic variant in which one to three pulmonary veins drain into the right atrium or its tributaries, rather than into the left atrium. This results in a lef...

  18. Magnetic resonance angiography: infrequent anatomic variants

    International Nuclear Information System (INIS)

    We studied through RM angiography (3D TOF) with high magnetic field equipment (1.5 T) different infrequent intracerebral vascular anatomic variants. For their detection we emphasise the value of post-processed images obtained after conventional angiographic sequences. These post-processed images should be included in routine protocols for evaluation of the intracerebral vascular structures. (author)

  19. New genetic variants associated with prostate cancer

    Science.gov (United States)

    Researchers have newly identified 23 common genetic variants -- one-letter changes in DNA known as single-nucleotide polymorphisms or SNPs -- that are associated with risk of prostate cancer. These results come from an analysis of more than 10 million SNP

  20. Cellobiohydrolase I gene and improved variants

    Science.gov (United States)

    Adney, William S.; Decker, Stephen R.; Mc Carter, Suzanne; Baker, John O.; Nieves, Raphael; Himmel, Michael E.; Vinzant, Todd B.

    2008-05-20

    The disclosure provides a method for preparing an active exoglucanase in a heterologous host of eukaryotic origin. The method includes mutagenesis to reduce glycosylation of the exoglucanase when expressed in a heterologous host. It is further disclosed a method to produce variant cellobiohydrolase that is stable at high temperature through mutagenesis.

  1. Truncated variants of apolipoprotein B cause hypobetalipoproteinaemia

    Energy Technology Data Exchange (ETDEWEB)

    Collins, D.R.; Knott, T.J.; Pease, R.J.; Powell, L.M.; Wallis, S.C.; Robertson, S.; Pullinger, C.R.; Lloyd, K.; Miller, N.E.; Muller, D.; Scott, J. (MRC Clinical Research Centre, Harrow (England)); Humphries, S.E.; Talmud, P.J. (Charing Cross Sunley Research Centre, London (England)); Milne, R.W.; Marcel, Y.L. (Clinical Research Institute of Montreal, Quebec (Canada))

    1988-09-12

    Familial hypobetalipoproteinaemia is a rare autosomal dominant disorder in which levels of apo-B-containing plasma lipoproteins are approximately half-normal in heterozygotes and virtually absent in homozygotes. Here the authors describe mutations of the apo-B gene that cause two different truncated variants of apo-B in unrelated individuals with hypobetalipoproteinaemia. One variant is predicted to be 1,799 amino acids long and arises from deletion of a single nucleotide (G) from leucine codon 1,794. This protein was found at low levels in very low density and low density lipoprotein fractions in the blood. The second, shorter variant is caused by mutation of a CpG dinucleotide in arginine codon 1,306 converting it to a stop codon and predicting a protein of 1,305 residues. The differences in size and behavior of these two variants compared to apo-B100 or apo-B48 point to domains that may be important for the assembly, secretion or stability of apo-B-containing lipoproteins.

  2. Progress in methods for rare variant association.

    Science.gov (United States)

    Santorico, Stephanie A; Hendricks, Audrey E

    2016-01-01

    Empirical studies and evolutionary theory support a role for rare variants in the etiology of complex traits. Given this motivation and increasing affordability of whole-exome and whole-genome sequencing, methods for rare variant association have been an active area of research for the past decade. Here, we provide a survey of the current literature and developments from the Genetics Analysis Workshop 19 (GAW19) Collapsing Rare Variants working group. In particular, we present the generalized linear regression framework and associated score statistic for the 2 major types of methods: burden and variance components methods. We further show that by simply modifying weights within these frameworks we arrive at many of the popular existing methods, for example, the cohort allelic sums test and sequence kernel association test. Meta-analysis techniques are also described. Next, we describe the 6 contributions from the GAW19 Collapsing Rare Variants working group. These included development of new methods, such as a retrospective likelihood for family data, a method using genomic structure to compare cases and controls, a haplotype-based meta-analysis, and a permutation-based method for combining different statistical tests. In addition, one contribution compared a mega-analysis of family-based and population-based data to meta-analysis. Finally, the power of existing family-based methods for binary traits was compared. We conclude with suggestions for open research questions. PMID:26866487

  3. A rare variant of common arterial trunk.

    OpenAIRE

    Rubay, J E; Macartney, F J; Anderson, R H

    1987-01-01

    A 13 day old baby was admitted to hospital with multiple abnormalities, increasing cyanosis, and cardiac failure. Cardiac catheterisation was performed on the day of admission and he died shortly after the procedure. A rare variant of common arterial trunk, in which the pulmonary arteries arose directly from the underside of the aortic arch, was found at necropsy.

  4. XVCL: XML-based Variant Configuration Language

    DEFF Research Database (Denmark)

    Jarzabek, Stan; Basset, Paul; Zhang, Hongyu; Zhang, Weishan

    XVCL (XML-based Variant Configuration Language) is a meta-programming technique and tool that provides effective reuse mechanisms. XVCL is an open source software developed at the National University of Singapore. Being a modern and versatile version of Bassett's frames, a technology that has...

  5. Splicing variants of porcine synphilin-1

    Directory of Open Access Journals (Sweden)

    Knud Larsen

    2015-09-01

    Full Text Available Parkinson's disease (PD, idiopathic and familial, is characterized by degradation of dopaminergic neurons and the presence of Lewy bodies (LB in the substantia nigra. LBs contain aggregated proteins of which α-synuclein is the major component. The protein synphilin-1 interacts and colocalizes with α-synuclein in LBs. The aim of this study was to isolate and characterize porcine synphilin-1 and isoforms hereof with the future perspective to use the pig as a model for Parkinson's disease. The porcine SNCAIP cDNA was cloned by reverse transcriptase PCR. The spatial expression of SNCAIP mRNA was investigated by RNAseq. The presented work reports the molecular cloning and characterization of the porcine (Sus scrofa synphilin-1 cDNA (SNCAIP and three splice variants hereof. The porcine SNCAIP cDNA codes for a protein (synphilin-1 of 919 amino acids which shows a high similarity to human (90% and to mouse (84% synphilin-1. Three shorter transcript variants of the synphilin-1 gene were identified, all lacking one or more exons. SNCAIP transcripts were detected in most examined organs and tissues and the highest expression was found in brain tissues and lung. Conserved splicing variants and a novel splice form of synhilin-1 were found in this study. All synphilin-1 isoforms encoded by the identified transcript variants lack functional domains important for protein degradation.

  6. Plasmodium falciparum-infected erythrocyte knob density is linked to the PfEMP1 variant expressed

    DEFF Research Database (Denmark)

    Subramani, Ramesh; Quadt, Katharina; Jeppesen, Anine Engholm;

    2015-01-01

    UNLABELLED: Members of the clonally variant Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family mediate adhesion of infected erythrocytes (IEs) to vascular receptors. PfEMP1 expression is normally confined to nanoscale knob protrusions on the IE surface membrane. To investigate the...... relationship between the densities of these IE surface knobs and the PfEMP1 variant expressed, we used specific antibody panning to generate three sublines of the P. falciparum clone IT4, which expresses the PfEMP1 variants IT4VAR04, IT4VAR32b, and IT4VAR60. The knob density in each subline was then determined...... by atomic force microscopy (AFM) and scanning electron microscopy (SEM) and compared to PfEMP1 and knob-associated histidine-rich protein (KAHRP) expression. Selection for uniform expression of IT4VAR04 produced little change in knob density, compared to unselected IEs. In contrast, selection for IT4...

  7. Metabolic regulation and behavior: how hunger produces arousal - an insect study.

    Science.gov (United States)

    Wicher, Dieter

    2007-12-01

    The metabolic state affects the level of general activity of an organism. Satiety is related to relaxation while hunger is coupled to elevated activity which supports the chance to balance the energy deficiency. The unrestricted food availability in modern industrial nations along with no required locomotor activity are risk factors to develop disorders such as obesity. One of the strategies to find new targets for future treatment of metabolic disorders in men is to gain detailed knowledge of molecular and cellular mechanisms involved in the regulation of metabolic homeostasis in less complex, i.e. invertebrate systems. This review reports recent molecular studies in insects about how hunger signals may be linked to global activation. Adipokinetic peptide hormones (AKHs) are the insect counterpart to the mammalian glucagon. They are released upon lack of energy and mobilize internal fuel reserves. In addition, AKHs stimulate the locomotor activity which involves their activity within the central nervous system. In the cockroach Periplaneta americana various neurons express the AKH receptor. Some of these, the dorsal unpaired median (DUM) neurons belonging to a general arousal system, release the biogenic amine octopamine, the insect counterpart to mammalian adrenergic hormones. The two Periplaneta AKHs activate Gs proteins, and AKH I also potently activates Gq proteins. AKH I and - less effectively - AKH II accelerate spiking of DUM neurons via an increase of a pacemaking Ca2+ current. Systemically injected AKH I stimulates locomotion in contrast to AKH II. This behavioral difference corresponds to the different effectiveness of the AKHs on the level of G-proteins. PMID:18220952

  8. The serotonin 5-HT7 receptors: two decades of research.

    Science.gov (United States)

    Gellynck, Evelien; Heyninck, Karen; Andressen, Kjetil W; Haegeman, Guy; Levy, Finn Olav; Vanhoenacker, Peter; Van Craenenbroeck, Kathleen

    2013-10-01

    Like most neurotransmitters, serotonin possesses a simple structure. However, the pharmacological consequences are more complex and diverse. Serotonin is involved in numerous functions in the human body including the control of appetite, sleep, memory and learning, temperature regulation, mood, behavior, cardiovascular function, muscle contraction, endocrine regulation, and depression. Low levels of serotonin may be associated with several disorders, namely increase in aggressive and angry behaviors, clinical depression, Parkinson's disease, obsessive-compulsive disorder, eating disorders, migraine, irritable bowel syndrome, tinnitus, and bipolar disease. These effects are mediated via different serotonin (5-HT) receptors. In this review, we will focus on the last discovered member of this serotonin receptor family, the 5-HT7 receptor. This receptor belongs to the G protein-coupled receptor superfamily and was cloned two decades ago. Later, different splice variants were described but no major functional differences have been described so far. All 5-HT7 receptor variants are coupled to Gαs proteins and stimulate cAMP formation. Recently, several interacting proteins have been reported, which can influence receptor signaling and trafficking. PMID:24042216

  9. Structure of the H107R variant of the extracellular domain of mouse NKR-P1A at 2.3 Å resolution

    International Nuclear Information System (INIS)

    The crystal structure of the H107R variant of the extracellular domain of mouse NKR-P1A was determined using X-ray diffraction from a merohedrally twinned crystal. The structure of the H107R variant of the extracellular domain of the mouse natural killer cell receptor NKR-P1A has been determined by X-ray diffraction at 2.3 Å resolution from a merohedrally twinned crystal. Unlike the structure of the wild-type receptor in space group I4122 with a single chain per asymmetric unit, the crystals of the variant belonged to space group I41 with a dimer in the asymmetric unit. Different degrees of merohedral twinning were detected in five data sets collected from different crystals. The mutation does not have a significant impact on the overall structure, but led to the binding of an additional phosphate ion at the interface of the molecules

  10. IDOL N342S Variant, Atherosclerosis Progression and Cardiovascular Disorders in the Italian General Population.

    Directory of Open Access Journals (Sweden)

    Ashish Dhyani

    Full Text Available Inducible degrader of the low density lipoprotein receptor (IDOL, is an E3 ubiquitin ligase that negatively modulates low density lipoprotein receptor (LDL-R expression. Genome-wide association studies (GWAS indicated that genetic variants in IDOL gene contributes to variation in LDL-C plasma levels and the detailed analysis of a specific locus resulted in the identification of the functional common single nucleotide polymorphism (SNP rs9370867 (c.G1025A, p.N342S associates with increased LDL-R degradation and increased LDL-C levels. These findings, however, were not confirmed in two other independent cohorts and no data about the impact of this variant on atherosclerosis progression and cardiovascular risk are available. Aim of this study was to investigate the association between a functional variant in IDOL and atherosclerosis progression in an Italian general population. 1384 subjects enrolled in the PLIC study (Progression of Lesions in the Intima of Carotid were genotyped by Q-PCR allelic discrimination and the association with anthropometric parameters, plasma lipids and the carotid intima media thickness (cIMT and the impact on cardiovascular disease (CVD incidence were investigated. The N342S variant was not associated with changes of the plasma lipid profile among GG, AG or AA carriers, including total cholesterol (249±21, 249±19 and 248±21 mg/dl respectively, LDL-C (158±25, 161±22 and 160±23 mg/dL, cIMT (0.74±0.14, 0.75±0.17 and 0.77±0.15 mm and CVD incidence. In agreement, the expression of LDLR and the uptake of LDL was similar in macrophages derived from GG and AA carriers. Taken together our findings indicate that the N342S variant does not impact plasma lipid profile and is not associated with atherosclerosis progression and CVD in the general population, suggesting that other variants in the IDOL gene might be functionally linked with cholesterol metabolism.

  11. MC1R gene variants and non-melanoma skin cancer: A pooled-analysis from the M-SKIP project

    NARCIS (Netherlands)

    E. Tagliabue; M.C. Fargnoli (Maria Concetta); S. Gandini (Sara); P. Maisonneuve (Patrick); F. Liu; M. Kayser; T.E.C. Nijsten (Tamar); J. Han; R. Kumar; N.A. Gruis (Nelleke); L. Ferrucci; W. Branicki (Wojciech); T. Dwyer; L. Blizzard; P. Helsing; P.J.M. Autier (Philippe); J.C. García-Borrón (José C); P.A. Kanetsky; M.T. Landi; J. Little; J. Newton-Bishop; J.P. de Sera; S. Raimondi (Susana); S. Raimondi (Sara); P. Autier (Philippe); M.C. Fargnoli (Maria Concetta); J. Han (Jiali); P.A. Kanetsky (Peter A.); M.T. Landi (Maria Teresa); J. Little (Julian); J. Little (Julian); J.A. Newton Bishop (Julia); S. Caini (Saverio); S. Gandini (Sara); P. Maisonneuve (Patrick); A. Hofman (Albert); M.H. Kayser (Manfred); F. Liu (Fan); T.E.C. Nijsten (Tamar); A.G. Uitterlinden (André); R. Kumar (Rajiv); R. Kumar (Rajiv); E. Nagore (Eduardo); J. Hansson (Johan); V. Höiom (Veronica); P. Ghiorzo (Paola); L. Pastorino (Lorenza); N.A. Gruis (Nelleke A.); J.N.B. Bavinck (Jan Nico Bouwes); P. Aguilera (Paula); C. Badenas (Celia); C. Carrera (Cristina); J. Malvehy (Josep); M.P. Mateu (Miriam Potrony); S. Puig (Susana); J.A. Puig-Butille (Joan Anton); G. Tell (Gemma); T. Dwyer (Terence); T. Dwyer (Terry); J. Cochrane (Jennifer); R. Fernandez-De-Misa (Ricardo); W. Branicki (Wojciech); T. Debniak (Tadeusz); N. Morling (Niels); P. Johansen (Peter); S. Mayne (Susan); A. Bale (Allen); B. Cartmel (Brenda); L. Ferrucci (Leah); R. Pfeiffer (Ruth); G. Palmieri (Giuseppe); G. Ribas (Gloria); A. Stratigos (Alexander); K. Kypreou (Katerina); A. Bowcock (Anne); L. Cornelius (Lynn); M.L. Council (M. Laurin); T. Motokawa (Tomonori); S. Anno (Sumiko); H. Anno (Hirofumi); P.A. Andresen (Per Arne); T.H. Wong (Terence H.); M. Berwick (Marianne); M. Berwick (Marianne); I. Orlow (Irene); U. Mujumdar (Urvi); A. Hummer (Amanda); K. Busam (Klaus); P. Roy (Pampa); R. Canchola (Rebecca); B. Clas (Brian); J. Cotignola (Javiar); Y. Monroe (Yvette); B. Armstrong (Bruce); A. Kricker (Anne); M. Litchfield (Melisa); T. Dwye (Terence); P. Tucker (Paul); N. Stephens (Nicola); R. Gallagher (Richard); T. Switzer (Teresa); L. Marrett (Loraine); B. Theis (Beth); L. From (Lynn); N. Chowdhury (Noori); L. Vanasse (Louise); M. Purdue (Mark); D. Northrup (David); R. Zanetti (Roberto); S.M. Rosso (Sonia); C. Sacerdote (Carlotta); H. Anton-Culver (Hoda); N. Leighton (Nancy); M. Gildea (Maureen); S.B. Gruber (Stephen); J. Bonner (Joe); J. Jeter (Joanne); J. Klotz (Judith); H. Wilcox (Homer); H. Weiss (Helen); R.M. Millikan (Robert); N. Thomas (Nancy); D. Mattingly (Dianne); J. Player (Jon); C.-K. Tse (Chiu-Kit); R. Rebbeck (Timothy); P.P. Kanetsky (Peter P.); A. Walker (Amy); S. Panossian (Saarene); H.W. Mohrenweiser (Harvey); R. Setlow (Richard)

    2015-01-01

    textabstractBackground:The melanocortin-1-receptor (MC1R) gene regulates human pigmentation and is highly polymorphic in populations of European origins. The aims of this study were to evaluate the association between MC1R variants and the risk of non-melanoma skin cancer (NMSC), and to investigate

  12. Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers

    DEFF Research Database (Denmark)

    French, Juliet D; Ghoussaini, Maya; Edwards, Stacey L;

    2013-01-01

    Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causativ...

  13. Combined analyses of 20 common obesity susceptibility variants

    DEFF Research Database (Denmark)

    Sandholt, Camilla Helene; Sparsø, Thomas; Grarup, Niels; Albrechtsen, Anders; Almind, Katrine; Hansen, Lars; Toft, Ulla; Jørgensen, Torben; Hansen, Torben; Pedersen, Oluf

    2010-01-01

    Genome-wide association studies and linkage studies have identified 20 validated genetic variants associated with obesity and/or related phenotypes. The variants are common, and they individually exhibit small-to-modest effect sizes.......Genome-wide association studies and linkage studies have identified 20 validated genetic variants associated with obesity and/or related phenotypes. The variants are common, and they individually exhibit small-to-modest effect sizes....

  14. The Structural Determinants behind the Epigenetic Role of Histone Variants

    OpenAIRE

    Manjinder S. Cheema; Juan Ausió

    2015-01-01

    Histone variants are an important part of the histone contribution to chromatin epigenetics. In this review, we describe how the known structural differences of these variants from their canonical histone counterparts impart a chromatin signature ultimately responsible for their epigenetic contribution. In terms of the core histones, H2A histone variants are major players while H3 variant CenH3, with a controversial role in the nucleosome conformation, remains the genuine epigenetic histone v...

  15. Managing Process Variants in the Process Life Cycle

    OpenAIRE

    Hallerbach, A.; Bauer, Th.; Reichert, M.U.

    2007-01-01

    When designing process-aware information systems, often variants of the same process have to be specified. Each variant then constitutes an adjustment of a particular process to specific requirements building the process context. Current Business Process Management (BPM) tools do not adequately support the management of process variants. Usually, the variants have to be kept in separate process models. This leads to huge modeling and maintenance efforts. In particular, more fundamental proces...

  16. Genetic association of marbling score with intragenic nucleotide variants at selection signals of the bovine genome.

    Science.gov (United States)

    Ryu, J; Lee, C

    2016-04-01

    Selection signals of Korean cattle might be attributed largely to artificial selection for meat quality. Rapidly increased intragenic markers of newly annotated genes in the bovine genome would help overcome limited findings of genetic markers associated with meat quality at the selection signals in a previous study. The present study examined genetic associations of marbling score (MS) with intragenic nucleotide variants at selection signals of Korean cattle. A total of 39 092 nucleotide variants of 407 Korean cattle were utilized in the association analysis. A total of 129 variants were selected within newly annotated genes in the bovine genome. Their genetic associations were analyzed using the mixed model with random polygenic effects based on identical-by-state genetic relationships among animals in order to control for spurious associations produced by population structure. Genetic associations of MS were found (Pbovine autosomes 3 (cache domain containing 1, CACHD1), 5 (like-glycosyltransferase, LARGE), 16 (cell division cycle 42 binding protein kinase alpha, CDC42BPA) and 21 (snurportin 1, SNUPN; protein tyrosine phosphatase, non-receptor type 9, PTPN9; chondroitin sulfate proteoglycan 4, CSPG4). In particular, the genetic associations with CDC42BPA and LARGE were confirmed using an independent data set of Korean cattle. The results implied that allele frequencies of functional variants and their proximity variants have been augmented by directional selection for greater MS and remain selection signals in the bovine genome. Further studies of fine mapping would be useful to incorporate favorable alleles in marker-assisted selection for MS of Korean cattle. PMID:26621608

  17. A Crohn's disease variant in Atg16l1 enhances its degradation by caspase 3

    Science.gov (United States)

    Murthy, Aditya; Li, Yun; Peng, Ivan; Reichelt, Mike; Katakam, Anand Kumar; Noubade, Rajkumar; Roose-Girma, Merone; Devoss, Jason; Diehl, Lauri; Graham, Robert R.; van Lookeren Campagne, Menno

    2014-02-01

    Crohn's disease is a debilitating inflammatory bowel disease (IBD) that can involve the entire digestive tract. A single-nucleotide polymorphism (SNP) encoding a missense variant in the autophagy gene ATG16L1 (rs2241880, Thr300Ala) is strongly associated with the incidence of Crohn's disease. Numerous studies have demonstrated the effect of ATG16L1 deletion or deficiency; however, the molecular consequences of the Thr300Ala (T300A) variant remains unknown. Here we show that amino acids 296-299 constitute a caspase cleavage motif in ATG16L1 and that the T300A variant (T316A in mice) significantly increases ATG16L1 sensitization to caspase-3-mediated processing. We observed that death-receptor activation or starvation-induced metabolic stress in human and murine macrophages increased degradation of the T300A or T316A variants of ATG16L1, respectively, resulting in diminished autophagy. Knock-in mice harbouring the T316A variant showed defective clearance of the ileal pathogen Yersinia enterocolitica and an elevated inflammatory cytokine response. In turn, deletion of the caspase-3-encoding gene, Casp3, or elimination of the caspase cleavage site by site-directed mutagenesis rescued starvation-induced autophagy and pathogen clearance, respectively. These findings demonstrate that caspase 3 activation in the presence of a common risk allele leads to accelerated degradation of ATG16L1, placing cellular stress, apoptotic stimuli and impaired autophagy in a unified pathway that predisposes to Crohn's disease.

  18. Genetic variants in AVPR1A linked to autism predict amygdala activation and personality traits in healthy humans

    OpenAIRE

    Meyer-Lindenberg, A; Kolachana, B; Gold, B; Olsh, A; Nicodemus, KK; Mattay, V; Dean, M.; Weinberger, DR

    2008-01-01

    In mammals, the neuropeptide vasopressin is a key molecule for complex emotional and social behaviours. Two microsatellite polymorphisms, RS1 and RS3, near the promoter of AVPR1A, encoding the receptor subtype most heavily implicated in behaviour regulation, have been linked to autism and behavioural traits. However, the impact of these variants on human brain function is unknown. Here we show that human amygdala function is strongly associated with genetic variation in AVPR1A. Using an imagi...

  19. Identification of Genome-Wide Variants and Discovery of Variants Associated with Brassica rapa Clubroot Resistance Gene Rcr1 through Bulked Segregant RNA Sequencing.

    Science.gov (United States)

    Yu, Fengqun; Zhang, Xingguo; Huang, Zhen; Chu, Mingguang; Song, Tao; Falk, Kevin C; Deora, Abhinandan; Chen, Qilin; Zhang, Yan; McGregor, Linda; Gossen, Bruce D; McDonald, Mary Ruth; Peng, Gary

    2016-01-01

    Clubroot, caused by Plasmodiophora brassicae, is an important disease on Brassica species worldwide. A clubroot resistance gene, Rcr1, with efficacy against pathotype 3 of P. brassicae, was previously mapped to chromosome A03 of B. rapa in pak choy cultivar "Flower Nabana". In the current study, resistance to pathotypes 2, 5 and 6 was shown to be associated with Rcr1 region on chromosome A03. Bulked segregant RNA sequencing was performed and short read sequences were assembled into 10 chromosomes of the B. rapa reference genome v1.5. For the resistant (R) bulks, a total of 351.8 million (M) sequences, 30,836.5 million bases (Mb) in length, produced 120-fold coverage of the reference genome. For the susceptible (S) bulks, 322.9 M sequences, 28,216.6 Mb in length, produced 109-fold coverage. In total, 776.2 K single nucleotide polymorphisms (SNPs) and 122.2 K insertion / deletion (InDels) in R bulks and 762.8 K SNPs and 118.7 K InDels in S bulks were identified; each chromosome had about 87% SNPs and 13% InDels, with 78% monomorphic and 22% polymorphic variants between the R and S bulks. Polymorphic variants on each chromosome were usually below 23%, but made up 34% of the variants on chromosome A03. There were 35 genes annotated in the Rcr1 target region and variants were identified in 21 genes. The numbers of poly variants differed significantly among the genes. Four out of them encode Toll-Interleukin-1 receptor / nucleotide-binding site / leucine-rich-repeat proteins; Bra019409 and Bra019410 harbored the higher numbers of polymorphic variants, which indicates that they are more likely candidates of Rcr1. Fourteen SNP markers in the target region were genotyped using the Kompetitive Allele Specific PCR method and were confirmed to associate with Rcr1. Selected SNP markers were analyzed with 26 recombinants obtained from a segregating population consisting of 1587 plants, indicating that they were completely linked to Rcr1. Nine SNP markers were used for marker

  20. Identification of Genome-Wide Variants and Discovery of Variants Associated with Brassica rapa Clubroot Resistance Gene Rcr1 through Bulked Segregant RNA Sequencing

    Science.gov (United States)

    Yu, Fengqun; Zhang, Xingguo; Huang, Zhen; Chu, Mingguang; Song, Tao; Falk, Kevin C.; Deora, Abhinandan; Chen, Qilin; Zhang, Yan; McGregor, Linda; Gossen, Bruce D.; McDonald, Mary Ruth; Peng, Gary

    2016-01-01

    Clubroot, caused by Plasmodiophora brassicae, is an important disease on Brassica species worldwide. A clubroot resistance gene, Rcr1, with efficacy against pathotype 3 of P. brassicae, was previously mapped to chromosome A03 of B. rapa in pak choy cultivar “Flower Nabana”. In the current study, resistance to pathotypes 2, 5 and 6 was shown to be associated with Rcr1 region on chromosome A03. Bulked segregant RNA sequencing was performed and short read sequences were assembled into 10 chromosomes of the B. rapa reference genome v1.5. For the resistant (R) bulks, a total of 351.8 million (M) sequences, 30,836.5 million bases (Mb) in length, produced 120-fold coverage of the reference genome. For the susceptible (S) bulks, 322.9 M sequences, 28,216.6 Mb in length, produced 109-fold coverage. In total, 776.2 K single nucleotide polymorphisms (SNPs) and 122.2 K insertion / deletion (InDels) in R bulks and 762.8 K SNPs and 118.7 K InDels in S bulks were identified; each chromosome had about 87% SNPs and 13% InDels, with 78% monomorphic and 22% polymorphic variants between the R and S bulks. Polymorphic variants on each chromosome were usually below 23%, but made up 34% of the variants on chromosome A03. There were 35 genes annotated in the Rcr1 target region and variants were identified in 21 genes. The numbers of poly variants differed significantly among the genes. Four out of them encode Toll-Interleukin-1 receptor / nucleotide-binding site / leucine-rich-repeat proteins; Bra019409 and Bra019410 harbored the higher numbers of polymorphic variants, which indicates that they are more likely candidates of Rcr1. Fourteen SNP markers in the target region were genotyped using the Kompetitive Allele Specific PCR method and were confirmed to associate with Rcr1. Selected SNP markers were analyzed with 26 recombinants obtained from a segregating population consisting of 1587 plants, indicating that they were completely linked to Rcr1. Nine SNP markers were used for marker

  1. Investigation of the vitamin D receptor gene (VDR) and its interaction with protein tyrosine phosphatase, non-receptor type 2 gene (PTPN2) on risk of islet autoimmunity and type 1 diabetes : The Diabetes Autoimmunity Study in the Young (DAISY)

    NARCIS (Netherlands)

    Frederiksen, B.; Liu, E.; Romanos, J.; Steck, A. K.; Yin, X.; Kroehl, M.; Fingerlin, T. E.; Erlich, H.; Eisenbarth, G. S.; Rewers, M.; Norris, J. M.

    2013-01-01

    The present study investigated the association between variants in the vitamin D receptor gene (VDR) and protein tyrosine phosphatase, non-receptor type 2 gene (PTPN2), as well as an interaction between VDR and PTPN2 and the risk of islet autoimmunity (IA) and progression to type 1 diabetes (T1D). T

  2. Identifying causal variants at loci with multiple signals of association.

    Science.gov (United States)

    Hormozdiari, Farhad; Kostem, Emrah; Kang, Eun Yong; Pasaniuc, Bogdan; Eskin, Eleazar

    2014-10-01

    Although genome-wide association studies have successfully identified thousands of risk loci for complex traits, only a handful of the biologically causal variants, responsible for association at these loci, have been successfully identified. Current statistical methods for identifying causal variants at risk loci either use the strength of the association signal in an iterative conditioning framework or estimate probabilities for variants to be causal. A main drawback of existing methods is that they rely on the simplifying assumption of a single causal variant at each risk locus, which is typically invalid at many risk loci. In this work, we propose a new statistical framework that allows for the possibility of an arbitrary number of causal variants when estimating the posterior probability of a variant being causal. A direct benefit of our approach is that we predict a set of variants for each locus that under reasonable assumptions will contain all of the true causal variants with a high confidence level (e.g., 95%) even when the locus contains multiple causal variants. We use simulations to show that our approach provides 20-50% improvement in our ability to identify the causal variants compared to the existing methods at loci harboring multiple causal variants. We validate our approach using empirical data from an expression QTL study of CHI3L2 to identify new causal variants that affect gene expression at this locus. CAVIAR is publicly available online at http://genetics.cs.ucla.edu/caviar/. PMID:25104515

  3. Variant of Rett syndrome and CDKL5 gene

    DEFF Research Database (Denmark)

    Pini, Giorgio; Bigoni, Stefania; Engerström, Ingegerd Witt;

    2012-01-01

    UNLABELLED: Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively females. The Hanefeld variant, or early-onset seizure variant, has been associated with mutations in CDKL5 gene. AIMS: In recent years more than 60 patients with mutations in the CDKL5 gene have...... the general Rett population, suggesting a specific behavioral and cardiorespiratory phenotype of the RTT the Hanefeld variant....

  4. Genetics Home Reference: GM2-gangliosidosis, AB variant

    Science.gov (United States)

    ... of GM2-gangliosidosis, AB variant: Genetic Testing Registry: Tay-Sachs disease, variant AB These resources from MedlinePlus offer ... AB variant Activator Deficiency/GM2 Gangliosidosis Activator-deficient Tay-Sachs disease GM2 Activator Deficiency Disease GM2 gangliosidosis, type ...

  5. Role of adipokinetic hormone and adenosine in the anti-stress response in Drosophila melanogaster.

    Science.gov (United States)

    Zemanová, Milada; Stašková, Tereza; Kodrík, Dalibor

    2016-01-01

    The role of adipokinetic hormone (AKH) and adenosine in the anti-stress response was studied in Drosophila melanogaster larvae and adults carrying a mutation in the Akh gene (Akh(1)), the adenosine receptor gene (AdoR(1)), or in both of these genes (Akh(1) AdoR(1) double mutant). Stress was induced by starvation or by the addition of an oxidative stressor paraquat (PQ) to food. Mortality tests revealed that the Akh(1) mutant was the most resistant to starvation, while the AdoR(1) mutant was the most sensitive. Conversely, the Akh(1) AdoR(1) double mutant was more sensitive to PQ toxicity than either of the single mutants. Administration of PQ significantly increased the Drome-AKH level in w(1118) and AdoR(1) larvae; however, this was not accompanied by a simultaneous increase in Akh gene expression. In contrast, PQ significantly increased the expression of the glutathione S-transferase D1 (GstD1) gene. The presence of both a functional adenosine receptor and AKH seem to be important for the proper control of GstD1 gene expression under oxidative stress, however, the latter appears to play more dominant role. On the other hand, differences in glutathione S-transferase (GST) activity among the strains, and between untreated and PQ-treated groups were minimal. In addition, the glutathione level was significantly lower in all untreated AKH- or AdoR-deficient mutant flies as compared with the untreated control w(1118) flies and further declined following treatment with PQ. All oxidative stress characteristics modified by mutations in Akh gene were restored or even improved by 'rescue' mutation in flies which ectopically express Akh. Thus, the results of the present study demonstrate the important roles of AKH and adenosine in the anti-stress response elicited by PQ in a D. melanogaster model, and provide the first evidence for the involvement of adenosine in the anti-oxidative stress response in insects. PMID:27374982

  6. Ancient human sialic acid variant restricts an emerging zoonotic malaria parasite

    OpenAIRE

    Dankwa, Selasi; Lim, Caeul; Bei, Amy K.; Jiang, Rays H. Y.; Abshire, James R.; Patel, Saurabh D.; Goldberg, Jonathan M; Moreno, Yovany; Kono, Maya; Niles, Jacquin C.; Duraisingh, Manoj T.

    2016-01-01

    Plasmodium knowlesi is a zoonotic parasite transmitted from macaques causing malaria in humans in Southeast Asia. Plasmodium parasites bind to red blood cell (RBC) surface receptors, many of which are sialylated. While macaques synthesize the sialic acid variant N-glycolylneuraminic acid (Neu5Gc), humans cannot because of a mutation in the enzyme CMAH that converts N-acetylneuraminic acid (Neu5Ac) to Neu5Gc. Here we reconstitute CMAH in human RBCs for the reintroduction of Neu5Gc, which resul...

  7. The Oxytocin Receptor Gene (OXTR) in Relation to State Levels of Loneliness in Adolescence: Evidence for Micro-Level Gene-Environment Interactions

    OpenAIRE

    2013-01-01

    Previous research has shown that the rs53576 variant of the oxytocin receptor gene (OXTR) is associated with trait levels of loneliness, but results are inconsistent. The aim of the present study is to examine micro-level effects of the OXTR rs53576 variant on state levels of loneliness in early adolescents. In addition, gene-environment interactions are examined between this OXTR variant and positive and negative perceptions of company. Data were collected in 278 adolescents (58% girls), by ...

  8. Studies of associations between the Arg389Gly polymorphism of the beta1-adrenergic receptor gene (ADRB1) and hypertension and obesity in 7677 Danish white subjects

    DEFF Research Database (Denmark)

    Gjesing, A P; Andersen, G; Albrechtsen, A; Glümer, C; Borch-Johnsen, K; Jørgensen, T; Hansen, T; Pedersen, O

    2007-01-01

    Activation of the beta(1)-adrenergic receptor (ADRB1) causes increased lipolysis in adipose tissue and enhances cardiac output. Analysis of the association of the functional ADRB1 Arg389Gly variant with obesity and hypertension has given ambiguous results. To clarify the potential impact of this...... variant on obesity and hypertension in the general population, we examined the Arg389Gly variant in a relatively large-scale population-based study....

  9. Angiography of histopathologic variants of synovial sarcoma

    International Nuclear Information System (INIS)

    Synovial sarcomas are rare soft tissue tumors which histopathologically can be divided into monophasic, biphasic and mixed variants. As part of a protocol for intra-arterial chemotherapy 12 patients with biopsy proven synovial sarcoma underwent angiography. The angiograms on these patients were reviewed to determine whether synovial sarcomas and their variants demonstrated a characteristic angiographic appearance. Synovial sarcomas appeared angiographically as soft tissue masses which showed a fine network of tumor vessels with an inhomogeneous capillary blush. Their degree of vascularity varied according to their histopathology. Monophasic synovial sarcomas demonstrated in general a higher degree of neovascularity than the biphasic form. This finding was also suggested by histopathologic analysis of the vessels in the tumor. Although angiography did not show a distinctive vascular pattern it may be useful to evaluate tumor size and vascularity. (orig.)

  10. The Saccharomyces Genome Database Variant Viewer.

    Science.gov (United States)

    Sheppard, Travis K; Hitz, Benjamin C; Engel, Stacia R; Song, Giltae; Balakrishnan, Rama; Binkley, Gail; Costanzo, Maria C; Dalusag, Kyla S; Demeter, Janos; Hellerstedt, Sage T; Karra, Kalpana; Nash, Robert S; Paskov, Kelley M; Skrzypek, Marek S; Weng, Shuai; Wong, Edith D; Cherry, J Michael

    2016-01-01

    The Saccharomyces Genome Database (SGD; http://www.yeastgenome.org) is the authoritative community resource for the Saccharomyces cerevisiae reference genome sequence and its annotation. In recent years, we have moved toward increased representation of sequence variation and allelic differences within S. cerevisiae. The publication of numerous additional genomes has motivated the creation of new tools for their annotation and analysis. Here we present the Variant Viewer: a dynamic open-source web application for the visualization of genomic and proteomic differences. Multiple sequence alignments have been constructed across high quality genome sequences from 11 different S. cerevisiae strains and stored in the SGD. The alignments and summaries are encoded in JSON and used to create a two-tiered dynamic view of the budding yeast pan-genome, available at http://www.yeastgenome.org/variant-viewer. PMID:26578556

  11. Development of industrial variant specification systems

    DEFF Research Database (Denmark)

    Hansen, Benjamin Loer

    With globalisation and increased competition industrial companies must be prepared to satisfy individual customer needs and still stay competitive with regards to lead times, quality, and prices. These factors require companies to be better prepared to handle specification activities during order...... developed from a holistic and strategically anchored point of view. Another assumption is that this is a challenge for many industrial companies. Even though the literature presents many considerations on general issues covering new information technology, little work is found on the business perspectives...... and the challenge of understanding the variant specification tasks and the connections between variant specification, product development, sales, manufacturing, and information technology. The present thesis seeks to meet this challenge with a procedure, concepts and tools. This is done through an...

  12. Wham: Identifying Structural Variants of Biological Consequence.

    Directory of Open Access Journals (Sweden)

    Zev N Kronenberg

    2015-12-01

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

  13. DRD4 rare variants in Attention-Deficit/Hyperactivity Disorder (ADHD: further evidence from a birth cohort study.

    Directory of Open Access Journals (Sweden)

    Luciana Tovo-Rodrigues

    Full Text Available The dopamine receptor D4 (DRD4 is one of the most studied candidate genes for Attention-Deficit/Hyperactivity Disorder (ADHD. An excess of rare variants and non-synonymous mutations in the VNTR region of 7R allele in ADHD subjects was observed in previous studies with clinical samples. We hypothesize that genetic heterogeneity in the VNTR is an important factor in the pathophysiology of ADHD. The subjects included in the present study are members of the 1993 Pelotas Birth Cohort Study (N=5,249. We conducted an association study with the 4,101 subjects who had DNA samples collected. The hyperactivity-inattention scores were assessed through the parent version of the Strengths and Difficulties Questionnaire at 11 and 15 years of age. The contribution of allele's length and rare variants to high hyperactivity/inattention scores predisposition was evaluated by multivariate logistic regression. No effect of allele length was observed on high scores of hyperactivity-inattention. By contrast, when resequencing/haplotyping was conducted in a subsample, all 7R rare variants as well as non-synonymous 7R rare variants were associated with high hyperactivity/inattention scores (OR=2.561; P=0.024 and OR=3.216; P=0.008 respectively. A trend for association was observed with 4R rare variants. New coding mutations covered 10 novel motifs and many of them are previously unreported deletions leading to different stop codons. Our findings suggest a contribution of DRD4 7R rare variants to high hyperactivity-inattention scores in a population-based sample from a large birth cohort. These findings provide further evidence for an effect of DRD4 7R rare variants and allelic heterogeneity in ADHD genetic susceptibility.

  14. Cough variant asthma and atopic cough

    OpenAIRE

    Magni Chiara; Chellini Elisa; Zanasi Alessandro

    2010-01-01

    Abstract Chronic cough has been reported to be the fifth most common complaint seen by primary care physicians in the world, the third in Italy. Chronic cough in non-smoking, non-treated with ACE-inhibitor adults with normal chest radiogram could be a symptom of asthma and can be sub-classified into: cough-variant asthma, atopic cough, and eosinophilic bronchitis. This review discusses the differential diagnosis of these three disorders.

  15. A Secure Variant of the Hill Cipher

    CERN Document Server

    Toorani, Mohsen; 10.1109/ISCC.2009.5202241

    2010-01-01

    The Hill cipher is a classical symmetric encryption algorithm that succumbs to the know-plaintext attack. Although its vulnerability to cryptanalysis has rendered it unusable in practice, it still serves an important pedagogical role in cryptology and linear algebra. In this paper, a variant of the Hill cipher is introduced that makes the Hill cipher secure while it retains the efficiency. The proposed scheme includes a ciphering core for which a cryptographic protocol is introduced.

  16. Variant position of the medial plantar nerve

    OpenAIRE

    Astik RB; Dave UH; Gajendra KS

    2011-01-01

    Knowledge of variation of position of the medial plantar nerve is important for the forefoot surgeon for plantar reconstruction, local injection therapy and an excision of interdigital neuroma. During routine dissection of 50-year-old female cadaver, we found the medial plantar nerve and vessels variably located between plantar aponeurosis and the muscles of the first layer of the sole of the right foot. Due to this variant position, the medial plantar nerve and vessels lose their protection ...

  17. The Saccharomyces Genome Database Variant Viewer

    OpenAIRE

    Sheppard, Travis K.; Gabdank, Idan; Engel, Stacia R.; Song, Giltae; Balakrishnan, Rama; Binkley, Gail; Costanzo, Maria C.; Dalusag, Kyla S.; Demeter, Janos; Hellerstedt, Sage T.; Karra, Kalpana; Nash, Robert S.; Paskov, Kelley M.; Skrzypek, Marek S.; Weng, Shuai

    2015-01-01

    The Saccharomyces Genome Database (SGD; http://www.yeastgenome.org) is the authoritative community resource for the Saccharomyces cerevisiae reference genome sequence and its annotation. In recent years, we have moved toward increased representation of sequence variation and allelic differences within S. cerevisiae. The publication of numerous additional genomes has motivated the creation of new tools for their annotation and analysis. Here we present the Variant Viewer: a dynamic open-source...

  18. MRI anatomical variants of mammillary bodies.

    Science.gov (United States)

    Tagliamonte, Micaela; Sestieri, Carlo; Romani, Gian Luca; Gallucci, Massimo; Caulo, Massimo

    2015-01-01

    The mammillary bodies (MBs) are classically defined as a pair of small round structures located on the undersurface of the diencephalon. The systematic observation of MR brain images of patients with neurological diseases, but also of healthy subjects enrolled in research protocols, reveals, however, a greater anatomical variability. The aim of the present study was to define the spectrum of such variability using spatial normalized 3D TFE T1-weighted MR images in a group of 151 healthy right-handed young subjects (78 females, age range 16-39 years). The MBs were identified on reformatted coronal and axial images and classified according to morphological, positional and numerical criteria. On the basis of coronal images, MBs were first divided into symmetrical (86.1 %) and asymmetrical (13.9 %), depending on their respective height. Symmetrical MBs were further subdivided into three variants [type A (2.7 %), B (76.2 %), C (7.3 %)] according to the depth of the intermammillary sulcus. Two morphological variants were defined on axial images, depending on whether the MBs were circular (63.6 %) or elliptic (36.4 %). This latter group was further divided in two subgroups, depending on whether the MBs were parallel (21.9 %) or convergent (14.6 %). Finally, two subjects (1.3 %) presented a supernumeral MB. The transverse size of the third ventricle was greater in the type A compared to the type B and C groups. Gender did not significantly affect the frequency of MBs variants, except for the three symmetrical subgroups in which the variants A and C were more frequent in males than in females. These findings suggest the presence of an anatomical variability of the MBs, in contrast to their classical definition. Therefore, atypical presentation of MBs can be the expression of this variability rather than a marker of neurological disorders (i.e. cerebral malformation, mesial temporal sclerosis, Wernicke-Korsakoff syndrome). PMID:24072163

  19. Lipoleiomyoma: A rare variant of uterine leiomyoma

    OpenAIRE

    D. Manimaran; Dost Mohamed Khan; Saba Yasmin; Anuradha, S.

    2014-01-01

    Uterine fatty tumors are rare variants of benign leiomyoma. Lipoleiomyoma, lipomyoma, fibromyolipoma are various synonyms for this lesion. They usually occur in the obese perimenopausal and postmenopausal females in the age group 50-70 years and 90% cases occur in patients older than 40 years. There were only few cases reported in the literature. These lesions are interesting due to the occasional diagnostic confusion with sarcomas and the curiosity regarding its histogenesis. We are presenti...

  20. Combination of TRAIL with Bortezomib Shifted Apoptotic Signaling from DR4 to DR5 Death Receptor by Selective Internalization and Degradation of DR4

    OpenAIRE

    Bychkov, Maxim L.; Gasparian, Marine E.; Dolgikh, Dmitry A; Kirpichnikov, Mikhail P.

    2014-01-01

    TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) mediates apoptosis in cancer cells through death receptors DR4 and DR5 preferring often one receptor over another in the cells expressing both receptors. Receptor selective mutant variants of TRAIL and agonistic antibodies against DR4 and DR5 are highly promising anticancer agents. Here using DR5 specific mutant variant of TRAIL - DR5-B we have demonstrated for the first time that the sensitivity of cancer cells can be shifted fr...

  1. MR imaging of the ankle: Normal variants

    International Nuclear Information System (INIS)

    Thirty asymptomatic ankles were studied with high-resolution surface coil MR imaging. The thirty ankles were reviewed for identification or normal structures. The MR appearance of the deltoid and posterior to talo-fibular ligaments, peroneous brevis and longus tendons, and posterior aspect of the tibial-talar joint demonstrated several normal variants not previously described. These should not be misinterpreted as pathologic processes. The specific findings included (1) cortical irregularity of the posterior tibial-talar joint in 27 of 30 cases which should not be mistaken for osteonecrois; (2) normal posterior talo-fibular ligament with irregular and frayed inhomogeneity, which represents a normal variant in seven of ten cases; and (3) fluid in the shared peroneal tendons sheath which may be confused for a longitudinal tendon tear in three of 30 cases. Ankle imaging with the use of MR is still a relatively new procedure. Further investigation is needed to better define normal anatomy as well as normal variants. The authors described several structures that normally present with variable MR imaging appearances. This is clinically significant in order to maintain a high sensitivity and specificity in MR imaging interpretation

  2. Association of genetic variants with diabetic nephropathy

    Institute of Scientific and Technical Information of China (English)

    Saliha; Rizvi; Syed; Tasleem; Raza; Farzana; Mahdi

    2014-01-01

    Diabetic nephropathy accounts for the most serious microvascular complication of diabetes mellitus. It is suggested that the prevalence of diabetic nephropathy will continue to increase in future posing a major challenge to the healthcare system resulting in increased morbidity and mortality. It occurs as a result of interaction between both genetic and environmental factors in individuals with both type 1 and type 2 diabetes. Genetic susceptibility has been proposed as an important factor for the development and progression of diabetic nephropathy, and various research efforts are being executed worldwide to identify the susceptibility gene for diabetic nephropathy. Numerous single nucleotide polymorphisms have been found in various genes giving rise to various gene variants which have been found to play a major role in genetic susceptibility to diabetic nephropathy. The risk of developing diabetic nephropathy is increased several times by inheriting risk alleles at susceptibility loci of various genes like ACE, IL, TNF-α, COL4A1, e NOS, SOD2, APOE, GLUT, etc. The identification of these genetic variants at a biomarker level could thus, allow the detection of those individuals at high risk for diabetic nephropathy which could thus help in the treatment, diagnosis and early prevention of the disease. The present review discusses about the various gene variants found till date to be associated with diabetic nephropathy.

  3. Alpha1a-Adrenoceptor Genetic Variant Triggers Vascular Smooth Muscle Cell Hyperproliferation and Agonist Induced Hypertrophy via EGFR Transactivation Pathway.

    Directory of Open Access Journals (Sweden)

    Irina Gradinaru

    Full Text Available α1a Adrenergic receptors (α1aARs are the predominant AR subtype in human vascular smooth muscle cells (SMCs. α1aARs in resistance vessels are crucial in the control of blood pressure, yet the impact of naturally occurring human α1aAR genetic variants in cardiovascular disorders remains poorly understood. To this end, we present novel findings demonstrating that 3D cultures of vascular SMCs expressing human α1aAR-247R (247R genetic variant demonstrate significantly increased SMC contractility compared with cells expressing the α1aAR-WT (WT receptor. Stable expression of 247R genetic variant also triggers MMP/EGFR-transactivation dependent serum- and agonist-independent (constitutive hyperproliferation and agonist-dependent hypertrophy of SMCs. Agonist stimulation reduces contractility Using pathway-specific inhibitors we determined that the observed hyperproliferation of 247R-expressing cells is triggered via β-arrestin1/Src/MMP-2/EGFR/ERK-dependent mechanism. MMP-2-specific siRNA inhibited 247R-triggered hyperproliferation indicating MMP-2 involvement in 247R-triggered hyperproliferation in SMCs. β-arrestin1-specific shRNA also inhibited 247R-triggered hyperproliferation but did not affect hypertrophy in 247R-expressing SMCs, indicating that agonist-dependent hypertrophy is independent of β-arrestin1. Our data reveal that in different cardiovascular cells the same human receptor genetic variant can activate alternative modulators of the same signaling pathway. Thus, our findings in SMCs demonstrate that depending on the type of cells expressing the same receptor (or receptor variant, different target-specific inhibitors could be used to modulate aberrant hyperproliferative or hypertrophic pathways in order to restore normal phenotype.

  4. Modulation of Transcriptional Activation and Coactivator Interaction by a Splicing Variation in the F Domain of Nuclear Receptor Hepatocyte Nuclear Factor 4α1

    OpenAIRE

    Sladek, Frances M.; Ruse, Michael D.; Nepomuceno, Luviminda; Huang, Shih-Ming; Stallcup, Michael R.

    1999-01-01

    Transcription factors, such as nuclear receptors, often exist in various forms that are generated by highly conserved splicing events. Whereas the functional significance of these splicing variants is often not known, it is known that nuclear receptors activate transcription through interaction with coactivators. The parameters, other than ligands, that might modulate those interactions, however, are not well characterized, nor is the role of splicing variants. In this study, transient transf...

  5. Contrasting changes in DRD1 and DRD2 splice variant expression in schizophrenia and affective disorders, and associations with SNPs in postmortem brain

    DEFF Research Database (Denmark)

    Kaalund, S S; Newburn, E N; Ye, Tuo;

    2014-01-01

    working memory that relies on normal dorsolateral prefrontal cortex (DLPFC) function. To better understand the association of dopamine receptors with SCZ, we studied the expression of three DRD2 splice variants and the DRD1 transcript in DLPFC, hippocampus and caudate nucleus in a large cohort of subjects......Dopamine 2 receptor (DRD2) is of major interest to the pathophysiology of schizophrenia (SCZ) both as a target for antipsychotic drug action as well as a SCZ-associated risk gene. The dopamine 1 receptor (DRD1) is thought to mediate some of the cognitive deficits in SCZ, including impairment of...

  6. [Pathophysiology, diagnosis and treatment of cough variant asthma].

    Science.gov (United States)

    Fujimura, Masaki

    2014-05-01

    Cough variant asthma (CVA) has been recognized as a precursor of asthma or a pre-asthmatic state because of the mildly heightened bronchial responsiveness and efficacy of bronchodilator therapy. Nevertheless, the accumulating evidence indicates that the pathophysiology is different between CVA and bronchial asthma. The most fundamental physiologic feature is a heightened cough response to methacholine-induced bronchoconstriction in CVA, while this response is rather reduced in bronchial asthma. The sensitivity of cough receptors located in the superficial layer of the airway wall is normal in CVA as well as bronchial asthma, but heightened in atopic cough. The pathologic feature of CVA is eosinophilic inflammation of the central to peripheral airway, reflected by eosinophilia in induced sputum, biopsied bronchial mucosa, and bronchoalveolar lavage fluid. The diagnosis of CVA has been commonly made based on therapeutic diagnostic procedures, while pathophysiologic diagnosis is ideal. The reason is that measurements of the sensitivity of cough receptors to inhaled capsaicin and cough response to induced bronchoconstriction are not possible at most chest clinics in the world. The efficacy of a beta2-agonist for a patient's coughing is evaluated to make a diagnosis of CVA. When the bronchodilator therapy is judged as efficacious, a tentative diagnosis of CVA is made. Then, induction therapy is initiated for resolution of the cough. The induction therapy consists of beta2-agonists, leukotriene receptor antagonists, and inhaled corticosteroids. In some patients whose cough does not subside with the therapy, short-burst oral corticosteroids (1 to 3 weeks) may be added. If the cough still does not subside with the therapy, the patient should be referred to cough specialists. When the cough subsides with the induction therapy, long-term management is recommended using inhaled corticosteroids, because 30% of patients develop typical bronchial asthma within several years

  7. Splicing analysis of 14 BRCA1 missense variants classifies nine variants as pathogenic

    DEFF Research Database (Denmark)

    Ahlborn, Lise B; Dandanell, Mette; Steffensen, Ane Y;

    2015-01-01

    needed to classify whether these uncertain variants are pathogenic or benign. In this study, we investigated 14 BRCA1 variants by in silico splicing analysis and mini-gene splicing assay. All 14 alterations were missense variants located within the BRCT domain of BRCA1 and had previously been examined by...... functional analysis at the protein level. Results from a validated mini-gene splicing assay indicated that nine BRCA1 variants resulted in splicing aberrations leading to truncated transcripts and thus can be considered pathogenic (c.4987A>T/p.Met1663Leu, c.4988T>A/p.Met1663Lys, c.5072C>T/p.Thr1691Ile, c...... have no or an uncertain effect on the protein level, whereas one variant (c.5072C>T/p.Thr1691Ile) were shown to have a strong effect on the protein level as well. In conclusion, our study emphasizes that in silico splicing prediction and mini-gene splicing analysis are important for the classification...

  8. Personal receptor repertoires: olfaction as a model

    Directory of Open Access Journals (Sweden)

    Olender Tsviya

    2012-08-01

    Full Text Available Abstract Background Information on nucleotide diversity along completely sequenced human genomes has increased tremendously over the last few years. This makes it possible to reassess the diversity status of distinct receptor proteins in different human individuals. To this end, we focused on the complete inventory of human olfactory receptor coding regions as a model for personal receptor repertoires. Results By performing data-mining from public and private sources we scored genetic variations in 413 intact OR loci, for which one or more individuals had an intact open reading frame. Using 1000 Genomes Project haplotypes, we identified a total of 4069 full-length polypeptide variants encoded by these OR loci, average of ~10 per locus, constituting a lower limit for the effective human OR repertoire. Each individual is found to harbor as many as 600 OR allelic variants, ~50% higher than the locus count. Because OR neuronal expression is allelically excluded, this has direct effect on smell perception diversity of the species. We further identified 244 OR segregating pseudogenes (SPGs, loci showing both intact and pseudogene forms in the population, twenty-six of which are annotatively “resurrected” from a pseudogene status in the reference genome. Using a custom SNP microarray we validated 150 SPGs in a cohort of 468 individuals, with every individual genome averaging 36 disrupted sequence variations, 15 in homozygote form. Finally, we generated a multi-source compendium of 63 OR loci harboring deletion Copy Number Variations (CNVs. Our combined data suggest that 271 of the 413 intact OR loci (66% are affected by nonfunctional SNPs/indels and/or CNVs. Conclusions These results portray a case of unusually high genetic diversity, and suggest that individual humans have a highly personalized inventory of functional olfactory receptors, a conclusion that might apply to other receptor multigene families.

  9. Microsatellite Instability Use in Mismatch Repair Gene Sequence Variant Classification

    Directory of Open Access Journals (Sweden)

    Bryony A. Thompson

    2015-03-01

    Full Text Available Inherited mutations in the DNA mismatch repair genes (MMR can cause MMR deficiency and increased susceptibility to colorectal and endometrial cancer. Microsatellite instability (MSI is the defining molecular signature of MMR deficiency. The clinical classification of identified MMR gene sequence variants has a direct impact on the management of patients and their families. For a significant proportion of cases sequence variants of uncertain clinical significance (also known as unclassified variants are identified, constituting a challenge for genetic counselling and clinical management of families. The effect on protein function of these variants is difficult to interpret. The presence or absence of MSI in tumours can aid in determining the pathogenicity of associated unclassified MMR gene variants. However, there are some considerations that need to be taken into account when using MSI for variant interpretation. The use of MSI and other tumour characteristics in MMR gene sequence variant classification will be explored in this review.

  10. Differential expression and functionality of TRPA1 protein genetic variants in conditions of thermal stimulation.

    Science.gov (United States)

    May, Denisa; Baastrup, Jonas; Nientit, Maria Raphaela; Binder, Andreas; Schünke, Michael; Baron, Ralf; Cascorbi, Ingolf

    2012-08-01

    The role of genetic modifications of the TRPA1 receptor has been well documented in inflammatory and neuropathic pain. We recently reported that the E179K variant of TRPA1 appears to be crucial for the generation of paradoxical heat sensation in pain patients. Here, we describe the consequences of the single amino acid exchange at position 179 in the ankyrin repeat 4 of human TRPA1. TRPA1 wild type Lys-179 protein expressed in HEK cells exhibited intact biochemical properties, inclusive trafficking into the plasma membrane, formation of large protein complexes, and the ability to be activated by cold. Additionally, a strong increase of Lys-179 protein expression was observed in cold (4 °C) and heat (49 °C)-treated cells. In contrast, HEK cells expressing the variant Lys-179 TRPA1 failed to get activated by cold possibly due to the loss of ability to interact with other proteins or other TRPA1 monomers during oligomerization. In conclusion, the detailed understanding of TRPA1 genetic variants might provide a fruitful strategy for future development of pain treatments. PMID:22665484

  11. Differential Expression and Functionality of TRPA1 Protein Genetic Variants in Conditions of Thermal Stimulation*

    Science.gov (United States)

    May, Denisa; Baastrup, Jonas; Nientit, Maria Raphaela; Binder, Andreas; Schünke, Michael; Baron, Ralf; Cascorbi, Ingolf

    2012-01-01

    The role of genetic modifications of the TRPA1 receptor has been well documented in inflammatory and neuropathic pain. We recently reported that the E179K variant of TRPA1 appears to be crucial for the generation of paradoxical heat sensation in pain patients. Here, we describe the consequences of the single amino acid exchange at position 179 in the ankyrin repeat 4 of human TRPA1. TRPA1 wild type Lys-179 protein expressed in HEK cells exhibited intact biochemical properties, inclusive trafficking into the plasma membrane, formation of large protein complexes, and the ability to be activated by cold. Additionally, a strong increase of Lys-179 protein expression was observed in cold (4 °C) and heat (49 °C)-treated cells. In contrast, HEK cells expressing the variant Lys-179 TRPA1 failed to get activated by cold possibly due to the loss of ability to interact with other proteins or other TRPA1 monomers during oligomerization. In conclusion, the detailed understanding of TRPA1 genetic variants might provide a fruitful strategy for future development of pain treatments. PMID:22665484

  12. A variant in ANKK1 modulates acute subjective effects of cocaine: a preliminary study.

    Science.gov (United States)

    Spellicy, C J; Harding, M J; Hamon, S C; Mahoney, J J; Reyes, J A; Kosten, T R; Newton, T F; De La Garza, R; Nielsen, D A

    2014-07-01

    This study aimed to evaluate whether functional variants in the ankyrin repeat and kinase domain-containing 1 (ANKK1) gene and/or the dopamine receptor D2 (DRD2) gene modulate the subjective effects (reward or non-reward response to a stimulus) produced by cocaine administration. Cocaine-dependent participants (N = 47) were administered 40 mg of cocaine or placebo at time 0, and a subjective effects questionnaire (visual analog scale) was administered 15 min prior to cocaine administration, and at 5, 10, 15 and 20 min following administration. The influence of polymorphisms in the ANKK1 and DRD2 genes on subjective experience of cocaine in the laboratory was tested. Participants with a T allele of ANKK1 rs1800497 experienced greater subjective 'high' (P = 0.00006), 'any drug effect' (P = 0.0003) and 'like' (P = 0.0004) relative to the CC genotype group. Although the variant in the DRD2 gene was shown to be associated with subjective effects, linkage disequilibrium analysis revealed that this association was driven by the ANKK1 rs1800497 variant. A participant's ANKK1 genotype may identify individuals who are likely to experience greater positive subjective effects following cocaine exposure, including greater 'high' and 'like', and these individuals may have increased vulnerability to continue using cocaine or they may be at greater risk to relapse during periods of abstinence. However, these results are preliminary and replication is necessary to confirm these findings. PMID:24528631

  13. Residue 146 regulates prolactin receptor folding, basal activity and ligand-responsiveness

    DEFF Research Database (Denmark)

    Zhang, Chi; Cherifi, Ibtissem; Nygaard, Mads;

    2015-01-01

    . Here, we used a mutational approach to address how the conservative I-to-L substitution induced constitutive activity. Using cell-based assays of different I146-PRLR variants in combination with spectroscopic/nuclear magnetic resonance analyses we found that chemical manipulation of position 146......PRLR(I146L) is the first identified gain-of-function variant of the prolactin receptor (PRLR) that was proposed to be associated with benign breast tumorigenesis. Structural investigations suggested this hydrophobic core position in the extracellular D2 domain to be linked to receptor dimerization...

  14. Polymorphisms in the endocannabinoid receptor 1 in relation to fat mass distribution

    DEFF Research Database (Denmark)

    Frost, M; Nielsen, T L; Wraae, K; Hagen, C; Piters, E; Beckers, S; De Freitas, F; Brixen, K; Van Hul, W; Andersen, M

    2010-01-01

    Both animal and human studies have associated the endocannabinoid system with obesity and markers of metabolic dysfunction. Blockade of the cannabinoid receptor 1 (CB1) caused weight loss and reduction in waist size in both obese and type II diabetics. Recent studies on common variants of the CB1...... receptor gene (CNR1) and the link to obesity have been conflicting. The aim of the present study was to evaluate whether selected common variants of the CNR1 are associated with measures of obesity and fat distribution....

  15. Influence of GRIK4 genetic variants on the electroconvulsive therapy response.

    Science.gov (United States)

    Minelli, Alessandra; Congiu, Chiara; Ventriglia, Mariacarla; Bortolomasi, Marco; Bonvicini, Cristian; Abate, Maria; Sartori, Riccardo; Gainelli, Giulio; Gennarelli, Massimo

    2016-07-28

    Several lines of evidence have shown the involvement of the glutamatergic system in the function of electroconvulsive therapy (ECT). In particular, patients with treatment resistant depression (TRD) and chronic depression have lower levels of glutamate/glutamine than controls, and ECT can reverse this deficit. Genetic factors might contribute to modulating the mechanisms underlying ECT. This study aimed to evaluate the relationship between three polymorphisms (rs1954787, rs4936554 and rs11218030) of the glutamate receptor ionotropic kainate 4 (GRIK4) gene and responsiveness to ECT treatment in a sample of one hundred individuals, TRD or depressive Bipolar Disorder patients resistant to pharmacological treatments. The results revealed that GRIK4 variants were significantly associated with the response to ECT. In particular, we found that patients carrying the G allele of the GRIK4 rs11218030 had a significantly poorer response to ECT (p=2.71×10(-4)), showing five times the risk of relapse after ECT compared to the AA homozygotes. Analogously, patients carrying the GG rs1954787 genotype and rs4936554A allele carriers presented a double risk of lack of response after ECT (p=0.013 and p=0.040, respectively). In conclusion, the current study provides new evidence, indicating that some GRIK4 variants modulate the response to ECT in patients with depression resistant to treatment, suggesting a role for kainate receptor modulation. PMID:27222927

  16. Joint Analysis of Multiple Traits in Rare Variant Association Studies.

    Science.gov (United States)

    Wang, Zhenchuan; Wang, Xuexia; Sha, Qiuying; Zhang, Shuanglin

    2016-05-01

    The joint analysis of multiple traits has recently become popular since it can increase statistical power to detect genetic variants and there is increasing evidence showing that pleiotropy is a widespread phenomenon in complex diseases. Currently, the majority of existing methods for the joint analysis of multiple traits test association between one common variant and multiple traits. However, the variant-by-variant methods for common variant association studies may not be optimal for rare variant association studies due to the allelic heterogeneity as well as the extreme rarity of individual variants. Current statistical methods for rare variant association studies are for one single trait only. In this paper, we propose an adaptive weighting reverse regression (AWRR) method to test association between multiple traits and rare variants in a genomic region. AWRR is robust to the directions of effects of causal variants and is also robust to the directions of association of traits. Using extensive simulation studies, we compare the performance of AWRR with canonical correlation analysis (CCA), Single-TOW, and the weighted sum reverse regression (WSRR). Our results show that, in all of the simulation scenarios, AWRR is consistently more powerful than CCA. In most scenarios, AWRR is more powerful than Single-TOW and WSRR. PMID:26990300

  17. Space-variant polarized Airy beam

    CERN Document Server

    Chen, Hao

    2015-01-01

    We experimentally generate an Airy beam with polarization structure while keeping its original amplitude and phase profile intact. This class of Airy beam preserves the acceleration properties. By monitoring their initial polarization structure we have provided insight concerning the self-healing mechanism of Airy beams. We investigate both theoretically and experimentally the self-healing polarization properties of the space-variant polarized Airy beams. Amplitude as well as the polarization structure tends to reform during propagation in spite of the severe truncation of the beam by finite apertures.

  18. Variant position of the medial plantar nerve

    Directory of Open Access Journals (Sweden)

    Astik RB

    2011-01-01

    Full Text Available Knowledge of variation of position of the medial plantar nerve is important for the forefoot surgeon for plantar reconstruction, local injection therapy and an excision of interdigital neuroma. During routine dissection of 50-year-old female cadaver, we found the medial plantar nerve and vessels variably located between plantar aponeurosis and the muscles of the first layer of the sole of the right foot. Due to this variant position, the medial plantar nerve and vessels lose their protection from the muscles of the first layer of the sole of the foot and became vulnerable for compression.

  19. Genetic variants associated with lung function

    DEFF Research Database (Denmark)

    Thyagarajan, Bharat; Wojczynski, Mary; Minster, Ryan L;

    2014-01-01

    with exceptional longevity have not been identified. METHOD: We conducted a genome wide association study (GWAS) to identify novel genetic variants associated with lung function in the Long Life Family Study (LLFS) (n = 3,899). Replication was performed using data from the CHARGE/SpiroMeta consortia....... The association between SNPs and FEV1 and FEV1/FVC was analyzed using a linear mixed effects model adjusted for age, age2, sex, height, field center, ancestry principal components and kinship structure to adjust for family relationships separately for ever smokers and never smokers. In the linkage...

  20. Performance comparison of various time variant filters

    Energy Technology Data Exchange (ETDEWEB)

    Kuwata, M. [JEOL Engineering Co. Ltd., Akishima, Tokyo (Japan); Husimi, K.

    1996-07-01

    This paper describes the advantage of the trapezoidal filter used in semiconductor detector system comparing with the other time variant filters. The trapezoidal filter is the compose of a rectangular pre-filter and a gated integrator. We indicate that the best performance is obtained by the differential-integral summing type rectangular pre-filter. This filter is not only superior in performance, but also has the useful feature that the rising edge of the output waveform is linear. We introduce an example of this feature used in a high-energy experiment. (author)

  1. Research progress of behavioral variant frontotemporal dementia

    Directory of Open Access Journals (Sweden)

    Xiao-hua GU

    2015-07-01

    Full Text Available There is no epidemiological data of frontotemporal dementia (FTD in China. The application of updated diagnostic criteria, publishing of frontotemporal lobar degeneration (FTLD consensus in China, development of multimodal imaging and biomarkers promote the clinical understanding on behavioral variant frontotemporal dementia (bvFTD. There is still no drugs treating FTD approved by U.S. Food and Drug Administration (FDA. Multidisciplinary intervention may delay the progression of bvFTD. DOI: 10.3969/j.issn.1672-6731.2015.07.006

  2. Space phobia: syndrome or agoraphobic variant?

    Science.gov (United States)

    Marks, I; Bebbington, P

    1976-08-01

    Four elderly women had intense fears of falling when there was no visible support at hand or on seeing space cues while driving. Two patients had cervical spondylosis. The mean age at onset of the fear was 54--thirty years later than that for agoraphobia. Fear of public places and of heights was not prominent, nor was depersonalisation or depression. These "space phobias" might be a hitherto unrecognised syndrome or an unusual variant of agoraphobia. The visuospatial reflexes involved might illuminate the pathogenesis of certain fears. PMID:947417

  3. Oral fibrolipoma: A rare histological variant

    Directory of Open Access Journals (Sweden)

    Treville Pereira

    2014-01-01

    Full Text Available Lipomas are benign soft tissue mesenchymal neoplasms. Fibrolipoma is a histological variant of lipoma that mostly affects the buccal mucosa and causes functional and cosmetic disabilities. The diagnosis and differentiation of fibrolipoma with clinically similar lesions such as fibroma and pleomorphic adenoma is very essential for a correct treatment plan and complete follow-up. This article presents a case of a 35-year-old female with a fibrolipoma on the lingual marginal gingiva of the mandibular left third molar.

  4. Variants of P Systems with Toxic Objects

    OpenAIRE

    Alhazov, Artiom; Freund, Rudolf; Ivanov, Sergiu; Research Group on Natural Computing (Universidad de Sevilla) (Coordinador)

    2015-01-01

    Toxic objects have been introduced to avoid trap rules, especially in (purely) catalytic P systems. No toxic object is allowed to stay idle during a valid derivation in a P system with toxic objects. In this paper we consider special variants of toxic P systems where the set of toxic objects is prede ned { either by requiring all objects to be toxic or all catalysts to be toxic or all objects except the catalysts to be toxic. With all objects staying inside and being toxic, pur...

  5. Human CRF2 α and β splice variants: pharmacological characterization using radioligand binding and a luciferase gene expression assay

    International Nuclear Information System (INIS)

    Corticotropin releasing factor (CRF) receptors belong to the super-family of G protein-coupled receptors. These receptors are classified into two subtypes (CRF1 and CRF2). Both receptors are positively coupled to adenylyl cyclase but they have a distinct pharmacology and distribution in brain. Two isoforms belonging to the CRF2 subtype receptors, CRF2α and CRF2β, have been identified in rat and man. The neuropeptides CRF and urocortin mediate their actions through this CRF G protein-coupled receptor family. In this report, we describe the pharmacological characterization of the recently identified hCRF2β receptor. We have used radioligand binding with [125I]-tyr0-sauvagine and a gene expression assay in which the firefly luciferase gene expression is under the control of cAMP responsive elements. Association kinetics of [125I]-tyr0-sauvagine binding to the hCRF2β receptor were monophasic while dissociation kinetics were biphasic, in agreement with the kinetics results obtained with the hCRF2α receptor. Saturation binding analysis revealed two affinity states in HEK 293 cells with binding parameters in accord with those determined kinetically and with parameters obtained with the hCRF2α receptor. A non-hydrolysable GTP analog, Gpp(NH)p, reduced the high affinity binding of [125I]-tyr0-sauvagine to both hCRF2 receptor isoforms in a similar manner. The rank order of potency of CRF agonist peptides in competition experiments was identical for both hCRF2α-helical CRF(9-41)oCRF). Similarly, agonist potency was similar for the two isoforms when studied using the luciferase gene reporter system. The peptide antagonist α-helical CRF(9-41) exhibited a non-competitive antagonism of urocortin-stimulated luciferase expression with both hCRF2 receptor isoforms. Taken together, these results indicate that the pharmacological profiles of the CRF2 splice variants are identical. This indicates that the region of the N-terminus that varies between the receptors is probably

  6. Second site escape of a T20-dependent HIV-1 variant by a single amino acid change in the CD4 binding region of the envelope glycoprotein

    Directory of Open Access Journals (Sweden)

    Berkhout Ben

    2006-11-01

    Full Text Available Abstract Background We previously described the selection of a T20-dependent human immunodeficiency virus type-1 (HIV-1 variant in a patient on T20 therapy. The fusion inhibitor T20 targets the viral envelope (Env protein by blocking a conformational switch that is critical for viral entry into the host cell. T20-dependent viral entry is the result of 2 mutations in Env (GIA-SKY, creating a protein that undergoes a premature conformational switch, and the presence of T20 prevents this premature switch and rescues viral entry. In the present study, we performed 6 independent evolution experiments with the T20-dependent HIV-1 variant in the absence of T20, with the aim to identify second site compensatory changes, which may provide new mechanistic insights into Env function and the T20-dependence mechanism. Results Escape variants with improved replication capacity appeared within 42 days in 5 evolution cultures. Strikingly, 3 cultures revealed the same single amino acid change in the CD4 binding region of Env (glycine at position 431 substituted for arginine: G431R. This mutation was sufficient to abolish the T20-dependence phenotype and restore viral replication in the absence of T20. The GIA-SKY-G431R escape variant produces an Env protein that exhibits reduced syncytia formation and reduced cell-cell fusion activity. The escape variant was more sensitive to an antibody acting on an early gp41 intermediate, suggesting that the G431R mutation helps preserve a pre-fusion Env conformation, similar to T20 action. The escape variant was also less sensitive to soluble CD4, suggesting a reduced CD4 receptor affinity. Conclusion The forced evolution experiments indicate that the premature conformational switch of the T20-dependent HIV-1 Env variant (GIA-SKY can be corrected by a second site mutation in Env (GIA-SKY-G431R that affects the interaction with the CD4 receptor.

  7. FGF receptor genes and breast cancer susceptibility

    DEFF Research Database (Denmark)

    Agarwal, D; Pineda, S; Michailidou, K;

    2014-01-01

    Background:Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying......, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression.Results:Little evidence of association with breast cancer risk...... that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2....

  8. Clinical relevance of hepatitis B virus variants

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    The hepatitis B virus (HBV) is a global public health problem with more than 240 million people chronicallyinfected worldwide, who are at risk for end-stage liverdisease and hepatocellular carcinoma. There are anestimated 600000 deaths annually from complications ofHBV-related liver disease. Antiviral therapy with nucleos/tide analogs (NA) targeting the HBV polymerase (P) caninhibit disease progression by long-term suppression ofHBV replication. However, treatment may fail with firstgeneration NA therapy due to the emergence of drugresistantmutants, as well as incomplete medicationadherence. The HBV replicates via an error-prone reversetranscriptase leading to quasispecies. Due to overlappingopen reading frames mutations within the HBV P cancause concomitant changes in the HBV surface gene (S )and vice versa. HBV quasispecies diversity is associatedwith response to antiviral therapy, disease severity andlong-term clinical outcomes. Specific mutants havebeen associated with antiviral drug resistance, immuneescape, liver fibrosis development and tumorgenesis.An understanding of HBV variants and their clinicalrelevance may be important for monitoring chronichepatitis B disease progression and treatment response.In this review, we will discuss HBV molecular virology,mechanism of variant development, and their potentialclinical impact.

  9. Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants

    Science.gov (United States)

    Romanos, Jihane; Rosén, Anna; Kumar, Vinod; Trynka, Gosia; Franke, Lude; Szperl, Agata; Gutierrez-Achury, Javier; van Diemen, Cleo C; Kanninga, Roan; Jankipersadsing, Soesma A; Steck, Andrea; Eisenbarth, Georges; van Heel, David A; Cukrowska, Bozena; Bruno, Valentina; Mazzilli, Maria Cristina; Núñez, Concepcion; Bilbao, Jose Ramon; Mearin, M Luisa; Barisani, Donatella; Rewers, Marian; Norris, Jill M; Ivarsson, Anneli; Boezen, H Marieke; Liu, Edwin; Wijmenga, Cisca

    2014-01-01

    Background The majority of coeliac disease (CD) patients are not being properly diagnosed and therefore remain untreated, leading to a greater risk of developing CD-associated complications. The major genetic risk heterodimer, HLA-DQ2 and DQ8, is already used clinically to help exclude disease. However, approximately 40% of the population carry these alleles and the majority never develop CD. Objective We explored whether CD risk prediction can be improved by adding non-HLA-susceptible variants to common HLA testing. Design We developed an average weighted genetic risk score with 10, 26 and 57 single nucleotide polymorphisms (SNP) in 2675 cases and 2815 controls and assessed the improvement in risk prediction provided by the non-HLA SNP. Moreover, we assessed the transferability of the genetic risk model with 26 non-HLA variants to a nested case–control population (n=1709) and a prospective cohort (n=1245) and then tested how well this model predicted CD outcome for 985 independent individuals. Results Adding 57 non-HLA variants to HLA testing showed a statistically significant improvement compared to scores from models based on HLA only, HLA plus 10 SNP and HLA plus 26 SNP. With 57 non-HLA variants, the area under the receiver operator characteristic curve reached 0.854 compared to 0.823 for HLA only, and 11.1% of individuals were reclassified to a more accurate risk group. We show that the risk model with HLA plus 26 SNP is useful in independent populations. Conclusions Predicting risk with 57 additional non-HLA variants improved the identification of potential CD patients. This demonstrates a possible role for combined HLA and non-HLA genetic testing in diagnostic work for CD. PMID:23704318

  10. Maternal Inheritance and Mitochondrial DNA Variants in Familial Parkinson's Disease

    OpenAIRE

    Pfeiffer Ronald F; Rudolph Alice; Halter Cheryl A; Pauciulo Michael W; Kissell Diane K; Pankratz Nathan; Simon David K; Nichols William C; Foroud Tatiana

    2010-01-01

    Abstract Background Mitochondrial function is impaired in Parkinson's disease (PD) and may contribute to the pathogenesis of PD, but the causes of mitochondrial impairment in PD are unknown. Mitochondrial dysfunction is recapitulated in cell lines expressing mitochondrial DNA (mtDNA) from PD patients, implicating mtDNA variants or mutations, though the role of mtDNA variants or mutations in PD risk remains unclear. We investigated the potential contribution of mtDNA variants or mutations to t...

  11. Five functional adipokinetic peptides expressed in the corpus cardiacum of the moth genus Hippotion (Lepidoptera, Sphingidae).

    Science.gov (United States)

    Gäde, Gerd; Simek, Petr; Clark, Kevin D; Marco, Heather G

    2013-06-10

    This is the first study that finds five adipokinetic hormones (AKHs) in the corpus cardiacum of an insect. From two species of the sphingid moth genus Hippotion, eson and celerio, three novel and two known AKHs were isolated and sequenced by deduction from multiple MS(n) electrospray mass data: two octapeptides are pGlu-Leu-Thr-Phe-Thr-Ser-Ser-Trp amide (denoted Hipes-AKH-I) and its Thr(7) analogue (Hipes-AKH-II); two nonapeptides are pGlu-Leu-Thr-Phe-Thr-Ser-Ser-Trp-Gly amide (Manse-AKH) and its Thr(7) analogue (Hipes-AKH-III), as well as a decapeptide pGlu-Leu-Thr-Phe-Ser-Ser-Gly-Trp-Gly-Gln amide (Manse-AKH-II). All sequences were confirmed by identical behaviour of natural and synthetic peptides in reversed-phase HPLC and liquid chromatography coupled to electrospray mass spectrometry, resulting in identical retention times and tandem mass spectral data. High resolution mass spectrometry and retention time data also confirmed that the amino acid at position 10 in Manse-AKH-II is Gln and not the isobaric Lys. Conspecific injections of all five peptides in synthetic form and low doses caused hyperlipaemia in H. eson. Our results and pertaining literature suggest that five genes code for the mature peptides, which are very likely released during flight to provide energy for long distance migration in this genus via lipid oxidation; as all five peptides are active at low doses in a conspecific bioassay, it may be speculated, but not proven, that there is only one AKH receptor present in Hippotion that can bind all five peptides with high affinity. PMID:23541889

  12. Behavioral variant frontotemporal dementia with dominant gait disturbances - case report.

    Directory of Open Access Journals (Sweden)

    Wojciech Guenter

    2016-04-01

    Presented case emphasises the significance of accurately gathered anamnesis with patient and his family. Behavioural variant frontotemporal dementia should be considered in cases of unexplained gait abnormalities.

  13. The ARMA alphabet soup: A tour of ARMA model variants

    Directory of Open Access Journals (Sweden)

    Scott H. Holan

    2010-01-01

    Full Text Available Autoregressive moving-average (ARMA difference equations are ubiquitous models for short memory time series and have parsimoniously described many stationary series. Variants of ARMA models have been proposed to describe more exotic series features such as long memory autocovariances, periodic autocovariances, and count support set structures. This review paper enumerates, compares, and contrasts the common variants of ARMA models in today’s literature. After the basic properties of ARMA models are reviewed, we tour ARMA variants that describe seasonal features, long memory behavior, multivariate series, changing variances (stochastic volatility and integer counts. A list of ARMA variant acronyms is provided.

  14. Population structure analysis using rare and common functional variants

    Directory of Open Access Journals (Sweden)

    Ding Lili

    2011-11-01

    Full Text Available Abstract Next-generation sequencing technologies now make it possible to genotype and measure hundreds of thousands of rare genetic variations in individuals across the genome. Characterization of high-density genetic variation facilitates control of population genetic structure on a finer scale before large-scale genotyping in disease genetics studies. Population structure is a well-known, prevalent, and important factor in common variant genetic studies, but its relevance in rare variants is unclear. We perform an extensive population structure analysis using common and rare functional variants from the Genetic Analysis Workshop 17 mini-exome sequence. The analysis based on common functional variants required 388 principal components to account for 90% of the variation in population structure. However, an analysis based on rare variants required 532 significant principal components to account for similar levels of variation. Using rare variants, we detected fine-scale substructure beyond the population structure identified using common functional variants. Our results show that the level of population structure embedded in rare variant data is different from the level embedded in common variant data and that correcting for population structure is only as good as the level one wishes to correct.

  15. A unified phylogeny-based nomenclature for histone variants

    Directory of Open Access Journals (Sweden)

    Talbert Paul B

    2012-06-01

    Full Text Available Abstract Histone variants are non-allelic protein isoforms that play key roles in diversifying chromatin structure. The known number of such variants has greatly increased in recent years, but the lack of naming conventions for them has led to a variety of naming styles, multiple synonyms and misleading homographs that obscure variant relationships and complicate database searches. We propose here a unified nomenclature for variants of all five classes of histones that uses consistent but flexible naming conventions to produce names that are informative and readily searchable. The nomenclature builds on historical usage and incorporates phylogenetic relationships, which are strong predictors of structure and function. A key feature is the consistent use of punctuation to represent phylogenetic divergence, making explicit the relationships among variant subtypes that have previously been implicit or unclear. We recommend that by default new histone variants be named with organism-specific paralog-number suffixes that lack phylogenetic implication, while letter suffixes be reserved for structurally distinct clades of variants. For clarity and searchability, we encourage the use of descriptors that are separate from the phylogeny-based variant name to indicate developmental and other properties of variants that may be independent of structure.

  16. Determination of uranium by luminescent method (tablet variant)

    International Nuclear Information System (INIS)

    A new tablet variant of luminescent determination of uranium in rocks is developed. The analytical process includes the following operations: sample decomposition, uranium separation from luminescence quencher impurities, preparation of luminescent sample (tablet), photometry of the tablet. The method has two variants developed: the first one is characterized by a more hard decomposition, sample mass being 0.2 g; the second variant has a better detection limit (5x10-6%), the sample mass being 0.2-1 g. Procedures of the sample preparation for both variants of analysis are described

  17. Complex positive selection pressures drive the evolution of HIV-1 with different co-receptor tropisms

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    HIV-1 co-receptor tropism is central for understanding the transmission and pathogenesis of HIV-1 infection. We performed a genome-wide comparison between the adaptive evolution of R5 and X4 variants from HIV-1 subtypes B and C. The results showed that R5 and X4 variants experienced differential evolutionary patterns and different HIV-1 genes encountered various positive selection pressures, suggesting that complex selection pressures are driving HIV-1 evolution. Compared with other hypervariable regions of Gp120, significantly more positively selected sites were detected in the V3 region of subtype B X4 variants, V2 region of subtype B R5 variants, and V1 and V4 regions of subtype C X4 variants, indicating an association of positive selection with co-receptor recognition/binding. Intriguingly, a significantly higher proportion (33.3% and 55.6%, P<0.05) of positively selected sites were identified in the C3 region than other conserved regions of Gp120 in all the analyzed HIV-1 variants, indicating that the C3 region might be more important to HIV-1 adaptation than previously thought. Approximately half of the positively selected sites identified in the env gene were identical between R5 and X4 variants. There were three common positively selected sites (96, 113 and 281) identified in Gp41 of all X4 and R5 variants from subtypes B and C. These sites might not only suggest a functional importance in viral survival and adaptation, but also imply a potential cross-immunogenicity between HIV-1 R5 and X4 variants, which has important implications for AIDS vaccine development.

  18. Overexpression of ??3/??5/??4 nicotinic receptor subunits modifies impulsive-like behavior

    OpenAIRE

    Vi??als, Xavier; Molas Casacuberta, Susanna, 1985-; Gallego, Xavier; Fern??ndez Montes, Rub??n D.; Robledo, Patr??cia, 1958-; Dierssen, Mara; Maldonado, Rafael

    2012-01-01

    Recent studies have revealed that sequence variants in genes encoding the ??3/??5/??4 nicotinic acetylcholine receptor subunits are associated with nicotine dependence. In this study, we evaluated two specific aspects of executive functioning related to drug addiction (impulsivity and working memory) in transgenic mice over expressing ??3/??5/??4 nicotinic receptor subunits. Impulsivity and working memory were evaluated in an operant delayed alternation task, where mice must inhibit respondin...

  19. Evidence of the importance of the first intracellular loop of prokineticin receptor 2 in receptor function.

    Science.gov (United States)

    Abreu, Ana Paula; Noel, Sekoni D; Xu, Shuyun; Carroll, Rona S; Latronico, Ana Claudia; Kaiser, Ursula B

    2012-08-01

    Prokineticin receptors (PROKR) are G protein-coupled receptors (GPCR) that regulate diverse biological processes, including olfactory bulb neurogenesis and GnRH neuronal migration. Mutations in PROKR2 have been described in patients with varying degrees of GnRH deficiency and are located in diverse functional domains of the receptor. Our goal was to determine whether variants in the first intracellular loop (ICL1) of PROKR2 (R80C, R85C, and R85H) identified in patients with hypogonadotropic hypogonadism interfere with receptor function and to elucidate the mechanisms of these effects. Because of structural homology among GPCR, clarification of the role of ICL1 in PROKR2 activity may contribute to a better understanding of this domain across other GPCR. The effects of the ICL1 PROKR2 mutations on activation of signal transduction pathways, ligand binding, and receptor expression were evaluated. Our results indicated that the R85C and R85H PROKR2 mutations interfere only modestly with receptor function, whereas the R80C PROKR2 mutation leads to a marked reduction in receptor activity. Cotransfection of wild-type (WT) and R80C PROKR2 showed that the R80C mutant could exert a dominant negative effect on WT PROKR2 in vitro by interfering with WT receptor expression. In summary, we have shown the importance of Arg80 in ICL1 for PROKR2 expression and demonstrate that R80C PROKR2 exerts a dominant negative effect on WT PROKR2. PMID:22745195

  20. Detecting Association of Rare Variants by Testing an Optimally Weighted Combination of Variants for Quantitative Traits in General Families

    OpenAIRE

    Fang, Shurong; Zhang, Shuanglin; Sha, Qiuying

    2013-01-01

    Although next-generation sequencing technology allows sequencing the whole genome of large groups of individuals, the development of powerful statistical methods for rare variant association studies is still underway. Even though many statistical methods have been developed for mapping rare variants, most of these methods are for unrelated individuals only, whereas family data have been shown to improve power to detect rare variants. The majority of the existing methods for unrelated individu...

  1. Detecting association of rare and common variants by testing an optimally weighted combination of variants with longitudinal data

    OpenAIRE

    Wang, Shuaicheng; Fang, Shurong; Sha, Qiuying; Zhang, Shuanglin

    2014-01-01

    Increasing evidence shows that complex diseases are caused by both common and rare variants. Recently, several statistical methods for detecting associations of rare variants have been developed, including the test for testing the effect of an optimally weighted combination of variants (TOW) developed by our group in 2012. These methodologies consider phenotype measurement at only one time point. Because many sequence data have been developed on population cohorts that contain phenotype measu...

  2. Dopamine receptor D3 gene and essential tremor in large series of German, Danish and French patients

    DEFF Research Database (Denmark)

    Lorenz, Delia; Klebe, Stephan; Stevanin, Giovanni;

    2008-01-01

    The genetic causes of essential tremor (ET) seem to be heterogeneous. Recently, ET has been found associated with a functional variant (Ser9Gly) of the dopamine D(3) receptor (DRD3), located in the ETM1 locus on chromosome 3q13.3 described for the first time in 1997. We examined this variant in...... addition, the DRD3 variant was not found linked to the disease in a subset of informative ET families. We did not find a significant association of the DRD3 variant with ET nor linkage to the DRD3 receptor in German, Danish and French ET patients and families, suggesting that it is unlikely to be a causal...

  3. Genetic variants in FGFR2 and FGFR4 genes and skin cancer risk in the Nurses' Health Study

    International Nuclear Information System (INIS)

    The human fibroblast growth factor (FGF) and its receptor (FGFR) play an important role in tumorigenesis. Deregulation of the FGFR2 gene has been identified in a number of cancer sites. Overexpression of the FGFR4 protein has been linked to cutaneous melanoma progression. Previous studies reported associations between genetic variants in the FGFR2 and FGFR4 genes and development of various cancers. We evaluated the associations of four genetic variants in the FGFR2 gene highly related to breast cancer risk and the three common tag-SNPs in the FGFR4 gene with skin cancer risk in a nested case-control study of Caucasians within the Nurses' Health Study (NHS) among 218 melanoma cases, 285 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases, and 870 controls. We found no evidence for associations between these seven genetic variants and the risks of melanoma and nonmelanocytic skin cancer. Given the power of this study, we did not detect any contribution of genetic variants in the FGFR2 or FGFR4 genes to inherited predisposition to skin cancer among Caucasian women

  4. Autoimmune disease-associated variants of extracellular endoplasmic reticulum aminopeptidase 1 induce altered innate immune responses by human immune cells.

    Science.gov (United States)

    Aldhamen, Yasser A; Pepelyayeva, Yuliya; Rastall, David P W; Seregin, Sergey S; Zervoudi, Efthalia; Koumantou, Despoina; Aylsworth, Charles F; Quiroga, Dionisia; Godbehere, Sarah; Georgiadis, Dimitris; Stratikos, Efstratios; Amalfitano, Andrea

    2015-01-01

    Endoplasmic reticulum aminopeptidase 1 (ERAP1) gene polymorphisms have been linked to several autoimmune diseases; however, the molecular mechanisms underlying these associations are not well understood. Recently, we demonstrated that ERAP1 regulates key aspects of the innate immune response. Previous studies show ERAP1 to be endoplasmic reticulum-localized and secreted during inflammation. Herein, we investigate the possible roles that ERAP1 polymorphic variants may have in modulating the innate immune responses of human peripheral blood mononuclear cells (hPBMCs) using two experimental methods: extracellular exposure of hPBMCs to ERAP1 variants and adenovirus (Ad)-based ERAP1 expression. We found that exposure of hPBMCs to ERAP1 variant proteins as well as ERAP1 overexpression by Ad5 vectors increased inflammatory cytokine and chemokine production, and enhanced immune cell activation. Investigating the molecular mechanisms behind these responses revealed that ERAP1 is able to activate innate immunity via multiple pathways, including the NLRP3 (NOD-like receptor, pyrin domain-containing 3) inflammasome. Importantly, these responses varied if autoimmune disease-associated variants of ERAP1 were examined in the assay systems. Unexpectedly, blocking ERAP1 cellular internalization augmented IL-1β production. To our knowledge, this is the first report identifying ERAP1 as being involved in modulating innate responses of human immune cells, a finding that may explain why ERAP1 has been genetically associated with several autoimmune diseases. PMID:25591727

  5. TRPC1 transcript variants, inefficient nonsense-mediated decay and low up-frameshift-1 in vascular smooth muscle cells

    Directory of Open Access Journals (Sweden)

    Kumar Bhaskar

    2011-07-01

    Full Text Available Abstract Background Transient Receptor Potential Canonical 1 (TRPC1 is a widely-expressed mammalian cationic channel with functional effects that include stimulation of cardiovascular remodelling. The initial aim of this study was to investigate variation in TRPC1-encoding gene transcripts. Results Extensive TRPC1 transcript alternative splicing was observed, with exons 2, 3 and 5-9 frequently omitted, leading to variants containing premature termination codons. Consistent with the predicted sensitivity of such variants to nonsense-mediated decay (NMD the variants were increased by cycloheximide. However it was notable that control of the variants by NMD was prominent in human embryonic kidney 293 cells but not human vascular smooth muscle cells. The cellular difference was attributed in part to a critical protein in NMD, up-frameshift-1 (UPF1, which was found to have low abundance in the vascular cells. Rescue of UPF1 by expression of exogenous UPF1 was found to suppress vascular smooth muscle cell proliferation. Conclusions The data suggest: (i extensive NMD-sensitive transcripts of TRPC1; (ii inefficient clearance of aberrant transcripts and enhanced proliferation of vascular smooth muscle cells in part because of low UPF1 expression.

  6. Alternative splicing of the human IgA Fc receptor CD89 in neutrophils and eosinophils.

    Science.gov (United States)

    Pleass, R J; Andrews, P D; Kerr, M A; Woof, J M

    1996-09-15

    Receptors for the Fc portion of IgA (Fc alpha R) trigger important immunological elimination processes against IgA-coated targets. Investigation of human Fc alpha R (CD89) transcripts in neutrophils, eosinophils and a monocyte-like cell line, THP-1, with the use of reverse transcriptase PCR, Northern blotting and RNase protection analysis, has provided evidence in these cell types for at least two distinct transcripts generated by alternative splicing. The cDNAs derived from the two major transcripts of both neutrophils and eosinophils have been cloned and sequenced. For both cell types, the larger clone represents the previously described full-length receptor, whereas the second, shorter, splice variant lacks the entire second, membrane-proximal, Ig-like domain. Stable CHO-K1 transfectants have been obtained for both full-length and truncated variant neutrophil receptors. Whereas the full-length receptor is recognized by a panel of five anti-Fc alpha R monoclonal antibodies (mAbs), the shorter variant is bound weakly by only two of the antibodies, suggesting that the epitopes recognized by the majority of the mAbs lie at least in part in the second Ig-like domain of Fc alpha R. Both full-length and splice variant forms of the receptor bind secretory IgA, but the weak binding to serum IgA seen with the full-length receptor is not evident with the shorter variant. Alternative splicing might therefore serve as a means of diversifying Fc alpha R structure and function. PMID:8836118

  7. Human orexin/hypocretin receptors form constitutive homo- and heteromeric complexes with each other and with human CB1 cannabinoid receptors

    International Nuclear Information System (INIS)

    Highlights: • OX1 and OX2 orexin and CB1 cannabinoid receptor dimerization was investigated. • Bioluminescence resonance energy transfer method was used. • All receptors readily formed constitutive homo- and heteromeric complexes. - Abstract: Human OX1 orexin receptors have been shown to homodimerize and they have also been suggested to heterodimerize with CB1 cannabinoid receptors. The latter has been suggested to be important for orexin receptor responses and trafficking. In this study, we wanted to assess the ability of the other combinations of receptors to also form similar complexes. Vectors for expression of human OX1, OX2 and CB1 receptors, C-terminally fused with either Renilla luciferase or GFP2 green fluorescent protein variant, were generated. The constructs were transiently expressed in Chinese hamster ovary cells, and constitutive dimerization between the receptors was assessed by bioluminescence energy transfer (BRET). Orexin receptor subtypes readily formed homo- and hetero(di)mers, as suggested by significant BRET signals. CB1 receptors formed homodimers, and they also heterodimerized with both orexin receptors. Interestingly, BRET efficiency was higher for homodimers than for almost all heterodimers. This is likely to be due to the geometry of the interaction; the putatively symmetric dimers may place the C-termini in a more suitable orientation in homomers. Fusion of luciferase to an orexin receptor and GFP2 to CB1 produced more effective BRET than the opposite fusions, also suggesting differences in geometry. Similar was seen for the OX1–OX2 interaction. In conclusion, orexin receptors have a significant propensity to make homo- and heterodi-/oligomeric complexes. However, it is unclear whether this affects their signaling. As orexin receptors efficiently signal via endocannabinoid production to CB1 receptors, dimerization could be an effective way of forming signal complexes with optimal cannabinoid concentrations available for

  8. TLR9 polymorphisms in African populations: no association with severe malaria, but evidence of cis-variants acting on gene expression

    Directory of Open Access Journals (Sweden)

    Pinder Margaret

    2009-03-01

    Full Text Available Abstract Background During malaria infection the Toll-like receptor 9 (TLR9 is activated through induction with plasmodium DNA or another malaria motif not yet identified. Although TLR9 activation by malaria parasites is well reported, the implication to the susceptibility to severe malaria is not clear. The aim of this study was to assess the contribution of genetic variation at TLR9 to severe malaria. Methods This study explores the contribution of TLR9 genetic variants to severe malaria using two approaches. First, an association study of four common single nucleotide polymorphisms was performed on both family- and population-based studies from Malawian and Gambian populations (n>6000 individual. Subsequently, it was assessed whether TLR9 expression is affected by cis-acting variants and if these variants could be mapped. For this work, an allele specific expression (ASE assay on a panel of HapMap cell lines was carried out. Results No convincing association was found with polymorphisms in TLR9 for malaria severity, in either Gambian or Malawian populations, using both case-control and family based study designs. Using an allele specific expression assay it was observed that TLR9 expression is affected by cis-acting variants, these results were replicated in a second experiment using biological replicates. Conclusion By using the largest cohorts analysed to date, as well as a standardized phenotype definition and study design, no association of TLR9 genetic variants with severe malaria was found. This analysis considered all common variants in the region, but it is remains possible that there are rare variants with association signals. This report also shows that TLR9 expression is potentially modulated through cis-regulatory variants, which may lead to differential inflammatory responses to infection between individuals.

  9. Differential dimerization of variants linked to enhanced S-Cone Sensitivity Syndrome (ESCS) located in the NR2E3 ligand-binding domain

    Science.gov (United States)

    von Alpen, Désirée; Tran, H. Viet; Guex, Nicolas; Venturini, Giulia; Munier, Francis L.; Schorderet, Daniel F.; Haider, Neena B.; Escher, Pascal

    2016-01-01

    NR2E3 encodes the photoreceptor-specific nuclear hormone receptor that acts as a repressor of cone-specific gene expression in rod photoreceptors, and as an activator of several rod-specific genes. Recessive variants located in the ligand-binding domain (LBD) of NR2E3 cause enhanced short wavelength sensitive- (S-) cone syndrome (ESCS), a retinal degeneration characterized by an excess of Scones and non-functional rods. We analyzed the dimerization properties of NR2E3 and the effect of disease-causing LBD missense variants by bioluminescence resonance energy transfer (BRET2) protein interaction assays. Homodimerization was not affected in presence of p.A256V, p.R039G, p.R311Q and p.R334G variants, but abolished in presence of p.L263P, p.L336P, p.L353V, p.R385P and p.M407K variants. Homology modeling predicted structural changes induced by NR2E3 LBD variants. NR2E3 LBD variants did not affect interaction with CRX, but with NRL and rev-erbα/NR1D1. CRX and NRL heterodimerized more efficiently together, than did either with NR2E3. NR2E3 did not heterodimerize with TLX/NR2E1 and RXRα/NR2C1. The identification of a new compound heterozygous patient with detectable rod function, who expressed solely the p.A256V variant protein, suggests a correlation between LBD variants able to form functional NR2E3 dimers and atypical mild forms of ESCS with residual rod function. PMID:25703721

  10. Some variants of SAT and their properties

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    A new model for the well-known problem, the satisfiablility problem of boolean formula (SAT), is introduced. Based on this model, some variants of SAT and their properties are presented. Denote by NP the class of all languages which can be decided by a non-deterministic polynomial Turing machine and by P the class of all languages which can be decided by a deterministic polynomial-time Turing machine. This model also allows us to give another candidate for the natural problems in ((NP-NPC)-P), denoted as NPI, under the assumption P≠NP, where NPC represents NP-complete. It is proven that this candidate is not in NPC under P≠NP. While, it is indeed in NPI under some stronger but reasonable assumption, specifically, under the Exponential-Time Hypothesis (ETH). Thus we can partially solve this long standing important open problem.

  11. Genetic variants in periodontal health and disease

    Energy Technology Data Exchange (ETDEWEB)

    Dumitrescu, Alexandrina L. [Tromsoe Univ. (Norway). Inst. of Clinical Dentistry; Kobayashi, Junya [Kyoto Univ. (Japan). Dept. of Genome Repair Dynamics

    2010-07-01

    Periodontitis is a complex, multifactorial disease and its susceptibility is genetically determined. The present book systematically reviews the evidence of the association between the genetic variants and periodontitis progression and/or treatment outcomes. Genetic syndromes known to be associated with periodontal disease, the candidate gene polymorphisms investigated in relation to periodontitis, the heritability of chronic and aggressive periodontitis, as well as common guidelines for association studies are described. This growing understanding of the role of genetic variation in inflammation and periodontal chronic disease presents opportunities to identify healthy persons who are at increased risk of disease and to potentially modify the trajectory of disease to prolong healthy aging. The book represents a new concept in periodontology with its pronounced focus on understanding through knowledge rather than presenting the presently valid answers. Connections between genetics and periodontology are systematically reviewed and covered in detail. (orig.)

  12. Current conveyors variants, applications and hardware implementations

    CERN Document Server

    Senani, Raj; Singh, A K

    2015-01-01

    This book serves as a single-source reference to Current Conveyors and their use in modern Analog Circuit Design. The authors describe the various types of current conveyors discovered over the past 45 years, details of all currently available, off-the-shelf integrated circuit current conveyors, and implementations of current conveyors using other, off-the-shelf IC building blocks. Coverage includes prominent bipolar/CMOS/Bi-CMOS architectures of current conveyors, as well as all varieties of starting from third generation current conveyors to universal current conveyors, their implementations and applications. •Describes all commercially available off-the-shelf IC current conveyors, as well as hardware implementations of current conveyors using other off-the-shelf ICs; • Describes numerous variants of current conveyors evolved over the past forty five years; • Describes a number of Bipolar/CMOS/Bi-CMOS architectures of current conveyors, along with their characteristic features; • Includes a comprehe...

  13. A look-ahead variant of TFQMR

    Energy Technology Data Exchange (ETDEWEB)

    Freund, R.W. [AT& T Bell Labs., Murray Hill, NJ (United States); Nachtigal, N.M. [Oak Ridge National Lab., TN (United States)

    1994-12-31

    Recently, Freund proposed a Krylov subspace iteration, the transpose-free quasi-minimal residual method (TFQMR), for solving general nonsingular non-Hermitian linear systems. The algorithm relies on a version of the squared Lanczos process to generate the basis vectors for the underlying Krylov subspace. It then constructs iterates defined by a quasi-minimization property, which leads to a smooth and nearly monotone convergence behavior. The authors investigate a variant of TFQMR that uses look-ahead to avoid some of the problems associated with breakdowns in the underlying squared Lanczos procedure. They also present some numerical examples that illustrate the properties of the new method, as compared to the original TFQMR algorithm.

  14. Lipoleiomyoma: A rare variant of uterine leiomyoma

    Directory of Open Access Journals (Sweden)

    D Manimaran

    2014-01-01

    Full Text Available Uterine fatty tumors are rare variants of benign leiomyoma. Lipoleiomyoma, lipomyoma, fibromyolipoma are various synonyms for this lesion. They usually occur in the obese perimenopausal and postmenopausal females in the age group 50-70 years and 90% cases occur in patients older than 40 years. There were only few cases reported in the literature. These lesions are interesting due to the occasional diagnostic confusion with sarcomas and the curiosity regarding its histogenesis. We are presenting three cases of lipoleiomyoma whose age ranged from 40 to 50 years with clinical, radiologic and pathologic correlation. All three cases came with complaints of abnormal vaginal bleeding and found to have intramural heteroechoic nodule in the ultrasonogram.

  15. Possible new variant of Nijmegen breakage syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Der Kaloustian, V.M.; Booth, A.; Elliott, A.M. [Montreal Children`s Hospital and McGill Univ., Montreal (Canada)] [and others

    1996-10-02

    We report on a child with microcephaly, small facial and body size, and immune deficiency. The phenotype is consistent with Nijmegen breakage syndrome (NBS), with additional clinical manifestations and laboratory findings not reported heretofore. Most investigations, including the results of radiation-resistant DNA synthesis, concurred with the diagnosis of NBS. Cytogenetic analysis documented abnormalities in virtually all cells examined. Along with the high frequency of breaks and rearrangements of chromosomes 7 and 14, we found breakage and monosomies involving numerous other chromosomes. Because of some variation in the clinical presentation and some unusual cytogenetic findings, we suggest that our patient may represent a new variant of Nijmegen breakage syndrome. 34 refs., 3 figs., 7 tabs.

  16. TRPV1 splice variants: structure and function

    OpenAIRE

    Schumacher, Mark A; Eilers, Helge

    2010-01-01

    The capsaicin receptor (TRPV1) is a non-selective cation channel predominantly expressed in specialized sensory neurons that detect painful stimuli. Although its many functional roles continue to be revealed, it has been confirmed to play a critical role in the perception of peripheral inflammatory hyperalgesia and pain. TRPV1 not only is sensitized and/or activated under a wide range of conditions including inflammation and nerve injury but also undergoes changes in expressed levels in respo...

  17. The androgen receptor and estrogen receptor

    OpenAIRE

    Oosterkamp, H.M.; Bernards, R.A.

    2002-01-01

    The androgen receptor (AR) and the estrogen receptors (ER) are members of the nuclear receptor (NR) family. These NRs are distinguished from the other transcription factors by their ability to control gene expression upon ligand binding (steroids, retinoids, thyroid hormone, vitamin D, fatty acids, and other small hydrophobic molecules). Their combined effects are vast, influencing virtually every fundamental biological process, from development and homeostasis, to proliferation and different...

  18. Association analysis identifies ZNF750 regulatory variants in psoriasis

    Directory of Open Access Journals (Sweden)

    Birnbaum Ramon Y

    2011-12-01

    Full Text Available Abstract Background Mutations in the ZNF750 promoter and coding regions have been previously associated with Mendelian forms of psoriasis and psoriasiform dermatitis. ZNF750 encodes a putative zinc finger transcription factor that is highly expressed in keratinocytes and represents a candidate psoriasis gene. Methods We examined whether ZNF750 variants were associated with psoriasis in a large case-control population. We sequenced the promoter and exon regions of ZNF750 in 716 Caucasian psoriasis cases and 397 Caucasian controls. Results We identified a total of 47 variants, including 38 rare variants of which 35 were novel. Association testing identified two ZNF750 haplotypes associated with psoriasis (p ZNF750 promoter and 5' UTR variants displayed a 35-55% reduction of ZNF750 promoter activity, consistent with the promoter activity reduction seen in a Mendelian psoriasis family with a ZNF750 promoter variant. However, the rare promoter and 5' UTR variants identified in this study did not strictly segregate with the psoriasis phenotype within families. Conclusions Two haplotypes of ZNF750 and rare 5' regulatory variants of ZNF750 were found to be associated with psoriasis. These rare 5' regulatory variants, though not causal, might serve as a genetic modifier of psoriasis.

  19. Schizophrenia genetic variants are not associated with intelligence

    DEFF Research Database (Denmark)

    Van Scheltinga, A.F.T.; Bakker, S.C.; Van Haren, N.E.M.;

    2013-01-01

    BACKGROUND: Schizophrenia is associated with lower pre-morbid intelligence (IQ) in addition to (pre-morbid) cognitive decline. Both schizophrenia and IQ are highly heritable traits. Therefore, we hypothesized that genetic variants associated with schizophrenia, including copy number variants (CNV...

  20. The Structural Determinants behind the Epigenetic Role of Histone Variants.

    Science.gov (United States)

    Cheema, Manjinder S; Ausió, Juan

    2015-01-01

    Histone variants are an important part of the histone contribution to chromatin epigenetics. In this review, we describe how the known structural differences of these variants from their canonical histone counterparts impart a chromatin signature ultimately responsible for their epigenetic contribution. In terms of the core histones, H2A histone variants are major players while H3 variant CenH3, with a controversial role in the nucleosome conformation, remains the genuine epigenetic histone variant. Linker histone variants (histone H1 family) haven't often been studied for their role in epigenetics. However, the micro-heterogeneity of the somatic canonical forms of linker histones appears to play an important role in maintaining the cell-differentiated states, while the cell cycle independent linker histone variants are involved in development. A picture starts to emerge in which histone H2A variants, in addition to their individual specific contributions to the nucleosome structure and dynamics, globally impair the accessibility of linker histones to defined chromatin locations and may have important consequences for determining different states of chromatin metabolism. PMID:26213973

  1. The Structural Determinants behind the Epigenetic Role of Histone Variants

    Directory of Open Access Journals (Sweden)

    Manjinder S. Cheema

    2015-07-01

    Full Text Available Histone variants are an important part of the histone contribution to chromatin epigenetics. In this review, we describe how the known structural differences of these variants from their canonical histone counterparts impart a chromatin signature ultimately responsible for their epigenetic contribution. In terms of the core histones, H2A histone variants are major players while H3 variant CenH3, with a controversial role in the nucleosome conformation, remains the genuine epigenetic histone variant. Linker histone variants (histone H1 family haven’t often been studied for their role in epigenetics. However, the micro-heterogeneity of the somatic canonical forms of linker histones appears to play an important role in maintaining the cell-differentiated states, while the cell cycle independent linker histone variants are involved in development. A picture starts to emerge in which histone H2A variants, in addition to their individual specific contributions to the nucleosome structure and dynamics, globally impair the accessibility of linker histones to defined chromatin locations and may have important consequences for determining different states of chromatin metabolism.

  2. Foodborne Outbreak and Nonmotile Salmonella enterica Variant, France

    OpenAIRE

    Le Hello, Simon; Brisabois, Anne; Accou-Demartin, Marie; Josse, Adeline; Marault, Muriel; Francart, Sylvie; Nathalie, Jourdan-Da Silva; Weill, François-Xavier

    2012-01-01

    We report a food-related outbreak of salmonellosis in humans caused by a nonmotile variant of Salmonella enterica serotype Typhimurium in France in 2009. This nonmotile variant had been circulating in laying hens but was not considered as Typhimurium and consequently escaped European poultry fl ock regulations.

  3. Detecting rare variants in case-parents association studies.

    Directory of Open Access Journals (Sweden)

    Kuang-Fu Cheng

    Full Text Available Despite the success of genome-wide association studies (GWASs in detecting common variants (minor allele frequency ≥0.05 many suggested that rare variants also contribute to the genetic architecture of diseases. Recently, researchers demonstrated that rare variants can show a strong stratification which may not be corrected by using existing methods. In this paper, we focus on a case-parents study and consider methods for testing group-wise association between multiple rare (and common variants in a gene region and a disease. All tests depend on the numbers of transmitted mutant alleles from parents to their diseased children across variants and hence they are robust to the effect of population stratification. We use extensive simulation studies to compare the performance of four competing tests: the largest single-variant transmission disequilibrium test (TDT, multivariable test, combined TDT, and a likelihood ratio test based on a random-effects model. We find that the likelihood ratio test is most powerful in a wide range of settings and there is no negative impact to its power performance when common variants are also included in the analysis. If deleterious and protective variants are simultaneously analyzed, the likelihood ratio test was generally insensitive to the effect directionality, unless the effects are extremely inconsistent in one direction.

  4. CBH1 homologs and variant CBH1 cellulases

    Energy Technology Data Exchange (ETDEWEB)

    Goedegebuur, Frits (Rozenlaan, NL); Gualfetti, Peter (San Francisco, CA); Mitchinson, Colin (Half Moon Bay, CA); Neefe, Paulien (Zoetermeer, NL)

    2011-05-31

    Disclosed are a number of homologs and variants of Hypocrea jecorina Cel7A (formerly Trichoderma reesei cellobiohydrolase I or CBH1), nucleic acids encoding the same and methods for producing the same. The homologs and variant cellulases have the amino acid sequence of a glycosyl hydrolase of family 7A wherein one or more amino acid residues are substituted and/or deleted.

  5. Gene Variant Databases and Sharing: Creating a Global Genomic Variant Database for Personalized Medicine.

    Science.gov (United States)

    Bean, Lora J H; Hegde, Madhuri R

    2016-06-01

    Revolutionary changes in sequencing technology and the desire to develop therapeutics for rare diseases have led to the generation of an enormous amount of genomic data in the last 5 years. Large-scale sequencing done in both research and diagnostic laboratories has linked many new genes to rare diseases, but has also generated a number of variants that we cannot interpret today. It is clear that we remain a long way from a complete understanding of the genomic variation in the human genome and its association with human health and disease. Recent studies identified susceptibility markers to infectious diseases and also the contribution of rare variants to complex diseases in different populations. The sequencing revolution has also led to the creation of a large number of databases that act as "keepers" of data, and in many cases give an interpretation of the effect of the variant. This interpretation is based on reports in the literature, prediction models, and in some cases is accompanied by functional evidence. As we move toward the practice of genomic medicine, and consider its place in "personalized medicine," it is time to ask ourselves how we can aggregate this wealth of data into a single database for multiple users with different goals. PMID:26931283

  6. Relationship between Toll-Like Receptor 8 Gene Polymorphisms and Pediatric Pulmonary Tuberculosis

    Directory of Open Access Journals (Sweden)

    Nazan Dalgic

    2011-01-01

    Full Text Available Objectives: Genetic variants in Toll-like receptors (TLRs are considered a potential indicator for host susceptibility to and outcome of several infectious diseases including tuberculosis. The aim of this study was to determine whether −129 C/G and Met1Val polymorphisms of TLR8 were associated with pediatric pulmonary tuberculosis in Turkish population.

  7. Peroxisome proliferator-activated receptor alpha polymorphisms and postprandial lipemia in healthy men

    Science.gov (United States)

    Peroxisome proliferator-activated receptor alpha (PPARA) is a ligand-dependent transcription factor that plays a key role in lipid and glucose homeostasis. This study evaluated whether variants of PPARA are associated with postprandial lipemia. Subjects were given a single fat load comprised of 60% ...

  8. Conflicting selective forces affect T cell receptor contacts in an immunodominant human immunodeficiency virus epitope

    DEFF Research Database (Denmark)

    Iversen, Astrid K N; Stewart-Jones, Guillaume; Learn, Gerald H; Christie, Natasha; Sylvester-Hviid, Christina; Armitage, Andrew E; Kaul, Rupert; Beattie, Tara; Lee, Jean K; Li, Yanping; Chotiyarnwong, Pojchong; Dong, Tao; Xu, Xiaoning; Luscher, Mark A; MacDonald, Kelly; Ullum, Henrik; Klarlund-Pedersen, Bente; Skinhøj, Peter; Fugger, Lars; Buus, Søren; Mullins, James I; Jones, E Yvonne; van der Merwe, P Anton; McMichael, Andrew J

    2006-01-01

    two principal, diametrically opposed evolutionary pathways that exclusively affect T cell-receptor contact residues. One pathway was characterized by acquisition of CTL escape mutations and the other by selection for wild-type amino acids. The pattern of CTL responses to epitope variants shaped which...

  9. Scavenger receptor AI/II truncation, lung function and COPD: a large population-based study

    DEFF Research Database (Denmark)

    Thomsen, M; Nordestgaard, B G; Tybjærg-Hansen, Anne;

    2011-01-01

    The scavenger receptor A-I/II (SRA-I/II) on alveolar macrophages is involved in recognition and clearance of modified lipids and inhaled particulates. A rare variant of the SRA-I/II gene, Arg293X, truncates the distal collagen-like domain, which is essential for ligand recognition. We tested whet...

  10. Antisocial behavior and polymorphisms in the oxytocin receptor gene : findings in two independent samples

    OpenAIRE

    Hovey, Daniel; Lindstedt, Måns; Zettergren, Anna; Jonsson, Lina; Johansson, Ada; Melke, Jonas; Kerekes, Nora; Anckarsäter, Henrik; Lichtenstein, Paul; Lundström, Sebastian; Westberg, Lars

    2015-01-01

    Importance: The quantitative genetic contribution to antisocial behavior is well established, but few, if any, genetic variants are established as risk factors. Emerging evidence suggests that the neuropeptide oxytocin may modulate interpersonal aggression. Objective: To investigate whether single nucleotide polymorphisms in the oxytocin receptor gene are associated with the expression of antisocial behavior. Design, setting, and participants: A discovery sample, including both se...

  11. Interleukin-17 receptor polymorphism predisposes to primary graft dysfunction after lung transplantation

    OpenAIRE

    Somers, Jana; Ruttens, David; Verleden, Stijn; Vandermeulen, Elly; Piloni, Davide; Wauters, Els; Lambrechts, Diether; Vos, Robin; Verleden, Geert; Vanaudenaerde, Bart; Van Raemdonck, Dirk

    2015-01-01

    Primary graft dysfunction (PGD), with an incidence of 11% to 57%, is a major cause of morbidity and mortality within the first 30 days after lung transplantation (LTx). In this study, we postulate that recipient genetic variants in interleukin-17 and -23 receptor genes (IL-17R and IL-23R, respectively) may predispose LTx recipients to an increased risk for developing PGD.

  12. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

    NARCIS (Netherlands)

    F.J. Couch (Fergus); K.B. Kuchenbaecker (Karoline); K. Michailidou (Kyriaki); G.A. Mendoza-Fandino (Gustavo A.); S. Nord (Silje); J. Lilyquist (Janna); C. Olswold (Curtis); B. Hallberg (Boubou); S. Agata (Simona); H. Ahsan (Habibul); K. Aittomäki (Kristiina); C.B. Ambrosone (Christine B.); I.L. Andrulis (Irene); H. Anton-Culver (Hoda); V. Arndt (Volker); B.K. Arun (Banu); B. Arver (Brita Wasteson); M. Barile (Monica); R.B. Barkardottir (Rosa); D. Barrowdale (Daniel); L. Beckmann (Lars); M.W. Beckmann (Matthias); J. Benítez (Javier); S.V. Blank (Stephanie); C. Blomqvist (Carl); N.V. Bogdanova (Natalia); S.E. Bojesen (Stig); M.K. Bolla (Manjeet); B. Bonnani (Bernardo); H. Brauch (Hiltrud); H. Brenner (Hermann); B. Burwinkel (Barbara); S.S. Buys (Saundra S.); T. Caldes (Trinidad); M.A. Caligo (Maria); F. Canzian (Federico); T.A. Carpenter (Adrian); J. Chang-Claude (Jenny); S.J. Chanock (Stephen J.); W.K. Chung (Wendy K.); K.B.M. Claes (Kathleen B.M.); A. Cox (Angela); S.S. Cross (Simon); J.M. Cunningham (Julie); K. Czene (Kamila); M.B. Daly (Mary B.); F. Damiola (Francesca); H. Darabi (Hatef); M. de La Hoya (Miguel); P. Devilee (Peter); O. Díez (Orland); Y.C. Ding (Yuan); R. Dolcetti (Riccardo); S.M. Domchek (Susan); C.M. Dorfling (Cecilia); I. dos Santos Silva (Isabel); M. Dumont (Martine); A.M. Dunning (Alison); D. Eccles (Diana); H. Ehrencrona (Hans); A.B. Ekici (Arif); H. Eliassen (Heather); S.D. Ellis (Steve); P.A. Fasching (Peter); J.D. Figueroa (Jonine); D. Flesch-Janys (Dieter); A. Försti (Asta); F. Fostira (Florentia); W.D. Foulkes (William); M.O.W. Friebel (Mark ); E. Friedman (Eitan); D. Frost (Debra); M. Gabrielson (Marike); M. Gammon (Marilie); P.A. Ganz (Patricia A.); S.M. Gapstur (Susan M.); J. Garber (Judy); M.M. Gaudet (Mia); S.A. Gayther (Simon); A-M. Gerdes (Anne-Marie); M. Ghoussaini (Maya); G.G. Giles (Graham); G. Glendon (Gord); A.K. Godwin (Andrew K.); M.S. Goldberg (Mark); D. Goldgar (David); A. González-Neira (Anna); M.H. Greene (Mark H.); J. Gronwald (Jacek); P. Guénel (Pascal); M.J. Gunter (Marc J.); L. Haeberle (Lothar); C.A. Haiman (Christopher A.); U. Hamann (Ute); T.V.O. Hansen (Thomas); S. Hart (Stewart); S. Healey (Sue); T. Heikkinen (Tuomas); B.E. Henderson (Brian); J. Herzog (Josef); F.B.L. Hogervorst (Frans); A. Hollestelle (Antoinette); M.J. Hooning (Maartje); R.N. Hoover (Robert); J.L. Hopper (John); K. Humphreys (Keith); D. Hunter (David); T. Huzarski (Tomasz); E.N. Imyanitov (Evgeny N.); C. Isaacs (Claudine); A. Jakubowska (Anna); M. James (Margaret); R. Janavicius (Ramunas); U.B. Jensen; E.M. John (Esther); M. Jones (Michael); M. Kabisch (Maria); S. Kar (Siddhartha); B.Y. Karlan (Beth Y.); S. Khan (Sofia); K.T. Khaw; M.G. Kibriya (Muhammad); J.A. Knight (Julia); Y.-D. Ko (Yon-Dschun); I. Konstantopoulou (I.); V-M. Kosma (Veli-Matti); V. Kristensen (Vessela); A. Kwong (Ava); Y. Laitman (Yael); D. Lambrechts (Diether); C. Lazaro (Conxi); E. Lee (Eunjung); L. Le Marchand (Loic); K.J. Lester (Kathryn); A. Lindblom (Annika); N.M. Lindor (Noralane); S. Lindstrom (Stephen); J. Liu (Jianjun); J. Long (Jirong); J. Lubinski (Jan); P.L. Mai (Phuong); E. Makalic (Enes); K.E. Malone (Kathleen E.); A. Mannermaa (Arto); S. Manoukian (Siranoush); S. Margolin (Sara); F. Marme (Federick); J.W.M. Martens (John); L. McGuffog (Lesley); A. Meindl (Alfons); A. Miller (Austin); R.L. Milne (Roger); P. Miron (Penelope); M. Montagna (Marco); S. Mazoyer (Sylvie); A.-M. Mulligan (Anna-Marie); T.A. Muranen (Taru); K.L. Nathanson (Katherine); S.L. Neuhausen (Susan); H. Nevanlinna (Heli); B.G. Nordestgaard (Børge); R. Nussbaum (Robert); K. Offit (Kenneth); E. Olah; O.I. Olopade (Olufunmilayo I.); J.E. Olson (Janet); A. Osorio (Ana); S.K. Park (Sue K.); P.H.M. Peeters; B. Peissel (Bernard); P. Peterlongo (Paolo); J. Peto (Julian); C. Phelan (Catherine); R. Pilarski (Robert); B. Poppe (Bruce); K. Pykäs (Katri); P. Radice (Paolo); N. Rahman (Nazneen); J. Rantala (Johanna); C. Rappaport (Christine); G. Rennert (Gad); A.L. Richardson (Andrea); M. Robson (Mark); I. Romieu (Isabelle); A. Rudolph (Anja); E.J.T. Rutgers (Emiel); M.-J. Sanchez (Maria-Jose); R. Santella (Regina); E.J. Sawyer (Elinor); D.F. Schmidt (Daniel); M.K. Schmidt (Marjanka); R.K. Schmutzler (Rita); F.R. Schumacher (Fredrick); R.J. Scott (Rodney); L. Senter (Leigha); P. Sharma (Priyanka); J. Simard (Jacques); C.F. Singer (Christian); O. Sinilnikova (Olga); P. Soucy (Penny); M.C. Southey (Melissa); D. Steinemann (Doris); M. Stenmark-Askmalm (Marie); D. Stoppa-Lyonnet (Dominique); A.J. Swerdlow (Anthony ); C. Szabo (Csilla); R. Tamimi (Rulla); W. Tapper (William); P.J. Teixeira; S.-H. Teo; M.B. Terry (Mary Beth); M. Thomassen (Mads); D. Thompson (Deborah); L. Tihomirova (Laima); A.E. Toland (Amanda); R.A.E.M. Tollenaar (Rob); I.P. Tomlinson (Ian); T. Truong (Thérèse); H. Tsimiklis (Helen); A. Teulé (A.); R. Tumino (Rosario); N. Tung (Nadine); C. Turnbull (Clare); G. Ursin (Giski); C.H.M. van Deurzen (Carolien); E.J. van Rensburg (Elizabeth); R. Varon-Mateeva (Raymonda); Z. Wang (Zhaoming); S. Wang-Gohrke (Shan); E. Weiderpass (Elisabete); J.N. Weitzel (Jeffrey); A.S. Whittemore (Alice S.); H. Wildiers (Hans); R. Winqvist (Robert); X.R. Yang (Xiaohong R.); D. Yannoukakos (Drakoulis); S. Yao (Song); M.P. Zamora (Pilar); W. Zheng (Wei); P. Hall (Per); P. Kraft (Peter); C. Vachon (Celine); S. Slager (Susan); G. Chenevix-Trench (Georgia); P.D.P. Pharoah (Paul); A.A.N. Monteiro (Alvaro A. N.); M. García-Closas (Montserrat); D.F. Easton (Douglas F.); A.C. Antoniou (Antonis C.)

    2016-01-01

    textabstractCommon variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10-8) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibili

  13. Electrophoretic variants of blood proteins in Japanese, 7

    International Nuclear Information System (INIS)

    A total of 16,835 children, of whom 11,737 are unrelated, from Hiroshima and Nagasaki were examined for erythrocyte cytoplasmic glutamate-oxaloacetate transaminase (GOT1) by starch gel electrophoresis. A variant allele named GOT1*2HR1 which seems to be identical with GOT1*2 was encountered in polymorphic frequency. Five kinds of rare variants, 3NG1, 4NG1, 5NG1, 6HR1, and 7NG1 were encountered in a total of 109 children. Except for 7NG1 for which complete family study was unable, family studies confirmed the genetic nature of these rare variants, since for all instances in which both parents could be examined, one of the parents exhibited the same variant as that of their child. Thermostability profiles of these six variants were normal. The enzyme activities of five were decreased, while the value of one was normal compared to that of GOT1 1. (author)

  14. Clinical and laboratory update on the DEL variant.

    Science.gov (United States)

    Nuchnoi, Pornlada; Thongbus, Jairak; Srisarin, Apapan; Kerdpin, Usanee; Prachayasittikul, Virapong

    2014-01-01

    Serological assays for the RhD blood group are based on detection of the RhD antigen on human red blood cells using a specific anti-D antibody. The weak expression of the RhD antigen in the DEL variant hinders the sensitivity of conventional serological assays. Evidence of anti-D immunization in patients with D-negativity who have received DEL-variant blood units has been reported in various populations. This observation has prompted the need for genetic epidemiological and clinical data on the DEL variant in the development of DEL molecular diagnostic testing. This review highlights the molecular features of the DEL variant, the clinical consequences of DEL-blood transfusion, and current approaches for detection of the DEL-variant for donor screening and transfusion. PMID:25316658

  15. Genetic variants in Alzheimer disease - molecular and brain network approaches.

    Science.gov (United States)

    Gaiteri, Chris; Mostafavi, Sara; Honey, Christopher J; De Jager, Philip L; Bennett, David A

    2016-07-01

    Genetic studies in late-onset Alzheimer disease (LOAD) are aimed at identifying core disease mechanisms and providing potential biomarkers and drug candidates to improve clinical care of AD. However, owing to the complexity of LOAD, including pathological heterogeneity and disease polygenicity, extraction of actionable guidance from LOAD genetics has been challenging. Past attempts to summarize the effects of LOAD-associated genetic variants have used pathway analysis and collections of small-scale experiments to hypothesize functional convergence across several variants. In this Review, we discuss how the study of molecular, cellular and brain networks provides additional information on the effects of LOAD-associated genetic variants. We then discuss emerging combinations of these omic data sets into multiscale models, which provide a more comprehensive representation of the effects of LOAD-associated genetic variants at multiple biophysical scales. Furthermore, we highlight the clinical potential of mechanistically coupling genetic variants and disease phenotypes with multiscale brain models. PMID:27282653

  16. Structure of a monomeric variant of rhodopsin kinase at 2.5 Å resolution

    International Nuclear Information System (INIS)

    The structure of the L166K variant of G protein-coupled receptor kinase 1 has been determined at 2.5 Å resolution in order to determine how a dimer interface observed in prior crystal structures influences the conformation of the enzyme and how the C-terminal amino acids are configured while in a monomeric state. G protein-coupled receptor kinase 1 (GRK1 or rhodopsin kinase) phosphorylates activated rhodopsin and initiates a cascade of events that results in the termination of phototransduction by the receptor. Although GRK1 seems to be a monomer in solution, seven prior crystal structures of GRK1 revealed a similar domain-swapped dimer interface involving the C-terminus of the enzyme. The influence of this interface on the overall conformation of GRK1 is not known. To address this question, the crystalline dimer interface was disrupted with a L166K mutation and the structure of GRK1-L166K was determined in complex with Mg2+·ATP to 2.5 Å resolution. GRK1-L166K crystallized in a novel space group as a monomer and exhibited little overall conformational difference from prior structures of GRK1, although the C-terminal domain-swapped region had reorganized owing to loss of the dimer interface

  17. Autoimmune Variant PTPN22 C1858T Is Associated With Impaired Responses to Influenza Vaccination.

    Science.gov (United States)

    Crabtree, Juliet N; He, Wenqian; Guan, Weihua; Flage, Mark; Miller, Matthew S; Peterson, Erik J

    2016-07-15

    High-affinity-antibody production, T-cell activation, and interferon upregulation all contribute to protective immunity that occurs in humans following influenza immunization. Hematopoietic cell-specific PTPN22 encodes lymphoid phosphatase (Lyp), which regulates lymphocyte antigen receptor and pattern recognition receptor (PRR) signaling. A PTPN22 variant, R620W (LypW), predisposes to autoimmune and infectious diseases and confers altered signaling through antigen receptors and PRRs. We tested the hypothesis that LypW-bearing humans would have diminished immune response to trivalent influenza vaccine (TIV). LypW carriers exhibited decreased induction of influenza virus-specific CD4(+) T cells expressing effector cytokines and failed to increase antibody affinity following TIV receipt. No differences between LypW carriers and noncarriers were observed in virus-specific CD8(+) T-cell responses, early interferon transcriptional responses, or myeloid antigen-presenting cell costimulatory molecule upregulation. The association of LypW with defects in TIV-induced CD4(+) T-cell expansion and antibody affinity maturation suggests that LypW may predispose individuals to have a diminished capacity to generate protective immunity against influenza virus. PMID:27034343

  18. Bayesian detection of causal rare variants under posterior consistency.

    KAUST Repository

    Liang, Faming

    2013-07-26

    Identification of causal rare variants that are associated with complex traits poses a central challenge on genome-wide association studies. However, most current research focuses only on testing the global association whether the rare variants in a given genomic region are collectively associated with the trait. Although some recent work, e.g., the Bayesian risk index method, have tried to address this problem, it is unclear whether the causal rare variants can be consistently identified by them in the small-n-large-P situation. We develop a new Bayesian method, the so-called Bayesian Rare Variant Detector (BRVD), to tackle this problem. The new method simultaneously addresses two issues: (i) (Global association test) Are there any of the variants associated with the disease, and (ii) (Causal variant detection) Which variants, if any, are driving the association. The BRVD ensures the causal rare variants to be consistently identified in the small-n-large-P situation by imposing some appropriate prior distributions on the model and model specific parameters. The numerical results indicate that the BRVD is more powerful for testing the global association than the existing methods, such as the combined multivariate and collapsing test, weighted sum statistic test, RARECOVER, sequence kernel association test, and Bayesian risk index, and also more powerful for identification of causal rare variants than the Bayesian risk index method. The BRVD has also been successfully applied to the Early-Onset Myocardial Infarction (EOMI) Exome Sequence Data. It identified a few causal rare variants that have been verified in the literature.

  19. Bayesian detection of causal rare variants under posterior consistency.

    Directory of Open Access Journals (Sweden)

    Faming Liang

    Full Text Available Identification of causal rare variants that are associated with complex traits poses a central challenge on genome-wide association studies. However, most current research focuses only on testing the global association whether the rare variants in a given genomic region are collectively associated with the trait. Although some recent work, e.g., the Bayesian risk index method, have tried to address this problem, it is unclear whether the causal rare variants can be consistently identified by them in the small-n-large-P situation. We develop a new Bayesian method, the so-called Bayesian Rare Variant Detector (BRVD, to tackle this problem. The new method simultaneously addresses two issues: (i (Global association test Are there any of the variants associated with the disease, and (ii (Causal variant detection Which variants, if any, are driving the association. The BRVD ensures the causal rare variants to be consistently identified in the small-n-large-P situation by imposing some appropriate prior distributions on the model and model specific parameters. The numerical results indicate that the BRVD is more powerful for testing the global association than the existing methods, such as the combined multivariate and collapsing test, weighted sum statistic test, RARECOVER, sequence kernel association test, and Bayesian risk index, and also more powerful for identification of causal rare variants than the Bayesian risk index method. The BRVD has also been successfully applied to the Early-Onset Myocardial Infarction (EOMI Exome Sequence Data. It identified a few causal rare variants that have been verified in the literature.

  20. The first decapeptide adipokinetic hormone (AKH) in Heteroptera: A novel AKH from a South African saucer bug, Laccocoris spurcus (Naucoridae, Laccocorinae)

    Czech Academy of Sciences Publication Activity Database

    Marco, H. G.; Šimek, Petr; Gäde, G.

    2011-01-01

    Roč. 32, č. 3 (2011), s. 454-460. ISSN 0196-9781 R&D Projects: GA ČR GA203/09/2014 Grant ostatní: National Research Foundation, Pretoria(ZA) FA2007021300002; National Research Foundation, Pretoria(ZA) IFR2008071500048 Institutional research plan: CEZ:AV0Z50070508 Keywords : Insects * Heteroptera * Laccocoris spurcus Subject RIV: ED - Physiology Impact factor: 2.434, year: 2011

  1. Heat Stress Upregulates the Expression of TLR4 and Its Alternative Splicing Variant in Bama Miniature Pigs

    Institute of Scientific and Technical Information of China (English)

    JU Xiang-hong; XU Han-jin; YONG Yan-hong; AN Li-long; XU Ying-mei; JIAO Pei-rong; LIAO Ming

    2014-01-01

    Alternative splicing is a cellular mechanism in eukaryotes that results in considerable diversity of gene products. It plays an important role in several diseases and cellular signal regulation. Heat stress is a major factor that induces immunosuppression in pigs. Little is known about the correlation between alternative splicing and heat stress in pigs. Therefore, this study aimed to clone, sequence and quantify the alternative splicing variant of toll-like receptor 4 (TLR4) in Bama miniature pigs (Sus scrofa domestica) following exposure to heat stress. The results showed that the second exon of TLR4 was spliced and 167 bp shorter in the alternative splicing variant, and the protein was putatively identiifed as a type of truncated membrane protein consisting of extramembrane, transmembrane and intramembrane regions lacking a signal peptide. Further, it was not a non-classical secretory protein. Five potential reference genes were screened for their potential as reliable standards to quantify the expression of TLR4 alternative spliced variants by real-time quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). The stability of these reference genes was ranked using the geNorm and NormFinder programs, and ribosomal protein L4 (RPL4) and TATA box-binding protein (TBP) were found to be the two genes showing the most stable expression in the in vitro cultured peripheral blood mononuclear cells (PBMCs) during heat shock. The mRNA level of the TLR4 gene (both classical and spliced) in stressed pigs increased signiifcantly (P<0.05). Further, the expression levels of the alternative spliced variant of TLR4 (TLR4-ASV) showed a 2-3 folds increase in heat-stressed PBMCs as compared to control pigs. The results of the present study suggested that heat shock might modulate the host immune response by regulating the expressions of TLR4 and its alternative splicing variant.

  2. IGF2R Genetic Variants, Circulating IGF2 Concentrations and Colon Cancer Risk in African Americans and Whites

    Directory of Open Access Journals (Sweden)

    Cathrine Hoyo

    2012-01-01

    Full Text Available The Mannose 6 Phosphate/Insulin-like Growth Factor Receptor-2 (IGF2R encodes a type-1 membrane protein that modulates availability of the potent mitogen, IGF2. We evaluated the associations between IGF2R non-synonymous genetic variants (c.5002G>A, Gly1619Arg(rs629849, and c.901C>G, Leu252Val(rs8191754, circulating IGF2 levels, and colon cancer (CC risk among African American and White participants enrolled in the North Carolina Colon Cancer Study (NCCCS. Generalized linear models were used to compare circulating levels of IGF2 among 298 African American and 518 White controls. Logistic regression models were used to estimate odds ratios (ORs and 95% confidence intervals (CIs for the association of IGF2R genetic variants and CC risk. Women homozygous for the IGF2R c.5002 G>A allele, had higher mean levels of circulating IGF2, 828 (SD=321 ng/ml compared to non-carriers, 595 (SD=217 ng/ml (p-value=0.01. This pattern was not apparent in individuals homozygous for the IGF2R c.901 C>G variant. Whites homozygous for the IGF2R c.901 C>G variant trended towards a higher risk of CC, OR=2.2 [95% CI(0.9–5.4], whereas carrying the IGF2R c.5002 G>A variant was not associated with CC risk. Our findings support the hypothesis that being homozygous for the IGF2R c.5002 G>A modulates IGF2 circulating levels in a sex-specific manner, and while carrying the IGF2R c.901 C>G may increase cancer risk, the mechanism may not involve modulation of circulating IGF2.

  3. Variation in umami perception and in candidate genes for the umami receptor in mice and humans1234

    OpenAIRE

    Shigemura, Noriatsu; Shirosaki, Shinya; Ohkuri, Tadahiro; Sanematsu, Keisuke; Islam, AA Shahidul; Ogiwara, Yoko; Kawai, Misako; Yoshida, Ryusuke; Ninomiya, Yuzo

    2009-01-01

    The unique taste induced by monosodium glutamate is referred to as umami taste. The umami taste is also elicited by the purine nucleotides inosine 5′-monophosphate and guanosine 5′-monophosphate. There is evidence that a heterodimeric G protein–coupled receptor, which consists of the T1R1 (taste receptor type 1, member 1, Tas1r1) and the T1R3 (taste receptor type 1, member 3, Tas1r3) proteins, functions as an umami taste receptor for rodents and humans. Splice variants of metabotropic glutama...

  4. Differences in Transcriptional Activation by the Two Allelic (L162V Polymorphic) Variants of PPARα after Omega-3 Fatty Acids Treatment

    OpenAIRE

    Iwona Rudkowska; Mélanie Verreault; Olivier Barbier; Marie-Claude Vohl

    2009-01-01

    Omega-3 fatty acids (FAs) have the potential to regulate gene expression via the peroxisome proliferator-activated receptor α (PPARα); therefore, genetic variations in this gene may impact its transcriptional activity on target genes. It is hypothesized that the transcriptional activity by wild-type L162-PPARα is enhanced to a greater extent than the mutated variant (V162-PPARα) in the presence of eicosapentaenoic acid (EPA), docosa...

  5. TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson¿s disease

    OpenAIRE

    Rayaprolu, Sruti; Mullen, Bianca; Baker, Matt; Lynch, Timothy; Finger, Elizabeth; Seeley, William W.; Hatanpaa, Kimmo J.; Lomen-Hoerth, Catherine; Kertesz, Andrew; Bigio, Eileen H; Lippa, Carol; Josephs, Keith A.; Knopman, David S.; White, Charles L.; Caselli, Richard

    2013-01-01

    Abstract Background A rare variant in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene has been reported to be a genetic risk factor for Alzheimer’s disease by two independent groups (Odds ratio between 2.9-4.5). Given the key role of TREM2 in the effective phagocytosis of apoptotic neuronal cells by microglia, we hypothesized that dysfunction of TREM2 may play a more generalized role in neurodegeneration. With this in mind we s...

  6. Private mitochondrial DNA variants in danish patients with hypertrophic cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Christian M Hagen

    Full Text Available Hypertrophic cardiomyopathy (HCM is a genetic cardiac disease primarily caused by mutations in genes coding for sarcomeric proteins. A molecular-genetic etiology can be established in ~60% of cases. Evolutionarily conserved mitochondrial DNA (mtDNA haplogroups are susceptibility factors for HCM. Several polymorphic mtDNA variants are associated with a variety of late-onset degenerative diseases and affect mitochondrial function. We examined the role of private, non-haplogroup associated, mitochondrial variants in the etiology of HCM. In 87 Danish HCM patients, full mtDNA sequencing revealed 446 variants. After elimination of 312 (69.9% non-coding and synonymous variants, a further 109 (24.4% with a global prevalence > 0.1%, three (0.7% haplogroup associated and 19 (2.0% variants with a low predicted in silico likelihood of pathogenicity, three variants: MT-TC: m.5772G>A, MT-TF: m.644A>G, and MT-CYB: m.15024G>A, p.C93Y remained. A detailed analysis of these variants indicated that none of them are likely to cause HCM. In conclusion, private mtDNA mutations are frequent, but they are rarely, if ever, associated with HCM.

  7. The Clinical Significance of Unknown Sequence Variants in BRCA Genes

    International Nuclear Information System (INIS)

    Germline mutations in BRCA1/2 genes are responsible for a large proportion of hereditary breast and/or ovarian cancers. Many highly penetrant predisposition alleles have been identified and include frameshift or nonsense mutations that lead to the translation of a truncated protein. Other alleles contain missense mutations, which result in amino acid substitution and intronic variants with splicing effect. The discovery of variants of uncertain/unclassified significance (VUS) is a result that can complicate rather than improve the risk assessment process. VUSs are mainly missense mutations, but also include a number of intronic variants and in-frame deletions and insertions. Over 2,000 unique BRCA1 and BRCA2 missense variants have been identified, located throughout the whole gene (Breast Cancer Information Core Database (BIC database)). Up to 10–20% of the BRCA tests report the identification of a variant of uncertain significance. There are many methods to discriminate deleterious/high-risk from neutral/low-risk unclassified variants (i.e., analysis of the cosegregation in families of the VUS, measure of the influence of the VUSs on the wild-type protein activity, comparison of sequence conservation across multiple species), but only an integrated analysis of these methods can contribute to a real interpretation of the functional and clinical role of the discussed variants. The aim of our manuscript is to review the studies on BRCA VUS in order to clarify their clinical relevance

  8. The Clinical Significance of Unknown Sequence Variants in BRCA Genes

    Energy Technology Data Exchange (ETDEWEB)

    Calò, Valentina; Bruno, Loredana; Paglia, Laura La; Perez, Marco; Margarese, Naomi [Department of Surgery and Oncology, Regional Reference Center for the Biomolecular Characterization and Genetic Screening of Hereditary Tumors, University of Palermo, Via del Vespro 127, 90127 Palermo (Italy); Gaudio, Francesca Di [Department of Medical Biotechnologies and Legal Medicine, University of Palermo, Palermo (Italy); Russo, Antonio, E-mail: lab-oncobiologia@usa.net [Department of Surgery and Oncology, Regional Reference Center for the Biomolecular Characterization and Genetic Screening of Hereditary Tumors, University of Palermo, Via del Vespro 127, 90127 Palermo (Italy)

    2010-09-10

    Germline mutations in BRCA1/2 genes are responsible for a large proportion of hereditary breast and/or ovarian cancers. Many highly penetrant predisposition alleles have been identified and include frameshift or nonsense mutations that lead to the translation of a truncated protein. Other alleles contain missense mutations, which result in amino acid substitution and intronic variants with splicing effect. The discovery of variants of uncertain/unclassified significance (VUS) is a result that can complicate rather than improve the risk assessment process. VUSs are mainly missense mutations, but also include a number of intronic variants and in-frame deletions and insertions. Over 2,000 unique BRCA1 and BRCA2 missense variants have been identified, located throughout the whole gene (Breast Cancer Information Core Database (BIC database)). Up to 10–20% of the BRCA tests report the identification of a variant of uncertain significance. There are many methods to discriminate deleterious/high-risk from neutral/low-risk unclassified variants (i.e., analysis of the cosegregation in families of the VUS, measure of the influence of the VUSs on the wild-type protein activity, comparison of sequence conservation across multiple species), but only an integrated analysis of these methods can contribute to a real interpretation of the functional and clinical role of the discussed variants. The aim of our manuscript is to review the studies on BRCA VUS in order to clarify their clinical relevance.

  9. VCF-Miner: GUI-based application for mining variants and annotations stored in VCF files

    OpenAIRE

    Steven N Hart; Duffy, Patrick; Quest, Daniel J.; Hossain, Asif; Meiners, Mike A; Kocher, Jean-Pierre

    2015-01-01

    Next-generation sequencing platforms are widely used to discover variants associated with disease. The processing of sequencing data involves read alignment, variant calling, variant annotation and variant filtering. The standard file format to hold variant calls is the variant call format (VCF) file. According to the format specifications, any arbitrary annotation can be added to the VCF file for downstream processing. However, most downstream analysis programs disregard annotations already ...

  10. Identification of copy number variants in horses

    KAUST Repository

    Doan, R.

    2012-03-01

    Copy number variants (CNVs) represent a substantial source of genetic variation in mammals. However, the occurrence of CNVs in horses and their subsequent impact on phenotypic variation is unknown. We performed a study to identify CNVs in 16 horses representing 15 distinct breeds (Equus caballus) and an individual gray donkey (Equus asinus) using a whole-exome tiling array and the array comparative genomic hybridization methodology. We identified 2368 CNVs ranging in size from 197 bp to 3.5 Mb. Merging identical CNVs from each animal yielded 775 CNV regions (CNVRs), involving 1707 protein- and RNA-coding genes. The number of CNVs per animal ranged from 55 to 347, with median and mean sizes of CNVs of 5.3 kb and 99.4 kb, respectively. Approximately 6% of the genes investigated were affected by a CNV. Biological process enrichment analysis indicated CNVs primarily affected genes involved in sensory perception, signal transduction, and metabolism. CNVs also were identified in genes regulating blood group antigens, coat color, fecundity, lactation, keratin formation, neuronal homeostasis, and height in other species. Collectively, these data are the first report of copy number variation in horses and suggest that CNVs are common in the horse genome and may modulate biological processes underlying different traits observed among horses and horse breeds.

  11. CRY2 genetic variants associate with dysthymia.

    Directory of Open Access Journals (Sweden)

    Leena Kovanen

    Full Text Available People with mood disorders often have disruptions in their circadian rhythms. Recent molecular genetics has linked circadian clock genes to mood disorders. Our objective was to study two core circadian clock genes, CRY1 and CRY2 as well as TTC1 that interacts with CRY2, in relation to depressive and anxiety disorders. Of these three genes, 48 single-nucleotide polymorphisms (SNPs whose selection was based on the linkage disequilibrium and potential functionality were genotyped in 5910 individuals from a nationwide population-based sample. The diagnoses of major depressive disorder, dysthymia and anxiety disorders were assessed with a structured interview (M-CIDI. In addition, the participants filled in self-report questionnaires on depressive and anxiety symptoms. Logistic and linear regression models were used to analyze the associations of the SNPs with the phenotypes. Four CRY2 genetic variants (rs10838524, rs7121611, rs7945565, rs1401419 associated significantly with dysthymia (false discovery rate q<0.05. This finding together with earlier CRY2 associations with winter depression and with bipolar type 1 disorder supports the view that CRY2 gene has a role in mood disorders.

  12. Spatially variant morphological restoration and skeleton representation.

    Science.gov (United States)

    Bouaynaya, Nidhal; Charif-Chefchaouni, Mohammed; Schonfeld, Dan

    2006-11-01

    The theory of spatially variant (SV) mathematical morphology is used to extend and analyze two important image processing applications: morphological image restoration and skeleton representation of binary images. For morphological image restoration, we propose the SV alternating sequential filters and SV median filters. We establish the relation of SV median filters to the basic SV morphological operators (i.e., SV erosions and SV dilations). For skeleton representation, we present a general framework for the SV morphological skeleton representation of binary images. We study the properties of the SV morphological skeleton representation and derive conditions for its invertibility. We also develop an algorithm for the implementation of the SV morphological skeleton representation of binary images. The latter algorithm is based on the optimal construction of the SV structuring element mapping designed to minimize the cardinality of the SV morphological skeleton representation. Experimental results show the dramatic improvement in the performance of the SV morphological restoration and SV morphological skeleton representation algorithms in comparison to their translation-invariant counterparts. PMID:17076415

  13. DRD4 Rare Variants in Attention-Deficit/Hyperactivity Disorder (ADHD): Further Evidence from a Birth Cohort Study

    OpenAIRE

    Tovo-Rodrigues, Luciana; Rohde, Luis A.; Ana M. B. Menezes; Polanczyk, Guilherme V; Kieling, Christian; Julia P Genro; Anselmi, Luciana; Mara H. Hutz

    2013-01-01

    The dopamine receptor D4 (DRD4) is one of the most studied candidate genes for Attention-Deficit/Hyperactivity Disorder (ADHD). An excess of rare variants and non-synonymous mutations in the VNTR region of 7R allele in ADHD subjects was observed in previous studies with clinical samples. We hypothesize that genetic heterogeneity in the VNTR is an important factor in the pathophysiology of ADHD. The subjects included in the present study are members of the 1993 Pelotas Birth Cohort Study (N=5,...

  14. CLA-1 and its splicing variant CLA-2 mediate bacterial adhesion and cytosolic bacterial invasion in mammalian cells

    OpenAIRE

    Vishnyakova, Tatyana G.; Kurlander, Roger; Bocharov, Alexander V.; Baranova, Irina N.; CHEN, ZHIGANG; Abu-Asab, Mones S.; Tsokos, Maria; Malide, Daniela; Basso, Federica; Remaley, Alan; Csako, Gyorgy; Eggerman, Thomas L.; Patterson, Amy P.

    2006-01-01

    CD36 and LIMPII analog 1, CLA-1, and its splicing variant, CLA-2 (SR-BI and SR-BII in rodents), are human high density lipoprotein receptors with an identical extracellular domain which binds a spectrum of ligands including bacterial cell wall components. In this study, CLA-1- and CLA-2-stably transfected HeLa and HEK293 cells demonstrated several-fold increases in the uptake of various bacteria over mock-transfected cells. All bacteria tested, including both Gram-negatives (Escherichia coli ...

  15. IGF2R Genetic Variants, Circulating IGF2 Concentrations and Colon Cancer Risk in African Americans and Whites

    OpenAIRE

    Cathrine Hoyo; Susan K Murphy; Schildkraut, Joellen M; Vidal, Adriana C.; David Skaar; Millikan, Robert C.; Joseph Galanko; Sandler, Robert S.; Randy Jirtle; Temitope Keku

    2012-01-01

    The Mannose 6 Phosphate/Insulin-like Growth Factor Receptor-2 (IGF2R) encodes a type-1 membrane protein that modulates availability of the potent mitogen, IGF2. We evaluated the associations between IGF2R non-synonymous genetic variants (c.5002G>A, Gly1619Arg(rs629849), and c.901C>G, Leu252Val(rs8191754)), circulating IGF2 levels, and colon cancer (CC) risk among African American and White participants enrolled in the North Carolina Colon Cancer Study (NCCCS). Generalized linear models were u...

  16. Global displacement of canine parvovirus by a host-adapted variant: structural comparison between pandemic viruses with distinct host ranges.

    Science.gov (United States)

    Organtini, Lindsey J; Allison, Andrew B; Lukk, Tiit; Parrish, Colin R; Hafenstein, Susan

    2015-02-01

    Canine parvovirus type 2 (CPV-2) emerged in 1978 and spread worldwide within 2 years. Subsequently, CPV-2 was completely replaced by the variant CPV-2a, which is characterized by four specific capsid (VP2) mutations. The X-ray crystal structure of the CPV-2a capsid shows that each mutation confers small local changes. The loss of a hydrogen bond and introduction of a glycine residue likely introduce flexibility to sites that control interactions with the host receptor, antibodies, and sialic acids. PMID:25410876

  17. Dopamine receptor repertoire of human granulosa cells

    Directory of Open Access Journals (Sweden)

    Kunz Lars

    2007-10-01

    Full Text Available Abstract Background High levels of dopamine (DA were described in human ovary and recently evidence for DA receptors in granulosa and luteal cells has been provided, as well. However, neither the full repertoire of ovarian receptors for DA, nor their specific role, is established. Human granulosa cells (GCs derived from women undergoing in vitro fertilization (IVF are an adequate model for endocrine cells of the follicle and the corpus luteum and were therefore employed in an attempt to decipher their DA receptor repertoire and functionality. Methods Cells were obtained from patients undergoing IVF and examined using cDNA-array, RT-PCR, Western blotting and immunocytochemistry. In addition, calcium measurements (with FLUO-4 were employed. Expression of two DA receptors was also examined by in-situ hybridization in rat ovary. Effects of DA on cell viability and cell volume were studied by using an ATP assay and an electronic cell counter system. Results We found members of the two DA receptor families (D1- and D2 -like associated with different signaling pathways in human GCs, namely D1 (as expected and D5 (both are Gs coupled and linked to cAMP increase and D2, D4 (Gi/Gq coupled and linked to IP3/DAG. D3 was not found. The presence of the trophic hormone hCG (10 IU/ml in the culture medium for several days did not alter mRNA (semiquantitative RT-PCR or protein levels (immunocytochemistry/Western blotting of D1,2,4,5 DA receptors. Expression of prototype receptors for the two families, D1 and D2, was furthermore shown in rat granulosa and luteal cells by in situ hybridization. Among the DA receptors found in human GCs, D2 expression was marked both at mRNA and protein levels and it was therefore further studied. Results of additional RT-PCR and Western blots showed two splice variants (D2L, D2S. Irrespective of these variants, D2 proved to be functional, as DA raised intracellular calcium levels. This calcium mobilizing effect of DA was observed

  18. Mutations in CDON, encoding a hedgehog receptor, result in holoprosencephaly and defective interactions with other hedgehog receptors.

    Science.gov (United States)

    Bae, Gyu-Un; Domené, Sabina; Roessler, Erich; Schachter, Karen; Kang, Jong-Sun; Muenke, Maximilian; Krauss, Robert S

    2011-08-12

    Holoprosencephaly (HPE), a common human congenital anomaly defined by a failure to delineate the midline of the forebrain and/or midface, is associated with diminished Sonic hedgehog (SHH)-pathway activity in development of these structures. SHH signaling is regulated by a network of ligand-binding factors, including the primary receptor PTCH1 and the putative coreceptors, CDON (also called CDO), BOC, and GAS1. Although binding of SHH to these receptors promotes pathway activity, it is not known whether interactions between these receptors are important. We report here identification of missense CDON mutations in human HPE. These mutations diminish CDON's ability to support SHH-dependent gene expression in cell-based signaling assays. The mutations occur outside the SHH-binding domain of CDON, and the encoded variant CDON proteins do not display defects in binding to SHH. In contrast, wild-type CDON associates with PTCH1 and GAS1, but the variants do so inefficiently, in a manner that parallels their activity in cell-based assays. Our findings argue that CDON must associate with both ligand and other hedgehog-receptor components, particularly PTCH1, for signaling to occur and that disruption of the latter interactions is a mechanism of HPE. PMID:21802063

  19. Vitamin D binding protein variants associate with asthma susceptibility in the Chinese han population

    Directory of Open Access Journals (Sweden)

    Zhang Youming

    2011-08-01

    Full Text Available Abstract Background Asthma is a genetically heterogeneous disease. Polymorphisms of genes encoding components of the vitamin D pathway have been reported to associate with the risk of asthma. We have previously demonstrated that vitamin D status was associated with lung function in Chinese asthma patients. In this study, we tested whether polymorphisms of genes encoding for vitamin D receptor (VDR, vitamin D 25-hydroxylase (CYP2R1 and vitamin D binding protein (GC were associated with asthma in the Chinese Han population. Methods We sequenced all 8 exons of VDR and all 5 exons of CYP2R1 in a Chinese case-control cohort of asthma consisting of 467 cases and 288 unrelated healthy controls. Two mutations were identified in these regions. These variants were specified as rs2228570 in exon 2 of VDR and rs12794714 in exon 1 of CYP2R1. We also genotyped two common polymorphisms in GC gene (rs4588 and rs7041 by a PCR-restriction fragment length polymorphism (RFLP method. We analyzed the association between these 4 polymorphisms and asthma susceptibility and asthma-related traits. Results Polymorphic markers in VDR and CYP2R1 were not associated with asthma in the Chinese Han cohort. Importantly, variants in GC gene, which give rise to the two most common electrophoretic isoforms of the vitamin D binding protein, were associated with asthma susceptibility. Compared with isoform Gc1, Gc2 was significantly associated with the risk of asthma (OR = 1.35, 95% CI = 1.01-1.78 p = 0.006. Conclusions The results provide supporting evidence for association between GC variants and asthma susceptibility in the Chinese Han population.

  20. Plasmodium falciparum variant STEVOR antigens are expressed in merozoites and possibly associated with erythrocyte invasion

    Directory of Open Access Journals (Sweden)

    Petter Michaela

    2008-07-01

    Full Text Available Abstract Background Plasmodium falciparum STEVOR proteins, encoded by the multicopy stevor gene family have no known biological functions. Their expression and unique locations in different parasite life cycle stages evoke multiple functionalities. Their abundance and hypervariability support a role in antigenic variation. Methods Immunoblotting of total parasite proteins with an anti-STEVOR antibody was used to identify variant antigens of this gene family and to follow changes in STEVOR expression in parasite populations panned on CSA or CD36 receptors. Immunofluorescence assays and immunoelectron microscopy were performed to study the subcellular localization of STEVOR proteins in different parasite stages. The capacity of the antibody to inhibit merozoite invasion of erythrocytes was assessed to determine whether STEVOR variants were involved in the invasion process. Results Antigenic variation of STEVORs at the protein level was observed in blood stage parasites. STEVOR variants were found to be present on the merozoite surface and in rhoptries. An insight into a participation in erythrocyte invasion was gained through an immunofluorescence analysis of a sequence of thin slides representing progressive steps in erythrocyte invasion. An interesting feature of the staining pattern was what appeared to be the release of STEVORs around the invading merozoites. Because the anti-STEVOR antibody did not inhibit invasion, the role of STEVORs in this process remains unknown. Conclusion The localization of STEVOR proteins to the merozoite surface and the rhoptries together with its prevalence as a released component in the invading merozoite suggest a role of these antigens in adhesion and/or immune evasion in the erythrocyte invasion process. These observations would also justify STEVORs for undergoing antigenic variation. Even though a role in erythrocyte invasion remains speculative, an association of members of the STEVOR protein family with

  1. Multiple Sodium Channel Variants in the Mosquito Culex quinquefasciatus

    Directory of Open Access Journals (Sweden)

    Lin He, Ting Li, Lee Zhang, Nannan Liu

    2012-01-01

    Full Text Available Voltage-gated sodium channels are the target sites of both DDT and pyrethroid insecticides. The importance of alternative splicing as a key mechanism governing the structural and functional diversity of sodium channels and the resulting development of insecticide and acaricide resistance is widely recognized, as shown by the extensive research on characterizing alternative splicing and variants of sodium channels in medically and agriculturally important insect species. Here we present the first comparative study of multiple variants of the sodium channel transcripts in the mosquito Culex quinquefasciatus. The variants were classified into two categories, CxNa-L and CxNa-S based on their distinguishing sequence sizes of ~6.5 kb and ~4.0 kb, respectively, and generated via major extensive alternative splicing with minor small deletions/ insertions in susceptible S-Lab, low resistant HAmCqG0, and highly resistant HAmCqG8 Culex strains. Four alternative Cx-Na-L splice variants were identified, including three full length variants with three optional exons (2, 5, and 21i and one with in-frame-stop codons. Large, multi-exon-alternative splices were identified in the CxNa-S category. All CxNa-S splicing variants in the S-Lab and HAmCqG0 strains contained in-frame stop codons, suggesting that any resulting proteins would be truncated. The ~1000 to ~3000-fold lower expression of these splice variants with stop codons compared with the CxNa-L splicing variants may support the lower importance of these variants in S-Lab and HAmCqG0. Interestingly, two alternative splicing variants of CxNa-S in HAmCqG8 included entire ORFs but lacked exons 5 to18 and these two variants had much higher expression levels in HAmCqG8 than in S-Lab and HAmCqG0. These results provide a functional basis for further characterizing how alternative splicing of a voltage-gated sodium channel contributes to diversity in neuronal signaling in mosquitoes in response to pyrethroids, and

  2. Mitochondrial transfer RNA variants and primary congenital glaucoma.

    Science.gov (United States)

    Yi, Quan-Yong; Deng, Gang; Zhou, Hong-Jian; Wu, Guo-Hai; Tang, Luosheng

    2016-07-01

    Variants in mitochondrial DNA (mtDNA) are the most important causes for vision loss, the mt-tRNA variants being the largest group among them. In this study, we report the molecular characterization of 15 mt-tRNA variants with primary congenital glaucoma (PCG). Based on phylogenetic approach, we found that only half of them were definitely pathogenic with PCG, other mutations were single nucleotide polymorphisms (SNP) in human population. Thus, our study provided novel insight into the pathogenesis of PCG. PMID:25835039

  3. Geometric Structures of Stable Time-Variant State Feedback Systems

    Institute of Scientific and Technical Information of China (English)

    ZHONG Feng-wei; SUN Hua-fei; ZHANG Zhen-ning

    2007-01-01

    A new technique for considering the stabilizing time-variant state feedback gains is proposed from the viewpoint of information geometry. First, parametrization of the set of all stabilizing time-variant state feedback gains is given. Moreover, a diffeomorphic structure between the set of stabilizing time-variant state feedback gains and the Cartesian product of positive definite matrix and skew symmetric matrix satisfying certain algebraic conditions is constructed. Furth ermore, an immersion and some results about the eigenvalue locations of stable state feedback systems are derived.

  4. Variante de Dandy Walker: relato de caso = Dandy Walker variant: a case report

    Directory of Open Access Journals (Sweden)

    Khan, Richard Lester et al.

    2009-01-01

    Full Text Available Objetivos: relatar o caso de um paciente com variante de Dandy Walker, chamando atenção para a importância da suspeita, investigação e manejo das repercussões clínicas. Descrição do caso: é relatado o caso de um paciente do sexo masculino, com quadro clínico e radiológico típico da Variante de Dandy Walker. Durante o pré-natal, através de ecografia obstétrica com 23 semanas e 3 dias, apresentou alterações sugestivas de Síndrome de Dandy Walker. Ao nascimento apresentou exame físico com fenda palatina, criptorquidia à direita, hexodactilia em ambos os pés. Apresentava ainda ecocardiograma com forame oval patente e persistência do canal arterial. O diagnóstico foi estabelecido através da ressonância magnética realizada após o nascimento, que evidenciava hipoplasia do vermis cerebelar, alargamento da fossa posterior e leve dilatação ventricular. Conclusões: este artigo procura caracterizar a variante de Dandy Walker, que é uma malformação congênita do sistema nervoso central e é o tipo mais comum da Síndrome de Dandy Walker. Seu fenótipo é variável, devendo-se sempre pesquisar malformações tanto intra quanto extracranianas, visto que o risco de mortalidade pós-natal aumenta quando existe esta associação. O tratamento envolve equipe multidisciplinar e o prognóstico é reservado, variando conforme o fenótipo.

  5. Association Study of CHRNA7 Promoter Variants with Sensory and Sensorimotor Gating in Schizophrenia Patients and Healthy Controls: A Danish Case-Control Study.

    Science.gov (United States)

    Bertelsen, Birgitte; Oranje, Bob; Melchior, Linea; Fagerlund, Birgitte; Werge, Thomas M; Mikkelsen, Jens D; Tümer, Zeynep; Glenthøj, Birte Y

    2015-12-01

    Schizophrenia is a severe psychiatric disorder with a core component of impaired cognitive function still remaining as one of the greatest challenges in the pharmacological treatment of the disorder. The CHRNA7 gene, encoding the subunit of the human α7 nicotinic acetylcholine receptor (α7nAChR), is suggested as a susceptibility factor for schizophrenia. CHRNA7 has also been genetically linked to the P50 auditory evoked potential deficit, a candidate endophenotype of schizophrenia, but not to prepulse inhibition of the startle reflex (PPI). In this study, 95 antipsychotic-naïve schizophrenic patients and 450 unaffected controls were screened for CHRNA7 promoter variants to investigate the association with schizophrenia, P50 suppression and PPI. We found that the promoter variant -194C (rs28531779) was significantly associated with schizophrenia, but did not find any association of this variant with P50 suppression or PPI. In addition, individuals with CHRNA7 promoter variants had elevated startle magnitude in pulse-alone trials compared to individuals without a variant. The present findings provide further support for a role of the α7nAChR in schizophrenia and show a genetic link between CHRNA7 and startle magnitude, indicating that cholinergic neurotransmission involving the α7nAChR could be involved in sensory registration processes. PMID:26376812

  6. Detection of combined genomic variants in a Jordanian family with familial non-autoimmune hyperthyroidism

    Indian Academy of Sciences (India)

    Said I. Ismail; Ismail S. Mahmoud; Mahmoud Al-Ardah; Amid Abdelnour; Nidal A. Younes

    2009-08-01

    Five patients, four brothers and their paternal aunt, presented with a history of overt hyperthyroidism and goiter. Hyperthyroidism in this family was remarkable for its poor response to carbimazole (30–50 mg/d). The thyroid ultrasound showed a diffusely enlarged gland in all the affected members, and thyroid stimulating antibodies (TSAB) were negative. Screening for germline mutations in thyroid stimulating hormone (TSH) receptor (TSHR) gene was performed by direct sequencing of genomic DNA extracted from peripheral blood leukocytes of all family members. The sequence analysis of all TSHR gene exons and intron borders revealed two genomic variants. The first was a single nucleotide polymorphism (SNP) within exon seven (Asn187Asn), whereas the other was located in intron seven (IVS7+68T>G). All affected members, two asymptomatic brothers with sub-clinical hyperthyroidism, and their father were heterozygous for those two genomic variants. Anti-thyroid drug treatment for several months successfully relieved symptoms in one subject, whereas the remaining patients required total thyroidectomy to control their disease. This is the first Jordanian family with familial non-autoimmune hyperthyroidism, with mutations affecting the TSHR gene.

  7. Structure-function analysis of two variants of mumps virus hemagglutinin-neuraminidase protein

    Directory of Open Access Journals (Sweden)

    Gerardo Santos-López

    2009-02-01

    Full Text Available A point mutation from guanine (G to adenine (A at nucleotide position 1081 in the hemagglutinin-neuraminidase (HN gene has been associated with neurovirulence of Urabe AM9 mumps virus vaccine. This mutation corresponds to a glutamic acid (E to lysine (K change at position 335 in the HN glycoprotein. We have experimentally demonstrated that two variants of Urabe AM9 strain (HN-A1081 and HN-G1081 differ in neurotropism, sialic acidbinding affinity and neuraminidase activity. In the present study, we performed a structure-function analysis of that amino acid substitution; the structures of HN protein of both Urabe AM9 strain variants were predicted. Based on our analysis, the E/K mutation changes the protein surface properties and to a lesser extent their conformations, which in turn reflects in activity changes. Our modeling results suggest that this E/K interchange does not affect the structure of the sialic acid binding motif; however, the electrostatic surface differs drastically due to an exposed short alpha helix. Consequently, this mutation may affect the accessibility of HN to substrates and membrane receptors of the host cells. Our findings appear to explain the observed differences in neurotropism of these vaccine strains.

  8. The expression of the ACTH receptor

    Directory of Open Access Journals (Sweden)

    L.L.K. Elias

    2000-10-01

    Full Text Available Adrenal glucocorticoid secretion is regulated by adrenocorticotropic hormone (ACTH acting through a specific cell membrane receptor (ACTH-R. The ACTH-R is a member of the G protein superfamily-coupled receptors and belongs to the subfamily of melanocortin receptors. The ACTH-R is mainly expressed in the adrenocortical cells showing a restricted tissue specificity, although ACTH is recognized by the other four melanocortin receptors. The cloning of the ACTH-R was followed by the study of this gene in human diseases such as familial glucocorticoid deficiency (FGD and adrenocortical tumors. FGD is a rare autosomal recessive disease characterized by glucocorticoid deficiency, elevated plasma ACTH levels and preserved renin/aldosterone secretion. This disorder has been ascribed to an impaired adrenal responsiveness to ACTH due to a defective ACTH-R, a defect in intracellular signal transduction or an abnormality in adrenal cortical development. Mutations of the ACTH-R have been described in patients with FGD in segregation with the disease. The functional characterization of these mutations has been prevented by difficulties in expressing human ACTH-R in cells that lack endogenous melanocortin receptor activity. To overcome these difficulties we used Y6 cells, a mutant variant of the Y1 cell line, which possesses a non-expressed ACTH-R gene allowing the functional study without any background activity. Our results demonstrated that the several mutations of the ACTH-R found in FGD result in an impaired cAMP response or loss of sensitivity to ACTH stimulation. An ACTH-binding study showed an impairment of ligand binding with loss of the high affinity site in most of the mutations studied.

  9. The Role of Metabotropic Glutamate Receptor Genes in Schizophrenia.

    Science.gov (United States)

    Maj, Carlo; Minelli, Alessandra; Giacopuzzi, Edoardo; Sacchetti, Emilio; Gennarelli, Massimo

    2016-01-01

    Genomic studies revealed two main components in the genetic architecture of schizophrenia, one constituted by common variants determining a distributed polygenic effect and one represented by a large number of heterogeneous rare and highly disruptive mutations. These gene modifications often affect neural transmission and different studies proved an involvement of metabotropic glutamate receptors in schizophrenia phenotype. Through the combination of literature information with genomic data from public repositories, we analyzed the current knowledge on the involvement of genetic variations of the human metabotropic glutamate receptors in schizophrenia and related endophenotypes. Despite the analysis did not reveal a definitive connection, different suggestive associations have been identified and in particular a relevant role has emerged for GRM3 in affecting specific schizophrenia endophenotypes. This supports the hypothesis that these receptors are directly involved in schizophrenia disorder. PMID:27296644

  10. Rat liver insulin receptor

    International Nuclear Information System (INIS)

    Using insulin affinity chromatography, the authors have isolated highly purified insulin receptor from rat liver. When evaluated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions, the rat liver receptor contained the M/sub r/ 125,000 α-subunit, the M/sub r/ 90,000 β-subunit, and varying proportions of the M/sub r/ 45,000 β'-subunit. The specific insulin binding of the purified receptor was 25-30 μg of 125I-insulin/mg of protein, and the receptor underwent insulin-dependent autophosphorylation. Rat liver and human placental receptors differ from each other in several functional aspects: (1) the adsorption-desorption behavior from four insulin affinity columns indicated that the rat liver receptor binds less firmly to immobilized ligands; (2) the 125I-insulin binding affinity of the rat liver receptor is lower than that of the placental receptor; (3) partial reduction of the rat liver receptor with dithiothreitol increases its insulin binding affinity whereas the binding affinity of the placental receptor is unchanged; (4) at optimal insulin concentration, rat liver receptor autophosphorylation is stimulated 25-50-fold whereas the placental receptor is stimulated only 4-6-fold. Conversion of the β-subunit to β' by proteolysis is a major problem that occurs during exposure of the receptor to the pH 5.0 buffer used to elute the insulin affinity column. Proteolytic destruction and the accompanying loss of insulin-dependent autophosphorylation can be substantially reduced by proteolysis inhibitors. In summary, rat liver and human placental receptors differ functionally in both α- and β-subunits. Insulin binding to the α-subunit of the purified rat liver receptor communicates a signal that activates the β-subunit; however, major proteolytic destruction of the β-subunit does not affect insulin binding to the α-subunit

  11. Anti-CD25 monoclonal antibody Fc variants differentially impact regulatory T cells and immune homeostasis.

    Science.gov (United States)

    Huss, David J; Pellerin, Alex F; Collette, Brian P; Kannan, Arun K; Peng, Liaomin; Datta, Abhishek; Wipke, Brian T; Fontenot, Jason D

    2016-07-01

    Interleukin-2 (IL-2) is a critical regulator of immune homeostasis through its non-redundant role in regulatory T (Treg) cell biology. There is major interest in therapeutic modulation of the IL-2 pathway to promote immune activation in the context of tumour immunotherapy or to enhance immune suppression in the context of transplantation, autoimmunity and inflammatory diseases. Antibody-mediated targeting of the high-affinity IL-2 receptor α chain (IL-2Rα or CD25) offers a direct mechanism to target IL-2 biology and is being actively explored in the clinic. In mouse models, the rat anti-mouse CD25 clone PC61 has been used extensively to investigate the biology of IL-2 and Treg cells; however, there has been controversy and conflicting data on the exact in vivo mechanistic function of PC61. Engineering antibodies to alter Fc/Fc receptor interactions can significantly alter their in vivo function. In this study, we re-engineered the heavy chain constant region of an anti-CD25 monoclonal antibody to generate variants with highly divergent Fc effector function. Using these anti-CD25 Fc variants in multiple mouse models, we investigated the in vivo impact of CD25 blockade versus depletion of CD25(+) Treg cells on immune homeostasis. We report that immune homeostasis can be maintained during CD25 blockade but aberrant T-cell activation prevails when CD25(+) Treg cells are actively depleted. These results clarify the impact of PC61 on Treg cell biology and reveal an important distinction between CD25 blockade and depletion of CD25(+) Treg cells. These findings should inform therapeutic manipulation of the IL-2 pathway by targeting the high-affinity IL-2R. PMID:27012310

  12. Differential Compartmentalization and Distinct Functions of GABA(B) Receptor Variants

    Czech Academy of Sciences Publication Activity Database

    Vigot, B.; Barbieri, S.; Bräuner-Osborne, H.; Tureček, Rostislav; Shigemoto, R.; Zhang, Y.P.; Luján, R.; Jacobson, L.H.; Biermann, B.; Fritschy, J.M.; Vacher, C.M.; Müller, M.; Sansing, G.; Guetg, N.; Cryan, J.F.; Kaupmann, K.; Gassmann, M.; Oertner, T.G.; Bettler, B.

    2006-01-01

    Roč. 50, - (2006), s. 589-601. ISSN 0896-6273 R&D Projects: GA ČR GA309/03/1158 Institutional research plan: CEZ:AV0Z50390512 Keywords : GABA (B) Subject RIV: FH - Neurology Impact factor: 13.894, year: 2006

  13. Meta-analysis of Gene-Level Associations for Rare Variants Based on Single-Variant Statistics

    Science.gov (United States)

    Hu, Yi-Juan; Berndt, Sonja I.; Gustafsson, Stefan; Ganna, Andrea; Berndt, Sonja I.; Gustafsson, Stefan; Mägi, Reedik; Ganna, Andrea; Wheeler, Eleanor; Feitosa, Mary F.; Justice, Anne E.; Monda, Keri L.; Croteau-Chonka, Damien C.; Day, Felix R.; Esko, Tõnu; Fall, Tove; Ferreira, Teresa; Gentilini, Davide; Jackson, Anne U.; Luan, Jian’an; Randall, Joshua C.; Vedantam, Sailaja; Willer, Cristen J.; Winkler, Thomas W.; Wood, Andrew R.; Workalemahu, Tsegaselassie; Hu, Yi-Juan; Lee, Sang Hong; Liang, Liming; Lin, Dan-Yu; Min, Josine L.; Neale, Benjamin M.; Thorleifsson, Gudmar; Yang, Jian; Albrecht, Eva; Amin, Najaf; Bragg-Gresham, Jennifer L.; Cadby, Gemma; den Heijer, Martin; Eklund, Niina; Fischer, Krista; Goel, Anuj; Hottenga, Jouke-Jan; Huffman, Jennifer E.; Jarick, Ivonne; Johansson, Åsa; Johnson, Toby; Kanoni, Stavroula; Kleber, Marcus E.; König, Inke R.; Kristiansson, Kati; Kutalik, Zoltán; Lamina, Claudia; Lecoeur, Cecile; Li, Guo; Mangino, Massimo; McArdle, Wendy L.; Medina-Gomez, Carolina; Müller-Nurasyid, Martina; Ngwa, Julius S.; Nolte, Ilja M.; Paternoster, Lavinia; Pechlivanis, Sonali; Perola, Markus; Peters, Marjolein J.; Preuss, Michael; Rose, Lynda M.; Shi, Jianxin; Shungin, Dmitry; Smith, Albert Vernon; Strawbridge, Rona J.; Surakka, Ida; Teumer, Alexander; Trip, Mieke D.; Tyrer, Jonathan; Van Vliet-Ostaptchouk, Jana V.; Vandenput, Liesbeth; Waite, Lindsay L.; Zhao, Jing Hua; Absher, Devin; Asselbergs, Folkert W.; Atalay, Mustafa; Attwood, Antony P.; Balmforth, Anthony J.; Basart, Hanneke; Beilby, John; Bonnycastle, Lori L.; Brambilla, Paolo; Bruinenberg, Marcel; Campbell, Harry; Chasman, Daniel I.; Chines, Peter S.; Collins, Francis S.; Connell, John M.; Cookson, William; de Faire, Ulf; de Vegt, Femmie; Dei, Mariano; Dimitriou, Maria; Edkins, Sarah; Estrada, Karol; Evans, David M.; Farrall, Martin; Ferrario, Marco M.; Ferrières, Jean; Franke, Lude; Frau, Francesca; Gejman, Pablo V.; Grallert, Harald; Grönberg, Henrik; Gudnason, Vilmundur; Hall, Alistair S.; Hall, Per; Hartikainen, Anna-Liisa; Hayward, Caroline; Heard-Costa, Nancy L.; Heath, Andrew C.; Hebebrand, Johannes; Homuth, Georg; Hu, Frank B.; Hunt, Sarah E.; Hyppönen, Elina; Iribarren, Carlos; Jacobs, Kevin B.; Jansson, John-Olov; Jula, Antti; Kähönen, Mika; Kathiresan, Sekar; Kee, Frank; Khaw, Kay-Tee; Kivimaki, Mika; Koenig, Wolfgang; Kraja, Aldi T.; Kumari, Meena; Kuulasmaa, Kari; Kuusisto, Johanna; Laitinen, Jaana H.; Lakka, Timo A.; Langenberg, Claudia; Launer, Lenore J.; Lind, Lars; Lindström, Jaana; Liu, Jianjun; Liuzzi, Antonio; Lokki, Marja-Liisa; Lorentzon, Mattias; Madden, Pamela A.; Magnusson, Patrik K.; Manunta, Paolo; Marek, Diana; März, Winfried; Leach, Irene Mateo; McKnight, Barbara; Medland, Sarah E.; Mihailov, Evelin; Milani, Lili; Montgomery, Grant W.; Mooser, Vincent; Mühleisen, Thomas W.; Munroe, Patricia B.; Musk, Arthur W.; Narisu, Narisu; Navis, Gerjan; Nicholson, George; Nohr, Ellen A.; Ong, Ken K.; Oostra, Ben A.; Palmer, Colin N.A.; Palotie, Aarno; Peden, John F.; Pedersen, Nancy; Peters, Annette; Polasek, Ozren; Pouta, Anneli; Pramstaller, Peter P.; Prokopenko, Inga; Pütter, Carolin; Radhakrishnan, Aparna; Raitakari, Olli; Rendon, Augusto; Rivadeneira, Fernando; Rudan, Igor; Saaristo, Timo E.; Sambrook, Jennifer G.; Sanders, Alan R.; Sanna, Serena; Saramies, Jouko; Schipf, Sabine; Schreiber, Stefan; Schunkert, Heribert; Shin, So-Youn; Signorini, Stefano; Sinisalo, Juha; Skrobek, Boris; Soranzo, Nicole; Stančáková, Alena; Stark, Klaus; Stephens, Jonathan C.; Stirrups, Kathleen; Stolk, Ronald P.; Stumvoll, Michael; Swift, Amy J.; Theodoraki, Eirini V.; Thorand, Barbara; Tregouet, David-Alexandre; Tremoli, Elena; Van der Klauw, Melanie M.; van Meurs, Joyce B.J.; Vermeulen, Sita H.; Viikari, Jorma; Virtamo, Jarmo; Vitart, Veronique; Waeber, Gérard; Wang, Zhaoming; Widén, Elisabeth; Wild, Sarah H.; Willemsen, Gonneke; Winkelmann, Bernhard R.; Witteman, Jacqueline C.M.; Wolffenbuttel, Bruce H.R.; Wong, Andrew; Wright, Alan F.; Zillikens, M. Carola; Amouyel, Philippe; Boehm, Bernhard O.; Boerwinkle, Eric; Boomsma, Dorret I.; Caulfield, Mark J.; Chanock, Stephen J.; Cupples, L. Adrienne; Cusi, Daniele; Dedoussis, George V.; Erdmann, Jeanette; Eriksson, Johan G.; Franks, Paul W.; Froguel, Philippe; Gieger, Christian; Gyllensten, Ulf; Hamsten, Anders; Harris, Tamara B.; Hengstenberg, Christian; Hicks, Andrew A.; Hingorani, Aroon; Hinney, Anke; Hofman, Albert; Hovingh, Kees G.; Hveem, Kristian; Illig, Thomas; Jarvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Keinanen-Kiukaanniemi, Sirkka M.; Kiemeney, Lambertus A.; Kuh, Diana; Laakso, Markku; Lehtimäki, Terho; Levinson, Douglas F.; Martin, Nicholas G.; Metspalu, Andres; Morris, Andrew D.; Nieminen, Markku S.; Njølstad, Inger; Ohlsson, Claes; Oldehinkel, Albertine J.; Ouwehand, Willem H.; Palmer, Lyle J.; Penninx, Brenda; Power, Chris; Province, Michael A.; Psaty, Bruce M.; Qi, Lu; Rauramaa, Rainer; Ridker, Paul M.; Ripatti, Samuli; Salomaa, Veikko; Samani, Nilesh J.; Snieder, Harold; Sørensen, Thorkild I.A.; Spector, Timothy D.; Stefansson, Kari; Tönjes, Anke; Tuomilehto, Jaakko; Uitterlinden, André G.; Uusitupa, Matti; van der Harst, Pim; Vollenweider, Peter; Wallaschofski, Henri; Wareham, Nicholas J.; Watkins, Hugh; Wichmann, H.-Erich; Wilson, James F.; Abecasis, Goncalo R.; Assimes, Themistocles L.; Barroso, Inês; Boehnke, Michael; Borecki, Ingrid B.; Deloukas, Panos; Fox, Caroline S.; Frayling, Timothy; Groop, Leif C.; Haritunian, Talin; Heid, Iris M.; Hunter, David; Kaplan, Robert C.; Karpe, Fredrik; Moffatt, Miriam; Mohlke, Karen L.; O’Connell, Jeffrey R.; Pawitan, Yudi; Schadt, Eric E.; Schlessinger, David; Steinthorsdottir, Valgerdur; Strachan, David P.; Thorsteinsdottir, Unnur; van Duijn, Cornelia M.; Visscher, Peter M.; Di Blasio, Anna Maria; Hirschhorn, Joel N.; Lindgren, Cecilia M.; Morris, Andrew P.; Meyre, David; Scherag, André; McCarthy, Mark I.; Speliotes, Elizabeth K.; North, Kari E.; Loos, Ruth J.F.; Ingelsson, Erik; Hirschhorn, Joel; North, Kari E.; Ingelsson, Erik; Lin, Dan-Yu

    2013-01-01

    Meta-analysis of genome-wide association studies (GWASs) has led to the discoveries of many common variants associated with complex human diseases. There is a growing recognition that identifying “causal” rare variants also requires large-scale meta-analysis. The fact that association tests with rare variants are performed at the gene level rather than at the variant level poses unprecedented challenges in the meta-analysis. First, different studies may adopt different gene-level tests, so the results are not compatible. Second, gene-level tests require multivariate statistics (i.e., components of the test statistic and their covariance matrix), which are difficult to obtain. To overcome these challenges, we propose to perform gene-level tests for rare variants by combining the results of single-variant analysis (i.e., p values of association tests and effect estimates) from participating studies. This simple strategy is possible because of an insight that multivariate statistics can be recovered from single-variant statistics, together with the correlation matrix of the single-variant test statistics, which can be estimated from one of the participating studies or from a publicly available database. We show both theoretically and numerically that the proposed meta-analysis approach provides accurate control of the type I error and is as powerful as joint analysis of individual participant data. This approach accommodates any disease phenotype and any study design and produces all commonly used gene-level tests. An application to the GWAS summary results of the Genetic Investigation of ANthropometric Traits (GIANT) consortium reveals rare and low-frequency variants associated with human height. The relevant software is freely available. PMID:23891470

  14. Androgen receptor targeted therapies in castration-resistant prostate cancer: Bench to clinic.

    Science.gov (United States)

    Imamura, Yusuke; Sadar, Marianne D

    2016-08-01

    The androgen receptor is a transcription factor and validated therapeutic target for prostate cancer. Androgen deprivation therapy remains the gold standard treatment, but it is not curative, and eventually the disease will return as lethal castration-resistant prostate cancer. There have been improvements in the therapeutic landscape with new agents approved, such as abiraterone acetate, enzalutamide, sipuleucel-T, cabazitaxel and Ra-223, in the past 5 years. New insight into the mechanisms of resistance to treatments in advanced disease is being and has been elucidated. All current androgen receptor-targeting therapies inhibit the growth of prostate cancer by blocking the ligand-binding domain, where androgen binds to activate the receptor. Persuasive evidence supports the concept that constitutively active androgen receptor splice variants lacking the ligand-binding domain are one of the resistant mechanisms underlying advanced disease. Transcriptional activity of the androgen receptor requires a functional AF-1 region in its N-terminal domain. Preclinical evidence proved that this domain is a druggable target to forecast a potential paradigm shift in the management of advanced prostate cancer. This review presents an overview of androgen receptor-related mechanisms of resistance as well as novel therapeutic agents to overcome resistance that is linked to the expression of androgen receptor splice variants in castration-resistant prostate cancer. PMID:27302572

  15. Myostatin: genetic variants, therapy and gene doping

    Directory of Open Access Journals (Sweden)

    André Katayama Yamada

    2012-09-01

    Full Text Available Since its discovery, myostatin (MSTN has been at the forefront of muscle therapy research because intrinsic mutations or inhibition of this protein, by either pharmacological or genetic means, result in muscle hypertrophy and hyperplasia. In addition to muscle growth, MSTN inhibition potentially disturbs connective tissue, leads to strength modulation, facilitates myoblast transplantation, promotes tissue regeneration, induces adipose tissue thermogenesis and increases muscle oxidative phenotype. It is also known that current advances in gene therapy have an impact on sports because of the illicit use of such methods. However, the adverse effects of these methods, their impact on athletic performance in humans and the means of detecting gene doping are as yet unknown. The aim of the present review is to discuss biosynthesis, genetic variants, pharmacological/genetic manipulation, doping and athletic performance in relation to the MSTN pathway. As will be concluded from the manuscript, MSTN emerges as a promising molecule for combating muscle wasting diseases and for triggering wide-ranging discussion in view of its possible use in gene doping.Desde sua descoberta, a miostatina (MSTN entrou na linha de frente em pesquisas relacionadas às terapias musculares porque mutações intrínsecas ou inibição desta proteína tanto por abordagens farmacológicas como genéticas resultam em hipertrofia muscular e hiperplasia. Além do aumento da massa muscular, a inibição de MSTN potencialmente prejudica o tecido conectivo, modula a força muscular, facilita o transplante de mioblastos, promove regeneração tecidual, induz termogênese no tecido adiposo e aumenta a oxidação na musculatura esquelética. É também sabido que os atuais avanços em terapia gênica têm uma relação com o esporte devido ao uso ilícito de tal método. Os efeitos adversos de tal abordagem, seus efeitos no desempenho de atletas e métodos para detectar doping genético s

  16. A Unique Hairy Cell Leukemia Variant.

    Science.gov (United States)

    Jian, Charles; Hsia, Cyrus C

    2016-01-01

    A 65-year-old woman presented with easy bruising, left upper quadrant pain, decreased appetite, and weight loss. She had splenomegaly and lymphocytosis (lymphocyte count of 11.6 × 10(9)/l), with remarkably abnormal appearing morphology. Her hemoglobin and platelet counts were normal. Peripheral blood flow cytometry revealed a monoclonal B-cell population expressing CD11c, CD25, CD19, CD20, and CD103. An initial diagnosis of hairy cell leukemia (HCL) was made, and the patient was treated with a standard 5-day course of cladribine. However, her lymphocytosis improved transiently, with a relapse 4 months later. There was no improvement in her splenomegaly. An HCL variant (HCL-v) was considered based on her resistance to treatment with a purine nucleoside analog. A subsequent splenectomy improved symptoms. Two years after, the patient suffered a relapse and underwent 6 cycles of CHOP-R (cyclophosphamide, hydroxydaunomycin, oncovin, prednisone, and rituximab), achieving partial remission. While under observation, she progressed with lymphocytosis 6 months later and was treated with pentostatin. There was no significant improvement in her disease, and she died 8 weeks following treatment initiation. HCL-v is a clinically more aggressive mature B-cell lymphoma than HCL with worse splenomegaly, higher lymphocyte counts, and resistance to typical HCL therapy with purine nucleoside analogs. Early recognition of HCL-v in the history, physical examination, and investigations with morphology and flow cytometry is key to patient management. Further, as in our case of HCL-v, cell morphology can be distinctly atypical, with large nucleoli and extremely convoluted nuclei. The distinction between HCL and HCL-v is important as HCL-v patients require more aggressive therapy and closer follow-up. PMID:27462230

  17. Structure-based rational design of a Toll-like receptor 4 (TLR4 decoy receptor with high binding affinity for a target protein.

    Directory of Open Access Journals (Sweden)

    Jieun Han

    Full Text Available Repeat proteins are increasingly attracting much attention as alternative scaffolds to immunoglobulin antibodies due to their unique structural features. Nonetheless, engineering interaction interface and understanding molecular basis for affinity maturation of repeat proteins still remain a challenge. Here, we present a structure-based rational design of a repeat protein with high binding affinity for a target protein. As a model repeat protein, a Toll-like receptor4 (TLR4 decoy receptor composed of leucine-rich repeat (LRR modules was used, and its interaction interface was rationally engineered to increase the binding affinity for myeloid differentiation protein 2 (MD2. Based on the complex crystal structure of the decoy receptor with MD2, we first designed single amino acid substitutions in the decoy receptor, and obtained three variants showing a binding affinity (K(D one-order of magnitude higher than the wild-type decoy receptor. The interacting modes and contributions of individual residues were elucidated by analyzing the crystal structures of the single variants. To further increase the binding affinity, single positive mutations were combined, and two double mutants were shown to have about 3000- and 565-fold higher binding affinities than the wild-type decoy receptor. Molecular dynamics simulations and energetic analysis indicate that an additive effect by two mutations occurring at nearby modules was the major contributor to the remarkable increase in the binding affinities.

  18. Radioimmunological activity of 22K variant of human growth hormone

    International Nuclear Information System (INIS)

    From a preparation of human growth hormone its integral variant (hGH-22K) was isolated by isoelectric focusing, having a pI of 5,20 and relative mobility (Rm) of 0,621 in the polyacrylamide gel electrophoresis. Several experiments for the characterization of the isolated variant were carried out. The immunological properties was tested by radioimmunoassay (RIE), in which the activity of the isolated variant and the activity of the total preparation were compared. The dose response-curves obtained by RIE were found to be considered parallels (p < 0,01). It was checked using the F test between the slope of the two curves. The parallelism shown the immunochemical identity of the two preparation and indicates that the separation process developed does not produce alterations in the immunological properties of the variant. (Author)

  19. Leapfrog variants of iterative methods for linear algebra equations

    Science.gov (United States)

    Saylor, Paul E.

    1988-01-01

    Two iterative methods are considered, Richardson's method and a general second order method. For both methods, a variant of the method is derived for which only even numbered iterates are computed. The variant is called a leapfrog method. Comparisons between the conventional form of the methods and the leapfrog form are made under the assumption that the number of unknowns is large. In the case of Richardson's method, it is possible to express the final iterate in terms of only the initial approximation, a variant of the iteration called the grand-leap method. In the case of the grand-leap variant, a set of parameters is required. An algorithm is presented to compute these parameters that is related to algorithms to compute the weights and abscissas for Gaussian quadrature. General algorithms to implement the leapfrog and grand-leap methods are presented. Algorithms for the important special case of the Chebyshev method are also given.

  20. Behavioral variant of frontotemporal dementia mimicking Huntington's disease

    DEFF Research Database (Denmark)

    Nielsen, T Rune; Bruhn, Peter; Nielsen, Jørgen E;

    2010-01-01

    Behavioral changes and cognitive decline are the core clinical manifestations in the behavioral variant of frontotemporal dementia (bv-FTD). The behavioral changes may include characteristic stereotypic movements. These movements, although without clear purpose, are not involuntary. Involuntary...