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Sample records for q62p variant linked

  1. 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.

  2. Gene Variant from Africa Linked to Black Obesity

    Science.gov (United States)

    ... html Gene Variant From Africa Linked to Black Obesity Study sees first biological pathway to weight gain ... identified an Africa-specific gene variant associated with obesity. The team found that about 1 percent of ...

  3. FARVATX: Family-Based Rare Variant Association Test for X-Linked Genes.

    Science.gov (United States)

    Choi, Sungkyoung; Lee, Sungyoung; Qiao, Dandi; Hardin, Megan; Cho, Michael H; Silverman, Edwin K; Park, Taesung; Won, Sungho

    2016-09-01

    Although the X chromosome has many genes that are functionally related to human diseases, the complicated biological properties of the X chromosome have prevented efficient genetic association analyses, and only a few significantly associated X-linked variants have been reported for complex traits. For instance, dosage compensation of X-linked genes is often achieved via the inactivation of one allele in each X-linked variant in females; however, some X-linked variants can escape this X chromosome inactivation. Efficient genetic analyses cannot be conducted without prior knowledge about the gene expression process of X-linked variants, and misspecified information can lead to power loss. In this report, we propose new statistical methods for rare X-linked variant genetic association analysis of dichotomous phenotypes with family-based samples. The proposed methods are computationally efficient and can complete X-linked analyses within a few hours. Simulation studies demonstrate the statistical efficiency of the proposed methods, which were then applied to rare-variant association analysis of the X chromosome in chronic obstructive pulmonary disease. Some promising significant X-linked genes were identified, illustrating the practical importance of the proposed methods.

  4. Evidence for impaired CARD15 signalling in Crohn's disease without disease linked variants

    DEFF Research Database (Denmark)

    Seidelin, Jakob Benedict; Broom, Oliver Jay; Olsen, Jørgen

    2009-01-01

    BACKGROUND: Sensing of muramyl dipeptide (MDP) is impaired in Crohn's disease (CD) patients with disease-linked variants of the CARD15 (caspase activation and recruitment domain 15) gene. Animal studies suggest that normal CARD15 signalling prevents inflammatory bowel disease, and may be important...... for disease development in CD. However, only a small fraction of CD patients carry the disease linked CARD15 variants. The aim of this study was thus to investigate if changes could be found in CARD15 signalling in patients without disease associated CARD15 variants. METHODOLOGY/PRINCIPAL FINDINGS: By mapping...... the response to MDP in peripheral monocytes obtained from CD patients in remission not receiving immunosuppresives, an impaired response to MDP was found in patients without disease linked CARD15 variants compared to control monocytes. This impairment was accompanied by a decreased activation of IkappaB kinase...

  5. Selected Slither Link Variants are NP-complete

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    Kölker, Jonas

    2012-01-01

    In a Slither Link puzzle, the player must draw a cycle in a planar graph, such that the number of edges incident to a set of clue faces equals the set of given clue values. We show that for a number of commonly played graph classes, the Slither Link puzzle is NP-complete....

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

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    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. Identification of rare X-linked neuroligin variants by massively parallel sequencing in males with autism spectrum disorder

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    Steinberg Karyn

    2012-09-01

    Full Text Available Abstract Background Autism spectrum disorder (ASD is highly heritable, but the genetic risk factors for it remain largely unknown. Although structural variants with large effect sizes may explain up to 15% ASD, genome-wide association studies have failed to uncover common single nucleotide variants with large effects on phenotype. The focus within ASD genetics is now shifting to the examination of rare sequence variants of modest effect, which is most often achieved via exome selection and sequencing. This strategy has indeed identified some rare candidate variants; however, the approach does not capture the full spectrum of genetic variation that might contribute to the phenotype. Methods We surveyed two loci with known rare variants that contribute to ASD, the X-linked neuroligin genes by performing massively parallel Illumina sequencing of the coding and noncoding regions from these genes in males from families with multiplex autism. We annotated all variant sites and functionally tested a subset to identify other rare mutations contributing to ASD susceptibility. Results We found seven rare variants at evolutionary conserved sites in our study population. Functional analyses of the three 3’ UTR variants did not show statistically significant effects on the expression of NLGN3 and NLGN4X. In addition, we identified two NLGN3 intronic variants located within conserved transcription factor binding sites that could potentially affect gene regulation. Conclusions These data demonstrate the power of massively parallel, targeted sequencing studies of affected individuals for identifying rare, potentially disease-contributing variation. However, they also point out the challenges and limitations of current methods of direct functional testing of rare variants and the difficulties of identifying alleles with modest effects.

  8. Identification of Genetic Variants Linking Protein C and Lipoprotein Metabolism: The ARIC Study (Atherosclerosis Risk in Communities).

    Science.gov (United States)

    Pankow, James S; Tang, Weihong; Pankratz, Nathan; Guan, Weihua; Weng, Lu-Chen; Cushman, Mary; Boerwinkle, Eric; Folsom, Aaron R

    2017-03-01

    Previous studies have identified common genetic variants in 4 chromosomal regions that together account for 14% to 15% of the variance in circulating levels of protein C. To further characterize the genetic architecture of protein C, we obtained denser coverage at some loci, extended investigation of protein C to low-frequency and rare variants, and searched for new associations in genes known to influence protein C. Genetic associations with protein C antigen level were evaluated in ≤10 778 European and 3190 black participants aged 45 to 64 years. Analyses included >26 million autosomal variants available after imputation to the 1000 Genomes reference panel along with additional low-frequency and rare variants directly genotyped using the Illumina ITMAT-Broad-CARe chip and Illumina HumanExome BeadChip. Genome-wide significant associations (PC level in both whites and blacks, reaching genome-wide significance in a meta-analysis combining results from both groups (P=1.4×10(-9)). To further investigate a possible link between lipid metabolism and protein C level, we conducted Mendelian randomization analyses using 185 lipid-related genetic variants as instrumental variables. The results indicated that triglycerides, and possibly low-density lipoprotein cholesterol, influence protein C levels. Discovery of variants influencing circulating protein C levels in the CELSR2-PSRC1-SORT1 region may indicate a novel genetic link between lipoprotein metabolism and hemostasis. © 2017 American Heart Association, Inc.

  9. Rare novel variants in the ZIC3 gene cause X-linked heterotaxy

    DEFF Research Database (Denmark)

    Paulussen, Aimee D C; Steyls, Anja; Vanoevelen, Jo

    2016-01-01

    male deaths due to heterotaxy in the family (n=1). All variants were located within the zinc-finger domains or leading to a truncation before these domains. Truncating variants showed abnormal trafficking of mutated ZIC3 proteins, whereas the missense variant showed normal trafficking. Overexpression...

  10. Factor XIII A-Subunit V34L Variant Affects Thrombus Cross-Linking in a Murine Model of Thrombosis.

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    Duval, Cédric; Ali, Majid; Chaudhry, Waleed W; Ridger, Victoria C; Ariëns, Robert A S; Philippou, Helen

    2016-02-01

    Factor XIII (FXIII) cross-links fibrin upon activation by thrombin. Activation involves cleavage at residue 37 by thrombin, releasing an activation peptide. A common polymorphism (valine to leucine variant at residue 34, V34L), located in the activation peptide, has been associated with increased activation rates and paradoxically a protective effect in cardiovascular disease. There is, currently, no data available on the effects of V34L from in vivo models of thrombosis. We examined the effect of FXIII V34L on clot formation and cross-linking in vivo. We generated a panel of full-length recombinant human FXIII-A2 variants with amino acid substitutions in the activation peptide to investigate the effect of these variants on activation rate, and we used wild-type, V34L, and alanine to glycine variant at residue 33 variants to study the effects of varying FXIII activation rate on thrombus formation in a murine model of FeCl3 injury. FXIII activation assay showed that residues 29, 30, 33, and 34 play a critical role in thrombin interaction. Full-length recombinant human FXIII-A2 V34L has significant effects on clot formation, structure, and lysis in vitro, using turbidity assay. This variant influenced fibrin cross-linking but not size of the thrombus in vivo. Mutations in the activation peptide of full-length recombinant FXIII regulate activation rates by thrombin, and V34L influences in vivo thrombus formation by increased cross-linking of the clot. © 2016 American Heart Association, Inc.

  11. FTO Obesity Risk Variants Are Linked to Adipocyte IRX3 Expression and BMI of Children - Relevance of FTO Variants to Defend Body Weight in Lean Children?

    Science.gov (United States)

    Landgraf, Kathrin; Scholz, Markus; Kovacs, Peter; Kiess, Wieland; Körner, Antje

    2016-01-01

    Background Genome-wide association studies have identified variants within the FTO (fat mass and obesity associated) locus as the strongest predictors of obesity amongst all obesity-associated gene loci. Recent evidence suggests that variants in FTO directly affect human adipocyte function through targeting IRX3 and IRX5 and thermogenesis regulation. Aim We addressed the relevance of this proposed FTO-IRX pathway in adipose tissue (AT) of children. Results Expression of IRX3 was higher in adipocytes compared to SVF. We found increased adipocyte-specific expression of IRX3 and IRX5 with the presence of the FTO risk haplotype in lean children, whereas it was unaffected by risk variants in obese peers. We further show that IRX3 expression was elevated in isolated adipocytes and AT of lean compared to obese children, particularly in UCP1-negative adipocytes, and inversely correlated with BMI SDS. Independent of BMI, IRX3 expression in adipocytes was significantly related to adipocyte hypertrophy, and subsequent associations with AT inflammation and HOMA-IR in the children. Conclusion One interpretation of our observation of FTO risk variants linked to IRX3 expression and adipocyte size restricted to lean children, along with the decreased IRX3 expression in obese compared to lean peers, may reflect a defense mechanism for protecting body-weight, which is pertinent for lean children. PMID:27560134

  12. State of humoral link of immune system in children with mono- and mixed-variants of rotavirus infection

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    Катерина Олександрівна Сміян-Горбунова

    2015-09-01

    Full Text Available Connection of an immune system with infection agents defines the further development of infectious diseases especially rotavirus infection (RVI. The state of immune system before the beginning of disease and an adequacy of immune answer to causative agent defines the possibility of disease and its heaviness, duration of an acute period, cyclicity, time of pathogens elimination and period of reconvalescence. The humoral link is one of important components of immune system.Methods. 96 children 1 month-5 years old with acute intestinal infections of rotavirus etiology were under observation. 51 children with mono-variant of rotavirus infection formed the 1 group. The 11 group included 45 patients with mixed-variant of rotavirus infection. The control group included 32 practically healthy children. The research was carried out at the high point of disease (1–3 day and in period of reconvalescence. (5–6 day. The study of humoral link of immunity was carried out using the method of radial immunodiffusion in agar on Mancini G.Results. At comparison of indicators of the humoral link of immune system in children with mono- and mixed-variants of RVI at admission to hospital it was established that Ig М concentration in children of the 1 group was higher (р<0,05, and Ig G level in blood serum lower(р<0,05 than in the 11 group. So the study of the humoral immunity in blood serum in children with rotavirus infection revealed changes that were presented as an increase of Ig М and IgG indicators and also decrease of IgА. An assessment of an immune system after treatment within this research is characterized with an increase of IgА and IgG and decrease of IgМ.Conclusions. In blood serum of children with mono- and mixed-variants of rotavirus infection in an acute period of disease there was observed decrease of Ig А concentration and increase of Ig М і IgG. In the period of reconvalescence in children with mono- and mixed-variants of an acute

  13. Potentiated Hsp104 variants suppress toxicity of diverse neurodegenerative disease-linked proteins

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    Meredith E. Jackrel

    2014-10-01

    Full Text Available Protein misfolding is implicated in numerous lethal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS and Parkinson disease (PD. There are no therapies that reverse these protein-misfolding events. We aim to apply Hsp104, a hexameric AAA+ protein from yeast, to target misfolded conformers for reactivation. Hsp104 solubilizes disordered aggregates and amyloid, but has limited activity against human neurodegenerative disease proteins. Thus, we have previously engineered potentiated Hsp104 variants that suppress aggregation, proteotoxicity and restore proper protein localization of ALS and PD proteins in Saccharomyces cerevisiae, and mitigate neurodegeneration in an animal PD model. Here, we establish that potentiated Hsp104 variants possess broad substrate specificity and, in yeast, suppress toxicity and aggregation induced by wild-type TDP-43, FUS and α-synuclein, as well as missense mutant versions of these proteins that cause neurodegenerative disease. Potentiated Hsp104 variants also rescue toxicity and aggregation of TAF15 but not EWSR1, two RNA-binding proteins with a prion-like domain that are connected with the development of ALS and frontotemporal dementia. Thus, potentiated Hsp104 variants are not entirely non-specific. Indeed, they do not unfold just any natively folded protein. Rather, potentiated Hsp104 variants are finely tuned to unfold proteins bearing short unstructured tracts that are not recognized by wild-type Hsp104. Our studies establish the broad utility of potentiated Hsp104 variants.

  14. X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations.

    Science.gov (United States)

    Savige, Judith; Storey, Helen; Il Cheong, Hae; Gyung Kang, Hee; Park, Eujin; Hilbert, Pascale; Persikov, Anton; Torres-Fernandez, Carmen; Ars, Elisabet; Torra, Roser; Hertz, Jens Michael; Thomassen, Mads; Shagam, Lev; Wang, Dongmao; Wang, Yanyan; Flinter, Frances; Nagel, Mato

    2016-01-01

    Alport syndrome results from mutations in the COL4A5 (X-linked) or COL4A3/COL4A4 (recessive) genes. This study examined 754 previously- unpublished variants in these genes from individuals referred for genetic testing in 12 accredited diagnostic laboratories worldwide, in addition to all published COL4A5, COL4A3 and COL4A4 variants in the LOVD databases. It also determined genotype-phenotype correlations for variants where clinical data were available. Individuals were referred for genetic testing where Alport syndrome was suspected clinically or on biopsy (renal failure, hearing loss, retinopathy, lamellated glomerular basement membrane), variant pathogenicity was assessed using currently-accepted criteria, and variants were examined for gene location, and age at renal failure onset. Results were compared using Fisher's exact test (DNA Stata). Altogether 754 new DNA variants were identified, an increase of 25%, predominantly in people of European background. Of the 1168 COL4A5 variants, 504 (43%) were missense mutations, 273 (23%) splicing variants, 73 (6%) nonsense mutations, 169 (14%) short deletions and 76 (7%) complex or large deletions. Only 135 of the 432 Gly residues in the collagenous sequence were substituted (31%), which means that fewer than 10% of all possible variants have been identified. Both missense and nonsense mutations in COL4A5 were not randomly distributed but more common at the 70 CpG sequences (pAla substitutions were underrepresented in all three genes (p< 0.0001) probably because of an association with a milder phenotype. The average age at end-stage renal failure was the same for all mutations in COL4A5 (24.4 ±7.8 years), COL4A3 (23.3 ± 9.3) and COL4A4 (25.4 ± 10.3) (COL4A5 and COL4A3, p = 0.45; COL4A5 and COL4A4, p = 0.55; COL4A3 and COL4A4, p = 0.41). For COL4A5, renal failure occurred sooner with non-missense than missense variants (p<0.01). For the COL4A3 and COL4A4 genes, age at renal failure occurred sooner with two non

  15. Rare coding variants and X-linked loci associated with age at menarche

    NARCIS (Netherlands)

    Lunetta, Kathryn L.; Day, Felix R.; Sulem, Patrick; Ruth, Katherine S.; Tung, Joyce Y.; Hinds, David A.; Esko, Tonu; Elks, Cathy E.; Altmaier, Elisabeth; He, Chunyan; Huffman, Jennifer E.; Mihailov, Evelin; Porcu, Eleonora; Robino, Antonietta; Rose, Lynda M.; Schick, Ursula M.; Stolk, Lisette; Teumer, Alexander; Thompson, Deborah J.; Traglia, Michela; Wang, Carol A.; Yerges-Armstrong, Laura M.; Antoniou, Antonis C.; Barbieri, Caterina; Coviello, Andrea D.; Cucca, Francesco; Demerath, Ellen W.; Dunning, Alison M.; Gandin, Ilaria; Grove, Megan L.; Gudbjartsson, Daniel F.; Hocking, Lynne J.; Hofman, Albert; Huang, Jinyan; Jackson, Rebecca D.; Karasik, David; Kriebel, Jennifer; Lange, Ethan M.; Lange, Leslie A.; Langenberg, Claudia; Li, Xin; Luan, Jian'an; Maegi, Reedik; Morrison, Alanna C.; Padmanabhan, Sandosh; Pirie, Ailith; Polasek, Ozren; Porteous, David; Reiner, Alex P.; Rivadeneira, Fernando; Rudan, Igor; Sala, Cinzia F.; Schlessinger, David; Scott, Robert A.; Stoeckl, Doris; Visser, Jenny A.; Voelker, Uwe; Vozzi, Diego; Wilson, James G.; Zygmunt, Marek; Boerwinkle, Eric; Buring, Julie E.; Crisponi, Laura; Easton, Douglas F.; Hayward, Caroline; Hu, Frank B.; Liu, Simin; Metspalu, Andres; Pennell, Craig E.; Ridker, Paul M.; Strauch, Konstantin; Streeten, Elizabeth A.; Toniolo, Daniela; Uitterlinden, Andre G.; Ulivi, Sheila; Voelzke, Henry; Wareham, Nicholas J.; Wellons, Melissa; Franceschini, Nora; Chasman, Daniel I.; Thorsteinsdottir, Unnur; Murray, Anna; Stefansson, Kari; Murabito, Joanne M.; Ong, Ken K.; Perry, John R. B.; Forouhi, Nita G.; Kerrison, Nicola D.; Sharp, Stephen J.; Sims, Matt; Barroso, Ines; Deloukas, Panos; McCarthy, Mark I.; Arriola, Larraitz; Balkau, Beverley; Barricarte, Aurelio; Boeing, Heiner; Franks, Paul W.; Gonzalez, Carlos; Grioni, Sara; Kaaks, Rudolf; Key, Timothy J.; Navarro, Carmen; Nilsson, Peter M.; Overvad, Kim; Palli, Domenico; Panico, Salvatore; Ramon Quiros, J.; Rolandsson, Olov; Sacerdote, Carlotta; Sanchez, Maria-Jose; Slimani, Nadia; Tjonneland, Anne; Tumino, Rosario; van der A, Daphne L.; van der Schouw, Yvonne T.; Riboli, Elio; Smith, Blair H.; Campbell, Archie; Deary, Ian J.; McIntosh, Andrew M.

    2015-01-01

    More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only similar to 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency proteincoding variants and

  16. Rare coding variants and X-linked loci associated with age at menarche

    NARCIS (Netherlands)

    K.L. Lunetta (Kathryn); F.R. Day (Felix); P. Sulem (Patrick); K.S. Ruth (Katherine S.); J.Y. Tung (Joyce Y.); D.A. Hinds (David A.); T. Esko (Tõnu); C.E. Elks (Cathy); E.L. Altmaier (Elizabeth); C. He (Chunyan); J.E. Huffman (Jennifer); E. Mihailov (Evelin); E. Porcu (Eleonora); A. Robino (Antonietta); L.M. Rose (Lynda); U.M. Schick (Ursula); L. Stolk (Lisette); A. Teumer (Alexander); D. Thompson (Deborah); M. Traglia (Michela); C.A. Wang (Carol A.); L.M. Yerges-Armstrong (Laura); A.C. Antoniou (Antonis C.); C. Barbieri (Caterina); A.D. Coviello (Andrea); F. Cucca (Francesco); E.W. Demerath (Ellen); A.M. Dunning (Alison); I. Gandin (Ilaria); M.L. Grove (Megan L.); D.F. Gudbjartsson (Daniel); L.J. Hocking (Lynne); A. Hofman (Albert); J. Huang (Jian); R.D. Jackson (Rebecca); D. Karasik (David); J. Kriebel (Jennifer); E.M. Lange (Ethan); L.A. Lange (Leslie); C. Langenberg (Claudia); X. Li (Xin); J. Luan; R. Mägi (Reedik); A.C. Morrison (Alanna); S. Padmanabhan (Sandosh); A. Pirie (Ailith); O. Polasek (Ozren); D.J. Porteous (David J.); A. Reiner (Alexander); F. Rivadeneira Ramirez (Fernando); I. Rudan (Igor); C. Sala (Cinzia); D. Schlessinger (David); R.A. Scott (Robert); D. Stöckl (Doris); J.A. Visser (Jenny); U. Völker (Uwe); D. Vozzi (Diego); J.G. Wilson (James); M. Zygmunt (Marek); E.A. Boerwinkle (Eric); J.E. Buring (Julie); L. Crisponi (Laura); D.F. Easton (Douglas); C. Hayward (Caroline); F.B. Hu (Frank); S. Liu (Simin); A. Metspalu (Andres); C.E. Pennell (Craig); P.M. Ridker (Paul); K. Strauch (Konstantin); E.A. Streeten (Elizabeth); D. Toniolo (Daniela); A.G. Uitterlinden (André); S. Ulivi (Shelia); H. Völzke (Henry); N.J. Wareham (Nick); M. Wellons (Melissa); N. Franceschini (Nora); D.I. Chasman (Daniel); U. Thorsteinsdottir (Unnur); A. Murray (Anna); J-A. Zwart (John-Anker); J. Murabito (Joanne); K.K. Ong (Ken); J.R.B. Perry (John); N.G. Forouhi (Nita G.); N.D. Kerrison (Nicola D.); S.J. Sharp (Stephen J.); M.A. Sims (Matthew); I. Barroso (Inês); P. Deloukas (Panagiotis); M.I. McCarthy (Mark); L. Arriola (Larraitz); B. Balkau (Beverley); A. Barricarte (Aurelio); H. Boeing (Heiner); P.W. Franks; C. Gonzalez (Carlos); S. Grioni (Sara); R. Kaaks (Rudolf); T.J. Key (Timothy J.); C. Navarro (Carmen); P.M. Nilsson (Peter M.); K. Overvad (Kim); D. Palli (Domenico); S. Panico (Salvatore); J.R. Quirós; O. Rolandsson (Olov); C. Sacerdote (Carlotta); M.-J. Sánchez (María-José); N. Slimani (Nadia); A. Tjonneland (Anne); R. Tumino (Rosario); D.L. Van Der A (Daphne L.); Y.T. van der Schouw (Yvonne); E. Riboli (Elio); B.H. Smith (Blair); A. Campbell (Archie); I.J. Deary (Ian J.); A.M. McIntosh (Andrew)

    2015-01-01

    textabstractMore than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼ 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants

  17. A dominant variant in DMXL2 is linked to nonsyndromic hearing loss.

    Science.gov (United States)

    Chen, Dong-Ye; Liu, Xing-Feng; Lin, Xiao-Jiang; Zhang, Dan; Chai, Yong-Chuan; Yu, De-Hong; Sun, Chang-Ling; Wang, Xue-Ling; Zhu, Wei-Dong; Chen, Ying; Sun, Lian-Hua; Wang, Xiao-Wen; Shi, Fu-Xin; Huang, Zhi-Wu; Yang, Tao; Wu, Hao

    2017-05-01

    To explore the genetic etiology of deafness in a dominant family with late-onset, progressive, nonsyndromic hearing loss. Genome-wide linkage analysis was performed for 21 family members. Candidate pathogenic variants were identified by whole-exome sequencing of selected family members and confirmed by Sanger sequencing of all family members. Cochlear expression of Dmxl2 was investigated by reverse-transcription polymerase chain reaction (RT-PCR) and immunostaining of the organ of Corti from mice. The causative gene was mapped to a 9.68-Mb candidate region on chromosome 15q21.2 (maximum logarithm of the odds score = 4.03) that contained no previously described deafness genes. Whole-exome sequencing identified heterozygous c.7250G>A (p.Arg2417His) in DMXL2 as the only candidate pathogenic variant segregating the hearing loss. In mouse cochlea, expression of DMXL2 was restricted to the hair cells and the spiral ganglion neurons. Our data indicated that the p.Arg2417His variant in DMXL2 is associated with dominant, nonsyndromic hearing loss and suggested an important role of DMXL2 in inner ear function.Genet Med advance online publication 22 September 2016.

  18. A case cluster of variant Creutzfeldt-Jakob disease linked to the Kingdom of Saudi Arabia.

    Science.gov (United States)

    Coulthart, Michael B; Geschwind, Michael D; Qureshi, Shireen; Phielipp, Nicolas; Demarsh, Alex; Abrams, Joseph Y; Belay, Ermias; Gambetti, Pierluigi; Jansen, Gerard H; Lang, Anthony E; Schonberger, Lawrence B

    2016-10-01

    As of mid-2016, 231 cases of variant Creutzfeldt-Jakob disease-the human form of a prion disease of cattle, bovine spongiform encephalopathy-have been reported from 12 countries. With few exceptions, the affected individuals had histories of extended residence in the UK or other Western European countries during the period (1980-96) of maximum global risk for human exposure to bovine spongiform encephalopathy. However, the possibility remains that other geographic foci of human infection exist, identification of which may help to foreshadow the future of the epidemic. We report results of a quantitative analysis of country-specific relative risks of infection for three individuals diagnosed with variant Creutzfeldt-Jakob disease in the USA and Canada. All were born and raised in Saudi Arabia, but had histories of residence and travel in other countries. To calculate country-specific relative probabilities of infection, we aligned each patient's life history with published estimates of probability distributions of incubation period and age at infection parameters from a UK cohort of 171 variant Creutzfeldt-Jakob disease cases. The distributions were then partitioned into probability density fractions according to time intervals of the patient's residence and travel history, and the density fractions were combined by country. This calculation was performed for incubation period alone, age at infection alone, and jointly for incubation and age at infection. Country-specific fractions were normalized either to the total density between the individual's dates of birth and symptom onset ('lifetime'), or to that between 1980 and 1996, for a total of six combinations of parameter and interval. The country-specific relative probability of infection for Saudi Arabia clearly ranked highest under each of the six combinations of parameter × interval for Patients 1 and 2, with values ranging from 0.572 to 0.998, respectively, for Patient 2 (age at infection × lifetime) and

  19. Rare Genomic Variants Link Bipolar Disorder with Anxiety Disorders to CREB-Regulated Intracellular Signaling Pathways.

    Science.gov (United States)

    Kerner, Berit; Rao, Aliz R; Christensen, Bryce; Dandekar, Sugandha; Yourshaw, Michael; Nelson, Stanley F

    2013-01-01

    Bipolar disorder is a common, complex, and severe psychiatric disorder with cyclical disturbances of mood and a high suicide rate. Here, we describe a family with four siblings, three affected females and one unaffected male. The disease course was characterized by early-onset bipolar disorder and co-morbid anxiety spectrum disorders that followed the onset of bipolar disorder. Genetic risk factors were suggested by the early onset of the disease, the severe disease course, including multiple suicide attempts, and lack of adverse prenatal or early life events. In particular, drug and alcohol abuse did not contribute to the disease onset. Exome sequencing identified very rare, heterozygous, and likely protein-damaging variants in eight brain-expressed genes: IQUB, JMJD1C, GADD45A, GOLGB1, PLSCR5, VRK2, MESDC2, and FGGY. The variants were shared among all three affected family members but absent in the unaffected sibling and in more than 200 controls. The genes encode proteins with significant regulatory roles in the ERK/MAPK and CREB-regulated intracellular signaling pathways. These pathways are central to neuronal and synaptic plasticity, cognition, affect regulation and response to chronic stress. In addition, proteins in these pathways are the target of commonly used mood-stabilizing drugs, such as tricyclic antidepressants, lithium, and valproic acid. The combination of multiple rare, damaging mutations in these central pathways could lead to reduced resilience and increased vulnerability to stressful life events. Our results support a new model for psychiatric disorders, in which multiple rare, damaging mutations in genes functionally related to a common signaling pathway contribute to the manifestation of bipolar disorder.

  20. Rare genomic variants link bipolar disorder to CREB regulated intracellular signaling pathways

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    Berit eKerner

    2013-11-01

    Full Text Available Bipolar disorder is a common, complex, and severe psychiatric disorder with cyclical disturbances of mood and a high suicide rate. Here, we describe a family with four siblings, three affected females and one unaffected male. The disease course was characterized by early-onset bipolar disorder and co-morbid anxiety spectrum disorders that followed the onset of bipolar disorder. Genetic risk factors were suggested by the early onset of the disease, the severe disease course, including multiple suicide attempts, and lack of adverse prenatal or early life events. In particular, drug and alcohol abuse did not contribute to the disease onset. Exome sequencing identified very rare, heterozygous, and likely protein-damaging variants in eight brain-expressed genes: IQUB, JMJD1C, GADD45A, GOLGB1, PLSCR5, VRK2, MESDC2, and FGGY. The variants were shared among all three affected family members but absent in the unaffected sibling and in more than 200 controls. The genes encode proteins with significant regulatory roles in the ERK/MAPK and CREB-regulated intracellular signaling pathways. These pathways are central to neuronal and synaptic plasticity, cognition, affect regulation and response to chronic stress. In addition, proteins in these pathways are the target of commonly used mood stabilizing drugs, such as tricyclic antidepressants, lithium and valproic acid. The combination of multiple rare, damaging mutations in these central pathways could lead to reduced resilience and increased vulnerability to stressful life events. Our results support a new model for psychiatric disorders, in which multiple rare, damaging mutations in genes functionally related to a common signaling pathway contribute to the manifestation of bipolar disorder.

  1. A Macrohistone Variant Links Dynamic Chromatin Compaction to BRCA1-Dependent Genome Maintenance

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    Simran Khurana

    2014-08-01

    Full Text Available Appropriate DNA double-strand break (DSB repair factor choice is essential for ensuring accurate repair outcome and genomic integrity. The factors that regulate this process remain poorly understood. Here, we identify two repressive chromatin components, the macrohistone variant macroH2A1 and the H3K9 methyltransferase and tumor suppressor PRDM2, which together direct the choice between the antagonistic DSB repair mediators BRCA1 and 53BP1. The macroH2A1/PRDM2 module mediates an unexpected shift from accessible to condensed chromatin that requires the ataxia telangiectasia mutated (ATM-dependent accumulation of both proteins at DSBs in order to promote DSB-flanking H3K9 dimethylation. Remarkably, loss of macroH2A1 or PRDM2, as well as experimentally induced chromatin decondensation, impairs the retention of BRCA1, but not 53BP1, at DSBs. As a result, macroH2A1 and/or PRDM2 depletion causes epistatic defects in DSB end resection, homology-directed repair, and the resistance to poly(ADP-ribose polymerase (PARP inhibition—all hallmarks of BRCA1-deficient tumors. Together, these findings identify dynamic, DSB-associated chromatin reorganization as a critical modulator of BRCA1-dependent genome maintenance.

  2. INK4/ARF transcript expression is associated with chromosome 9p21 variants linked to atherosclerosis.

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    Yan Liu

    Full Text Available Genome-wide association studies (GWAS have linked common single nucleotide polymorphisms (SNPs on chromosome 9p21 near the INK4/ARF (CDKN2A/B tumor suppressor locus with risk of atherosclerotic diseases and type 2 diabetes mellitus. To explore the mechanism of this association, we investigated whether expression of proximate transcripts (p16(INK4a, p15(INK4b, ARF, ANRIL and MTAP correlate with genotype of representative 9p21 SNPs.We analyzed expression of 9p21 transcripts in purified peripheral blood T-cells (PBTL from 170 healthy donors. Samples were genotyped for six selected disease-related SNPs spanning the INK4/ARF locus. Correlations among these variables were determined by univariate and multivariate analysis. Significantly reduced expression of all INK4/ARF transcripts (p15(INK4b, p16(INK4a, ARF and ANRIL was found in PBTL of individuals harboring a common SNP (rs10757278 associated with increased risk of coronary artery disease, stroke and aortic aneurysm. Expression of MTAP was not influenced by rs10757278 genotype. No association of any these transcripts was noted with five other tested 9p21 SNPs.Genotypes of rs10757278 linked to increased risk of atherosclerotic diseases are also associated with decreased expression in PBTL of the INK4/ARF locus, which encodes three related anti-proliferative transcripts of known importance in tumor suppression and aging.

  3. Association of CHRDL1 mutations and variants with X-linked megalocornea, Neuhauser syndrome and central corneal thickness.

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    Alice E Davidson

    Full Text Available We describe novel CHRDL1 mutations in ten families with X-linked megalocornea (MGC1. Our mutation-positive cohort enabled us to establish ultrasonography as a reliable clinical diagnostic tool to distinguish between MGC1 and primary congenital glaucoma (PCG. Megalocornea is also a feature of Neuhäuser or megalocornea-mental retardation (MMR syndrome, a rare condition of unknown etiology. In a male patient diagnosed with MMR, we performed targeted and whole exome sequencing (WES and identified a novel missense mutation in CHRDL1 that accounts for his MGC1 phenotype but not his non-ocular features. This finding suggests that MMR syndrome, in some cases, may be di- or multigenic. MGC1 patients have reduced central corneal thickness (CCT; however no X-linked loci have been associated with CCT, possibly because the majority of genome-wide association studies (GWAS overlook the X-chromosome. We therefore explored whether variants on the X-chromosome are associated with CCT. We found rs149956316, in intron 6 of CHRDL1, to be the most significantly associated single nucleotide polymorphism (SNP (p = 6.81×10(-6 on the X-chromosome. However, this association was not replicated in a smaller subset of whole genome sequenced samples. This study highlights the importance of including X-chromosome SNP data in GWAS to identify potential loci associated with quantitative traits or disease risk.

  4. LMNA Sequences of 60,706 Unrelated Individuals Reveal 132 Novel Missense Variants in A-Type Lamins and Suggest a Link between Variant p.G602S and Type 2 Diabetes

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    Alyssa Florwick

    2017-06-01

    disease, identified known variant p.I299V as a potential risk factor for metabolic disease in Latinos, linked variant p.G602 with type 2 diabetes, and identified p.G602S as a predictor of diabetes risk in African Americans.

  5. Urodele p53 tolerates amino acid changes found in p53 variants linked to human cancer

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    Villiard Éric

    2007-09-01

    Full Text Available Abstract Background Urodele amphibians like the axolotl are unique among vertebrates in their ability to regenerate and their resistance to develop cancers. It is unknown whether these traits are linked at the molecular level. Results Blocking p53 signaling in axolotls using the p53 inhibitor, pifithrin-α, inhibited limb regeneration and the expression of p53 target genes such as Mdm2 and Gadd45, suggesting a link between tumor suppression and regeneration. To understand this relationship we cloned the p53 gene from axolotl. When comparing its sequence with p53 from other organisms, and more specifically human we observed multiple amino acids changes found in human tumors. Phylogenetic analysis of p53 protein sequences from various species is in general agreement with standard vertebrate phylogeny; however, both mice-like rodents and teleost fishes are fast evolving. This leads to long branch attraction resulting in an artefactual basal emergence of these groups in the phylogenetic tree. It is tempting to assume a correlation between certain life style traits (e.g. lifespan and the evolutionary rate of the corresponding p53 sequences. Functional assays of the axolotl p53 in human or axolotl cells using p53 promoter reporters demonstrated a temperature sensitivity (ts, which was further confirmed by performing colony assays at 37°C. In addition, axolotl p53 was capable of efficient transactivation at the Hmd2 promoter but has moderate activity at the p21 promoter. Endogenous axolotl p53 was activated following UV irradiation (100 j/m2 or treatment with an alkylating agent as measured using serine 15 phosphorylation and the expression of the endogenous p53 target Gadd45. Conclusion Urodele p53 may play a role in regeneration and has evolved to contain multiple amino acid changes predicted to render the human protein defective in tumor suppression. Some of these mutations were probably selected to maintain p53 activity at low temperature. However

  6. Reduced insulin exocytosis in human pancreatic β-cells with gene variants linked to type 2 diabetes

    DEFF Research Database (Denmark)

    Rosengren, Anders H; Braun, Matthias; Mahdi, Taman;

    2012-01-01

    The majority of genetic risk variants for type 2 diabetes (T2D) affect insulin secretion, but the mechanisms through which they influence pancreatic islet function remain largely unknown. We functionally characterized human islets to determine secretory, biophysical, and ultrastructural features...... in relation to genetic risk profiles in diabetic and nondiabetic donors. Islets from donors with T2D exhibited impaired insulin secretion, which was more pronounced in lean than obese diabetic donors. We assessed the impact of 14 disease susceptibility variants on measures of glucose sensing, exocytosis......, and structure. Variants near TCF7L2 and ADRA2A were associated with reduced glucose-induced insulin secretion, whereas susceptibility variants near ADRA2A, KCNJ11, KCNQ1, and TCF7L2 were associated with reduced depolarization-evoked insulin exocytosis. KCNQ1, ADRA2A, KCNJ11, HHEX/IDE, and SLC2A2 variants...

  7. Histiocytoid cardiomyopathy and microphthalmia with linear skin defects syndrome: phenotypes linked by truncating variants in NDUFB11

    Science.gov (United States)

    Rea, Gillian; Homfray, Tessa; Till, Jan; Roses-Noguer, Ferran; Buchan, Rachel J.; Wilkinson, Sam; Wilk, Alicja; Walsh, Roddy; John, Shibu; McKee, Shane; Stewart, Fiona J.; Murday, Victoria; Taylor, Robert W.; Ashworth, Michael; Baksi, A. John; Daubeney, Piers; Prasad, Sanjay; Barton, Paul J.R.; Cook, Stuart A.; Ware, James S.

    2017-01-01

    Variants in NDUFB11, which encodes a structural component of complex I of the mitochondrial respiratory chain (MRC), were recently independently reported to cause histiocytoid cardiomyopathy (histiocytoid CM) and microphthalmia with linear skin defects syndrome (MLS syndrome). Here we report an additional case of histiocytoid CM, which carries a de novo nonsense variant in NDUFB11 (ENST00000276062.8: c.262C > T; p.[Arg88*]) identified using whole-exome sequencing (WES) of a family trio. An identical variant has been previously reported in association with MLS syndrome. The case we describe here lacked the diagnostic features of MLS syndrome, but a detailed clinical comparison of the two cases revealed significant phenotypic overlap. Heterozygous variants in HCCS (which encodes an important mitochondrially targeted protein) and COX7B, which, like NDUFB11, encodes a protein of the MRC, have also previously been identified in MLS syndrome including a case with features of both MLS syndrome and histiocytoid CM. However, a systematic review of WES data from previously published histiocytoid CM cases, alongside four additional cases presented here for the first time, did not identify any variants in these genes. We conclude that NDUFB11 variants play a role in the pathogenesis of both histiocytoid CM and MLS and that these disorders are allelic (genetically related). PMID:28050600

  8. Increased vulnerability of human ventricle to re-entrant excitation in hERG-linked variant 1 short QT syndrome.

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    Ismail Adeniran

    2011-12-01

    Full Text Available The short QT syndrome (SQTS is a genetically heterogeneous condition characterized by abbreviated QT intervals and an increased susceptibility to arrhythmia and sudden death. This simulation study identifies arrhythmogenic mechanisms in the rapid-delayed rectifier K(+ current (I(Kr-linked SQT1 variant of the SQTS. Markov chain (MC models were found to be superior to Hodgkin-Huxley (HH models in reproducing experimental data regarding effects of the N588K mutation on KCNH2-encoded hERG. These ionic channel models were then incorporated into human ventricular action potential (AP models and into 1D and 2D idealised and realistic transmural ventricular tissue simulations and into a 3D anatomical model. In single cell models, the N588K mutation abbreviated ventricular cell AP duration at 90% repolarization (APD(90 and decreased the maximal transmural voltage heterogeneity (δV during APs. This resulted in decreased transmural heterogeneity of APD(90 and of the effective refractory period (ERP: effects that are anticipated to be anti-arrhythmic rather than pro-arrhythmic. However, with consideration of transmural heterogeneity of I(Kr density in the intact tissue model based on the ten Tusscher-Noble-Noble-Panfilov ventricular model, not only did the N588K mutation lead to QT-shortening and increases in T-wave amplitude, but δV was found to be augmented in some local regions of ventricle tissue, resulting in increased tissue vulnerability for uni-directional conduction block and predisposing to formation of re-entrant excitation waves. In 2D and 3D tissue models, the N588K mutation facilitated and maintained re-entrant excitation waves due to the reduced substrate size necessary for sustaining re-entry. Thus, in SQT1 the N588K-hERG mutation facilitates initiation and maintenance of ventricular re-entry, increasing the lifespan of re-entrant spiral waves and the stability of scroll waves in 3D tissue.

  9. 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

    regardless of the PfEMP1 expressed. Our study documents for the first time that knob density is related to the PfEMP1 variant expressed. This may reflect topological requirements to ensure optimal adhesive properties of the IEs. IMPORTANCE: Infections with Plasmodium falciparum malaria parasites are still...... responsible for many deaths, especially among children and pregnant women. New interventions are needed to reduce severe illness and deaths caused by this malaria parasite. Thus, a better understanding of the mechanisms behind the pathogenesis is essential. A main reason why Plasmodium falciparum malaria......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...

  10. 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...... regardless of the PfEMP1 expressed. Our study documents for the first time that knob density is related to the PfEMP1 variant expressed. This may reflect topological requirements to ensure optimal adhesive properties of the IEs. IMPORTANCE: Infections with Plasmodium falciparum malaria parasites are still...... responsible for many deaths, especially among children and pregnant women. New interventions are needed to reduce severe illness and deaths caused by this malaria parasite. Thus, a better understanding of the mechanisms behind the pathogenesis is essential. A main reason why Plasmodium falciparum malaria...

  11. 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 IT4VAR32b...

  12. Variants in Nebulin (NEB Are Linked to the Development of Familial Primary Angle Closure Glaucoma in Basset Hounds.

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    Dina F Ahram

    Full Text Available Several dog breeds are susceptible to developing primary angle closure glaucoma (PACG, which suggests a genetic basis for the disease. We have identified a four-generation Basset Hound pedigree with characteristic autosomal recessive PACG that closely recapitulates PACG in humans. Our aim is to utilize gene mapping and whole exome sequencing approaches to identify PACG-causing sequence variants in the Basset. Extensive clinical phenotyping of all pedigree members was conducted. SNP-chip genotyping was carried out in 9 affected and 15 unaffected pedigree members. Two-point and multipoint linkage analyses of genome-wide SNP data were performed using Superlink-Online SNP-1.1 and a locus was mapped to chromosome 19q with a maximum LOD score of 3.24. The locus contains 12 Ensemble predicted canine genes and is syntenic to a region on chromosome 2 in the human genome. Using exome-sequencing analysis, a possibly damaging, non-synonymous variant in the gene Nebulin (NEB was found to segregate with PACG which alters a phylogenetically conserved Lysine residue. The association of this variants with PACG was confirmed in a secondary cohort of unrelated Basset Hounds (p = 3.4 × 10-4, OR = 15.3 for homozygosity. Nebulin, a protein that promotes the contractile function of sarcomeres, was found to be prominently expressed in the ciliary muscles of the anterior segment. Our findings may provide insight into the molecular mechanisms that underlie PACG. The phenotypic similarities of disease presentation in dogs and humans may enable the translation of findings made in this study to patients with PACG.

  13. In Vitro Acid-Mediated Initial Dental Enamel Loss Is Associated with Genetic Variants Previously Linked to Caries Experience

    Science.gov (United States)

    Vieira, Alexandre R.; Bayram, Merve; Seymen, Figen; Sencak, Regina C.; Lippert, Frank; Modesto, Adriana

    2017-01-01

    We have previously shown that AQP5 and BTF3 genetic variation and expression in whole saliva are associated with caries experience suggesting that these genes may have a functional role in protecting against caries. To further explore these results, we tested ex vivo if variants in these genes are associated with subclinical dental enamel mineral loss. DNA and enamel samples were obtained from 53 individuals. Enamel samples were analyzed for Knoop hardness of sound enamel, integrated mineral loss after subclinical carious lesion creation, and change in integrated mineral loss after remineralization. DNA samples were genotyped for single nucleotide polymorphisms using TaqMan chemistry. Chi-square and Fisher's exact tests were used to compare individuals above and below the mean sound enamel microhardness of the cohort with alpha of 0.05. The A allele of BTF3 rs6862039 appears to be associated with harder enamel at baseline (p = 0.09), enamel more resistant to demineralization (p = 0.01), and enamel that more efficiently regain mineral and remineralize (p = 0.04). Similarly, the G allele of AQP5 marker rs3759129 and A allele of AQP5 marker rs296763 are associated with enamel more resistant to demineralization (p = 0.03 and 0.05, respectively). AQP5 and BTF3 genetic variations influence the initial subclinical stages of caries lesion formation in the subsurface of enamel. PMID:28275354

  14. In Vitro Acid-Mediated Initial Dental Enamel Loss Is Associated with Genetic Variants Previously Linked to Caries Experience.

    Science.gov (United States)

    Vieira, Alexandre R; Bayram, Merve; Seymen, Figen; Sencak, Regina C; Lippert, Frank; Modesto, Adriana

    2017-01-01

    We have previously shown that AQP5 and BTF3 genetic variation and expression in whole saliva are associated with caries experience suggesting that these genes may have a functional role in protecting against caries. To further explore these results, we tested ex vivo if variants in these genes are associated with subclinical dental enamel mineral loss. DNA and enamel samples were obtained from 53 individuals. Enamel samples were analyzed for Knoop hardness of sound enamel, integrated mineral loss after subclinical carious lesion creation, and change in integrated mineral loss after remineralization. DNA samples were genotyped for single nucleotide polymorphisms using TaqMan chemistry. Chi-square and Fisher's exact tests were used to compare individuals above and below the mean sound enamel microhardness of the cohort with alpha of 0.05. The A allele of BTF3 rs6862039 appears to be associated with harder enamel at baseline (p = 0.09), enamel more resistant to demineralization (p = 0.01), and enamel that more efficiently regain mineral and remineralize (p = 0.04). Similarly, the G allele of AQP5 marker rs3759129 and A allele of AQP5 marker rs296763 are associated with enamel more resistant to demineralization (p = 0.03 and 0.05, respectively). AQP5 and BTF3 genetic variations influence the initial subclinical stages of caries lesion formation in the subsurface of enamel.

  15. Causal discovery in an adult ADHD data set suggests indirect link between DAT1 genetic variants and striatal brain activation during reward processing.

    Science.gov (United States)

    Sokolova, Elena; Hoogman, Martine; Groot, Perry; Claassen, Tom; Vasquez, Alejandro Arias; Buitelaar, Jan K; Franke, Barbara; Heskes, Tom

    2015-09-01

    Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable disorder affecting both children and adults. One of the candidate genes for ADHD is DAT1, encoding the dopamine transporter. In an attempt to clarify its mode of action, we assessed brain activity during the reward anticipation phase of the Monetary Incentive Delay (MID) task in a functional MRI paradigm in 87 adult participants with ADHD and 77 controls (average age 36.5 years). The MID task activates the ventral striatum, where DAT1 is most highly expressed. A previous analysis based on standard statistical techniques did not show any significant dependencies between a variant in the DAT1 gene and brain activation [Hoogman et al. (2013); Neuropsychopharm 23:469-478]. Here, we used an alternative method for analyzing the data, that is, causal modeling. The Bayesian Constraint-based Causal Discovery (BCCD) algorithm [Claassen and Heskes (2012); Proceedings of the 28th Conference on Uncertainty in Artificial Intelligence] is able to find direct and indirect dependencies between variables, determines the strength of the dependencies, and provides a graphical visualization to interpret the results. Through BCCD one gets an opportunity to consider several variables together and to infer causal relations between them. Application of the BCCD algorithm confirmed that there is no evidence of a direct link between DAT1 genetic variability and brain activation, but suggested an indirect link mediated through inattention symptoms and diagnostic status of ADHD. Our finding of an indirect link of DAT1 with striatal activity during reward anticipation might explain existing discrepancies in the current literature. Further experiments should confirm this hypothesis. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

  16. X-chromosome tiling path array detection of copy number variants in patients with chromosome X-linked mental retardation

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    Martínez F

    2007-11-01

    Full Text Available Abstract Background Aproximately 5–10% of cases of mental retardation in males are due to copy number variations (CNV on the X chromosome. Novel technologies, such as array comparative genomic hybridization (aCGH, may help to uncover cryptic rearrangements in X-linked mental retardation (XLMR patients. We have constructed an X-chromosome tiling path array using bacterial artificial chromosomes (BACs and validated it using samples with cytogenetically defined copy number changes. We have studied 54 patients with idiopathic mental retardation and 20 controls subjects. Results Known genomic aberrations were reliably detected on the array and eight novel submicroscopic imbalances, likely causative for the mental retardation (MR phenotype, were detected. Putatively pathogenic rearrangements included three deletions and five duplications (ranging between 82 kb to one Mb, all but two affecting genes previously known to be responsible for XLMR. Additionally, we describe different CNV regions with significant different frequencies in XLMR and control subjects (44% vs. 20%. Conclusion This tiling path array of the human X chromosome has proven successful for the detection and characterization of known rearrangements and novel CNVs in XLMR patients.

  17. Apolipoprotein L1 (APOL1 Variants (Vs a Possible Link between Heroin-associated Nephropathy (HAN and HIV-associated Nephropathy (HIVAN

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    Xiqian eLan

    2015-06-01

    Full Text Available In 1970s, Heroin-associated Nephropathy (HAN, one form of focal and segmental glomerulosclerosis (FSGS, was a predominant cause of End-stage Kidney Disease (ESKD in African-Americans (AAs. In 1980s, with the surge of Acquired Immune Deficiency Syndrome (AIDS in AAs, HAN more or less disappeared, and the incidence of Human Immunodeficiency Virus associated Nephropathy (HIVAN markedly increased. Recent studies in AAs have identified those APOL1 variants (Vs as a major risk factor for the development and progression of non-diabetic kidney diseases including idiopathic FSGS and hypertension-attributed nephrosclerosis. These observations have also offered partial insights into the mechanisms of development, and higher rate of occurrence of both HAN and HIVAN in AAs. AAs with APOL1Vs develop idiopathic FSGS at 4 fold higher rate compared to European Americans. Similarly, HIV infected AAs with APOL1Vs (if not on antiviral therapy, risk a 50% (10 fold greater chance of developing HIVAN. It has been suggested that APOL1Vs expression may render podocytes more vulnerable to various types of injury: bacterial, viral and others. However, in addition to genetic variants, additional factors such as persistence of a second hit may determine the nature and severity of glomerular disease. In patients with HAN, heroin or contaminants may have been the offending second insult(s which caused renal disease in susceptible AA patients. In the 80’s, since heroin-induced second hit was neither consistent nor sustained (depending on drug availability in the street, the disease was masked or replaced HIV infected patients (especially in untreated subjects, by an overwhelming second hit by the virus which was both intense as well as persistent. It appears that APOL1Vs may be one of the links between the disappearance of HAN and emergence of HIVAN in AA patients.

  18. 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, Hoai Viet; Guex, Nicolas; Venturini, Giulia; Munier, Francis L; Schorderet, Daniel F; Haider, Neena B; Escher, Pascal

    2015-06-01

    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 S-cones 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 (BRET(2) ) 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.

  19. Carcinoma papilífero da tireoide e suas variantes histológicas associados à tireoidite de Hashimoto Thyroid papillary carcinoma and histologic variants linked to Hashimoto disease

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    Murilo Pedreira Neves Junior

    2009-10-01

    Full Text Available INTRODUÇÃO E OBJETIVO: A associação entre o carcinoma papilífero da tireoide e suas variantes e a tireoidite de Hashimoto (TH é bastante questionada no meio científico, pois compartilham diversos aspectos morfológicos, imuno-histoquímicos e biomoleculares. Os tumores da tireoide representam mais de 90% de todos os cânceres endócrinos e são caracterizados por alterações genéticas, entre as quais envolvem RET (rearranjos e BRAS, RAS, P53 (mutações. Já a TH é uma doença autoimune, caracterizada por falência tireoidiana secundária à destruição autoimune e que apresenta alterações de genes, entre eles RET/PTC, RAS e FAS. O objetivo deste trabalho é descrever a associação do carcinoma papilífero da tireoide com a TH, correlacionando-os com os dados demográficos e suas variantes histológicas. MÉTODO: Realizou-se um estudo de série de 466 casos de pacientes com diagnóstico anatomopatológico de carcinoma papilífero da tireoide de 2000 a dezembro de 2008. Foram feitas aplicações de formulários aos casos, visando coletar os dados demográficos e suas variantes. RESULTADOS: O estudo apresentou uma coexistência de 30% de TH em pacientes com carcinoma papilífero da tireoide. No sexo feminino, houve maior número de casos no grupo com TH, valor de p = 0,046. CONCLUSÃO: A série de casos apresentada mostrou frequência de 30% de TH nos casos de carcinoma papilífero da tireoide, sugerindo uma associação, não apenas casual, que levanta a possibilidade de uma relação de causa e efeito entre tireoidite e desenvolvimento do carcinoma.INTRODUCTION AND OBJECTIVE: The association between papillary thyroid carcinoma and its variants and Hashimoto's thyroiditis is widely questioned in the scientific area, as they both share several morphologic, immunohistochemical and biomolecular aspects. Thyroid tumors represent over 90% of all endocrine cancers and are characterized by genetic changes involving RET (rearrangements and

  20. 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.

  1. Minireview: Toward the establishment of a link between melatonin and glucose homeostasis: association of melatonin MT2 receptor variants with type 2 diabetes.

    Science.gov (United States)

    Karamitri, Angeliki; Renault, Nicolas; Clement, Nathalie; Guillaume, Jean-Luc; Jockers, Ralf

    2013-08-01

    The existence of interindividual variations in G protein-coupled receptor sequences has been recognized early on. Recent advances in large-scale exon sequencing techniques are expected to dramatically increase the number of variants identified in G protein-coupled receptors, giving rise to new challenges regarding their functional characterization. The current minireview will illustrate these challenges based on the MTNR1B gene, which encodes the melatonin MT2 receptor, for which exon sequencing revealed 40 rare nonsynonymous variants in the general population and in type 2 diabetes (T2D) cohorts. Functional characterization of these MT2 mutants revealed 14 mutants with loss of Gi protein activation that associate with increased risk of T2D development. This repertoire of disease-associated mutants is a rich source for structure-activity studies and will help to define the still poorly understood role of melatonin in glucose homeostasis and T2D development in humans. Defining the functional defects in carriers of rare MT2 mutations will help to provide personalized therapies to these patients in the future.

  2. Association of CHRDL1 mutations and variants with X-linked megalocornea, Neuhäuser syndrome and central corneal thickness

    DEFF Research Database (Denmark)

    Davidson, Alice E; Cheong, Sek-Shir; Hysi, Pirro G

    2014-01-01

    We describe novel CHRDL1 mutations in ten families with X-linked megalocornea (MGC1). Our mutation-positive cohort enabled us to establish ultrasonography as a reliable clinical diagnostic tool to distinguish between MGC1 and primary congenital glaucoma (PCG). Megalocornea is also a feature of Ne...

  3. The role of single-nucleotide variants of the energy metabolism-linked genes SIRT3, PPARGC1A and APOE in amyotrophic lateral sclerosis risk.

    Science.gov (United States)

    Albani, Diego; Pupillo, Elisabetta; Bianchi, Elisa; Chierchia, Armando; Martines, Rosalba; Forloni, Gianluigi; Beghi, Ettore

    2017-05-13

    Amyotrophic lateral sclerosis (ALS) is a multifactorial disease, possibly with contributions from genetics and lifestyle. We examined variants in genes relevant to energy metabolism and physical activity in a case-control association study, with the aim of assessing genetics and physical activity as contributors to ALS risk. A well-characterized sample of Italian ALS patients (101) and controls (101) from the EURALS Consortium underwent a questionnaire interview on demographic, physical and other lifestyle habits, and venipuncture for DNA extraction. The genes selected were sirtuin 3 (SIRT3), peroxisome proliferator-activated receptor-γ coactivator-1α (PPARGC1A) and apolipoprotein E (APOE). Genetic studies suggested, for the first time, a protective role of the SIRT3 single-nucleotide polymorphism rs4980329 in ALS risk, and a contribution of the APOE-ε2 allele, which was more frequent in ALS patients than in controls. A joint analysis coupling genetic data and sporting activity revealed opposite roles of APOE-ε2 and SIRT3 rs3825075, the former being more frequent in physically active ALS patients and the latter more frequent in physically inactive patients. These findings suggest a contribution to ALS risk of genetic and environmental factors involved in energy metabolism, and stress the importance of a multifactorial analysis for evaluating this risk.

  4. A new variant of endemic pemphigus foliaceus in El-Bagre, Colombia: the Hardy-Weinberg-Castle law and linked short tandem repeats

    Directory of Open Access Journals (Sweden)

    Ana María Abreu Velez

    2009-01-01

    Full Text Available Background : We reported a new variant of endemic pemphigus foliaceus in El Bagre, Colombia. Aims : Our study performed Complex Segregation Analysis (CSA and short tandem repeats to discriminate between environmental and/or genetic factors in this disorder. Materials and Methods: The CSA analysis was carried out according to the unified model, implemented using the transmission probabilities implemented in the computer program POINTER, and evaluated by using a software package for population genetic data analysis (GDA, Arlequin. We performed pedigree analyses by using Cyrillic 2.1 software, with a total of 30 families with 50 probands (47 males and 3 females tested. In parallel to the CSA, we tested for the presence of short tandem repeats from HLA class II, DQ alpha 1, involving the gene locus D6S291 by using the Hardy-Weinberg- Castle law. Results : Our results indicate that the best model of inheritance in this disease is a mixed model, with multifactorial effects within a recessive genotype. Two types of possible segregation patterns were found; one with strong recessive penetrance in families whose phenotype is more Amerindian-like, and another of possible somatic mutations. Conclusion : The penetrance of 10% or less in female patients 60 years of age or older indicates that hormones could protect younger females. The greatest risk factor for men being affected by the disorder was the NN genotype. These findings are only possible due to somatic mutations, and/or strong environmental effects. We also found a protective role for two genetic loci (D6S1019 AND D6S439 in the control group.

  5. Chromosome Y variants from different inbred mouse strains are linked to differences in the morphologic and molecular responses of cardiac cells to postpubertal testosterone

    Directory of Open Access Journals (Sweden)

    Churchill Gary A

    2009-04-01

    Full Text Available Abstract Background We have reported previously that when chromosome Y (chrY from the mouse strain C57BL/6J (ChrYC57 was substituted for that of A/J mice (ChrYA, cardiomyocytes from the resulting "chromosome substitution" C57BL/6J-chrYA strain were smaller than that of their C57BL/6J counterparts. In reverse, when chrYA from A/J mice was substituted for that of chrYC57, cardiomyocytes from the resulting A/J-chrYC57 strain were larger than in their A/J counterparts. We further used these strains to test whether: 1 the origin of chrY could also be linked to differences in the profile of gene expression in the hearts of adult male mice, and 2 post-pubertal testosterone could play a role in the differential morphologic and/or molecular effects of chrYC57 and chrYA. Results The increased size of cardiomyocytes from adult male C57BL/6J mice compared to C57BL/6J-chrYA resulted from the absence of hypertrophic effects of post-pubertal testosterone on cells from the latter strain. However, gene profiling revealed that the latter effect could not be explained on the basis of an insensitivity of cells from C57BL/6J-chrYA to androgens, since even more cardiac genes were affected by post-pubertal testosterone in C57BL/6J-chrYA hearts than in C57BL/6J. By testing for interaction between the effects of surgery and strain, we identified 249 "interaction genes" whose expression was affected by post-pubertal testosterone differentially according to the genetic origin of chrY. These interaction genes were found to be enriched within a limited number of signaling pathways, including: 1 p53 signaling, which comprises the interacting genes Ccnd1, Pten and Cdkn1a that are also potential co-regulators of the androgen receptors, and 2 circadian rhythm, which comprises Arntl/Bmal1, which may in turn regulate cell growth via the control of Cdkn1a. Conclusion Although post-pubertal testosterone increased the size of cardiomyocytes from male C56BL/6J mice but not that from

  6. Global Analysis of DNA Methylation Variation in Adipose Tissue from Twins Reveals Links to Disease-Associated Variants in Distal Regulatory Elements

    Science.gov (United States)

    Grundberg, Elin; Meduri, Eshwar; Sandling, Johanna K.; Hedman, Åsa K.; Keildson, Sarah; Buil, Alfonso; Busche, Stephan; Yuan, Wei; Nisbet, James; Sekowska, Magdalena; Wilk, Alicja; Barrett, Amy; Small, Kerrin S.; Ge, Bing; Caron, Maxime; Shin, So-Youn; Ahmadi, Kourosh R.; Ainali, Chrysanthi; Barrett, Amy; Bataille, Veronique; Bell, Jordana T.; Buil, Alfonso; Deloukas, Panos; Dermitzakis, Emmanouil T.; Dimas, Antigone S.; Durbin, Richard; Glass, Daniel; Grundberg, Elin; Hassanali, Neelam; Hedman, Åsa K.; Ingle, Catherine; Knowles, David; Krestyaninova, Maria; Lindgren, Cecilia M.; Lowe, Christopher E.; McCarthy, Mark I.; Meduri, Eshwar; di Meglio, Paola; Min, Josine L.; Montgomery, Stephen B.; Nestle, Frank O.; Nica, Alexandra C.; Nisbet, James; O’Rahilly, Stephen; Parts, Leopold; Potter, Simon; Sandling, Johanna; Sekowska, Magdalena; Shin, So-Youn; Small, Kerrin S.; Soranzo, Nicole; Spector, Tim D.; Surdulescu, Gabriela; Travers, Mary E.; Tsaprouni, Loukia; Tsoka, Sophia; Wilk, Alicja; Yang, Tsun-Po; Zondervan, Krina T.; Lathrop, Mark; Dermitzakis, Emmanouil T.; McCarthy, Mark I.; Spector, Timothy D.; Bell, Jordana T.; Deloukas, Panos

    2013-01-01

    Epigenetic modifications such as DNA methylation play a key role in gene regulation and disease susceptibility. However, little is known about the genome-wide frequency, localization, and function of methylation variation and how it is regulated by genetic and environmental factors. We utilized the Multiple Tissue Human Expression Resource (MuTHER) and generated Illumina 450K adipose methylome data from 648 twins. We found that individual CpGs had low variance and that variability was suppressed in promoters. We noted that DNA methylation variation was highly heritable (h2median = 0.34) and that shared environmental effects correlated with metabolic phenotype-associated CpGs. Analysis of methylation quantitative-trait loci (metQTL) revealed that 28% of CpGs were associated with nearby SNPs, and when overlapping them with adipose expression quantitative-trait loci (eQTL) from the same individuals, we found that 6% of the loci played a role in regulating both gene expression and DNA methylation. These associations were bidirectional, but there were pronounced negative associations for promoter CpGs. Integration of metQTL with adipose reference epigenomes and disease associations revealed significant enrichment of metQTL overlapping metabolic-trait or disease loci in enhancers (the strongest effects were for high-density lipoprotein cholesterol and body mass index [BMI]). We followed up with the BMI SNP rs713586, a cg01884057 metQTL that overlaps an enhancer upstream of ADCY3, and used bisulphite sequencing to refine this region. Our results showed widespread population invariability yet sequence dependence on adipose DNA methylation but that incorporating maps of regulatory elements aid in linking CpG variation to gene regulation and disease risk in a tissue-dependent manner. PMID:24183450

  7. Gene variant linked to lung cancer risk

    Science.gov (United States)

    A variation of the gene NFKB1, called rs4648127, is associated with an estimated 44 percent reduction in lung cancer risk. When this information, derived from samples obtained as part of a large NCI-sponsored prevention clinical trial, was compared with d

  8. Genetic variants linked to education predict longevity

    NARCIS (Netherlands)

    R.E. Marioni (Riccardo); Ritchie, S.J. (Stuart J.); P.K. Joshi (Peter); S. Hagenaars (Saskia); A. Okbay (Aysu); K. Fischer (Krista); Adams, M.J. (Mark J.); W.D. Hill (W. David); G. Davies (Gail); Nagy, R. (Reka); Amador, C. (Carmen); K. Läll; A. Metspalu (Andres); D.C. Liewald (David C.); A. Campbell (Archie); J.F. Wilson (James F.); C. Hayward (Caroline); T. Esko (Tõnu); D.J. Porteous (David J.); Gale, C.R. (Catharine R.); I.J. Deary (Ian J.)

    2016-01-01

    textabstractEducational attainment is associated with many health outcomes, including longevity. It is also known to be substantially heritable. Here, we used data from three large genetic epidemiology cohort studies (Generation Scotland, n = ∼17,000; UK Biobank, n = ∼115,000; and the Estonian Bioba

  9. Genetic variants linked to education predict longevity

    NARCIS (Netherlands)

    Marioni, R.E.; Ritchie, S.J.; Joshi, P.K.; Hagenaars, S.P.; Okbay, A.; Fischer, K.; Adams, M.J.; Hill, W.D.; Davies, G.; Nagy, R.; Amador, C.; Lall, K.; Metspalu, A.; Liewald, D.C.; Campbell, A.; Wilson, J.F.; Hayward, C.; Esko, T.; Porteous, D.J.; Gale, C.R.; Deary, I.J.; Galesloot, T.E.; Franke, B.; Kiemeney, L.A.L.M.

    2016-01-01

    Educational attainment is associated with many health outcomes, including longevity. It is also known to be substantially heritable. Here, we used data from three large genetic epidemiology cohort studies (Generation Scotland, n = approximately 17,000; UK Biobank, n = approximately 115,000; and the

  10. Variants in CUL4B are Associated with Cerebral Malformations

    NARCIS (Netherlands)

    Vulto-van Silfhout, Anneke T.; Nakagawa, Tadashi; Bahi-Buisson, Nadia; Haas, Stefan A.; Hu, Hao; Bienek, Melanie; Vissers, Lisenka E. L. M.; Gilissen, Christian; Tzschach, Andreas; Busche, Andreas; Muesebeck, Joerg; Rump, Patrick; Mathijssen, Inge B.; Avela, Kristiina; Somer, Mirja; Doagu, Fatma; Philips, Anju K.; Rauch, Anita; Baumer, Alessandra; Voesenek, Krysta; Poirier, Karine; Vigneron, Jacqueline; Amram, Daniel; Odent, Sylvie; Nawara, Magdalena; Obersztyn, Ewa; Lenart, Jacek; Charzewska, Agnieszka; Lebrun, Nicolas; Fischer, Ute; Nillesen, Willy M.; Yntema, Helger G.; Jarvela, Irma; Ropers, Hans-Hilger; de Vries, Bert B. A.; Brunner, Han G.; van Bokhoven, Hans; Raymond, F. Lucy; Willemsen, Michel A. A. P.; Chelly, Jamel; Xiong, Yue; Barkovich, A. James; Kalscheuer, Vera M.; Kleefstra, Tjitske; de Brouwer, Arjan P. M.

    2015-01-01

    Variants in cullin 4B (CUL4B) are a known cause of syndromic X-linked intellectual disability. Here, we describe an additional 25 patients from 11 families with variants in CUL4B. We identified nine different novel variants in these families and confirmed the pathogenicity of all nontruncating varia

  11. Variants in CUL4B are associated with cerebral malformations

    NARCIS (Netherlands)

    Vulto-van Silfhout, A.T.; Nakagawa, T.; Bahi-Buisson, N.; Haas, S.A.; Hu, H; Bienek, M.; Vissers, L.E.L.M.; Gilissen, C.F.H.A.; Tzschach, A.; Busche, A.; Musebeck, J.; Rump, P.; Mathijssen, I.B.; Avela, K.; Somer, M.; Doagu, F.; Philips, A.K.; Rauch, A.; Baumer, A.; Voesenek, K.E.J.; Poirier, K.; Vigneron, J.; Amram, D.; Odent, S.; Nawara, M.; Obersztyn, E.; Lenart, J.; Charzewska, A.; Lebrun, N.; Fischer, U.; Nillesen, W.M.; Yntema, H.G.; Jarvela, I.; Ropers, H.H.; Vries, B. de; Brunner, H.G.; Bokhoven, H. van; Raymond, F.L.; Willemsen, M.A.A.P.; Chelly, J.; Xiong, Y.; Barkovich, A.J.; Kalscheuer, V.M.; Kleefstra, T.; Brouwer, A.P.M. de

    2015-01-01

    Variants in cullin 4B (CUL4B) are a known cause of syndromic X-linked intellectual disability. Here, we describe an additional 25 patients from 11 families with variants in CUL4B. We identified nine different novel variants in these families and confirmed the pathogenicity of all nontruncating varia

  12. Dynamical fat link fermions

    CERN Document Server

    Kamleh, W; Williams, A G; Kamleh, Waseem; Leinweber, Derek B.; Williams, Anthony G.; 10.1016/j.nuclphysbps.2003.12.058

    2004-01-01

    The use of APE smearing or other blocking techniques in fermion actions can provide many advantages. There are many variants of these fat link actions in lattice QCD currently, such as FLIC fermions. Frequently, fat link actions make use of the APE blocking technique in combination with a projection of the blocked links back into the special unitary group. This reunitarisation is often performed using an iterative maximisation of a gauge invariant measure. This technique is not differentiable with respect to the gauge field and thus prevents the use of standard Hybrid Monte Carlo simulation algorithms. The use of an alternative projection technique circumvents this difficulty and allows the simulation of dynamical fat link fermions with standard HMC and its variants.

  13. Histone variants in plant transcriptional regulation.

    Science.gov (United States)

    Jiang, Danhua; Berger, Frédéric

    2017-01-01

    Chromatin based organization of eukaryotic genome plays a profound role in regulating gene transcription. Nucleosomes form the basic subunits of chromatin by packaging DNA with histone proteins, impeding the access of DNA to transcription factors and RNA polymerases. Exchange of histone variants in nucleosomes alters the properties of nucleosomes and thus modulates DNA exposure during transcriptional regulation. Growing evidence indicates the important function of histone variants in programming transcription during developmental transitions and stress response. Here we review how histone variants and their deposition machineries regulate the nucleosome stability and dynamics, and discuss the link between histone variants and transcriptional regulation in plants. This article is part of a Special Issue entitled: Plant Gene Regulatory Mechanisms and Networks, edited by Dr. Erich Grotewold and Dr. Nathan Springer.

  14. Assessment of Functional Effects of Unclassified Genetic Variants

    NARCIS (Netherlands)

    Couch, Fergus J.; Rasmussen, Lene Juel; Hofstra, Robert; Monteiro, Alvaro N. A.; Greenblatt, Marc S.; de Wind, Niels

    2008-01-01

    Inherited predisposition to disease is often linked to reduced activity of a disease associated gene product. Thus, quantitation of the influence of inherited variants on gene function can potentially be used to predict the disease relevance of these variants. While many disease genes have been exte

  15. Histone Variants and Epigenetics

    Science.gov (United States)

    Henikoff, Steven; Smith, M. Mitchell

    2015-01-01

    Histones package and compact DNA by assembling into nucleosome core particles. Most histones are synthesized at S phase for rapid deposition behind replication forks. In addition, the replacement of histones deposited during S phase by variants that can be deposited independently of replication provide the most fundamental level of chromatin differentiation. Alternative mechanisms for depositing different variants can potentially establish and maintain epigenetic states. Variants have also evolved crucial roles in chromosome segregation, transcriptional regulation, DNA repair, and other processes. Investigations into the evolution, structure, and metabolism of histone variants provide a foundation for understanding the participation of chromatin in important cellular processes and in epigenetic memory. PMID:25561719

  16. Histone variants: key players of chromatin.

    Science.gov (United States)

    Biterge, Burcu; Schneider, Robert

    2014-06-01

    Histones are fundamental structural components of chromatin. Eukaryotic DNA is wound around an octamer of the core histones H2A, H2B, H3, and H4. Binding of linker histone H1 promotes higher order chromatin organization. In addition to their structural role, histones impact chromatin function and dynamics by, e.g., post-translational histone modifications or the presence of specific histone variants. Histone variants exhibit differential expression timings (DNA replication-independent) and mRNA characteristics compared to canonical histones. Replacement of canonical histones with histone variants can affect nucleosome stability and help to create functionally distinct chromatin domains. In line with this, several histone variants have been implicated in the regulation of cellular processes such as DNA repair and transcriptional activity. In this review, we focus on recent progress in the study of core histone variants H2A.X, H2A.Z, macroH2A, H3.3, and CENP-A, as well as linker histone H1 variants, their functions and their links to development and disease.

  17. Allelic Variants in Arhgef11 via the Rho-Rock Pathway Are Linked to Epithelial-Mesenchymal Transition and Contributes to Kidney Injury in the Dahl Salt-Sensitive Rat.

    Directory of Open Access Journals (Sweden)

    Zhen Jia

    Full Text Available Previously, genetic analyses identified that variants in Arhgef11 may influence kidney injury in the Dahl salt-sensitive (S rat, a model of hypertensive chronic kidney disease. To understand the potential mechanism by which altered expression and/or protein differences in Arhgef11 could play a role in kidney injury, stably transduced Arhgef11 knockdown cell lines as well as primary cultures of proximal tubule cells were studied. Genetic knockdown of Arhgef11 in HEK293 and NRK resulted in reduced RhoA activity, decreased activation of Rho-ROCK pathway, and less stress fiber formation versus control, similar to what was observed by pharmacological inhibition (fasudil. Primary proximal tubule cells (PTC cultured from the S exhibited increased expression of Arhgef11, increased RhoA activity, and up regulation of Rho-ROCK signaling compared to control (small congenic. The cells were also more prone (versus control to TGFβ-1 induced epithelial-mesenchymal transition (EMT, a hallmark feature of the development of renal interstitial fibrosis, and characterized by development of spindle shape morphology, gene expression changes in EMT markers (Col1a3, Mmp9, Bmp7, and Ocln and increased expression of N-Cadherin and Vimentin. S derived PTC demonstrated a decreased ability to uptake FITC-albumin compared to the small congenic in vitro, which was confirmed by assessment of albumin re-uptake in vivo by infusion of FITC-albumin and immunofluorescence imaging. In summary, these studies suggest that genetic variants in the S form of Arhgef11 via increased expression and/or protein activity play a role in promoting kidney injury in the S rat through changes in cell morphology (Rho-Rock and/or EMT that impact the function of tubule cells.

  18. Desmoplastic variant of ameloblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Sohn, Jeong Ick; Kim, Dong Youn; Choi, Karp Shik [Dept. of Dental Radiology, College of Dentistry, Kyungpook National University, Daegu (Korea, Republic of)

    1995-02-15

    Desmoplastic variant of ameloblastoma is new and unusual variant of ameloblastoma with extensive stromal desmoplastic proliferation. The authors experienced a case of desmoplastic variant of amleloblastoma with moderate-defined radiolucency on the right maxillary anterior area in 62-year-old female. As a result of careful analysis of clinical, radiological examinations, we diagnosed it as desmoplastic variant of ameloblastoma. The following results were obtained; 1. Main clinical symptoms were nontender bony swelling with normal intact overlying mucosa on the right maxillary anterior area. 2. Radiographically, moderate-defined, multilocular radioluceney on the right maxillary anterior area were shown, and severe cortical bony thinning and expansion to labial and palatal sides were also observed. And this lesion was shown to be extended to the right nasal cavity. 3. Histopathologically, follicle-like epithelial islands with densely abundant collagenous stroma were morphologically compressed.

  19. Scandinavian links

    DEFF Research Database (Denmark)

    Matthiessen, Christian Wichmann; Knowles, Richard D.

    2014-01-01

    centres, one joins more thinly populated regions, and the last one links peripheral areas. Two of them (The Great Belt Link and the Oresund Link) have been constructed and are in full operation. The third (the Fehmarnbelt Link) has been decided 2008 on bilateral government level. The three links...

  20. The link in Linking

    Science.gov (United States)

    Caldwell, Jane C; Chiale, Pablo A; Gonzalez, Mario D; Baranchuk, Adrian

    2013-01-01

    We present 2 cases of the slow-fast form of AVNRT with initially narrow QRS complexes followed by sudden unexpected transition to persistently wide QRS complexes due to aberrant intraventricular conduction. Introduction of a properly timed extrastimulus in one case and critical oscillations in cycle length due to short-long coupling in the second case set the stage for the initial bundle branch block. However, persistence of the aberrancy pattern once the initial event abated was maintained by the "linking" phenomenon. Delayed, retrograde concealed activation from the contralateral bundle branch perpetuated the initial bundle branch block. PMID:23840106

  1. 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.

  2. New Variants of Ant Colony Optimization for Network Routing

    Directory of Open Access Journals (Sweden)

    Debasmita Mukherjee

    2012-12-01

    Full Text Available This paper suggests new variants of Ant Colony Optimization(ACOTechniques for Network Routing. There are three existing variants of ACO based on pheromone deposit calculation. In our earlier work we suggested three different heuristics for selecting the next node at each step of iteration. Incorporation of these heuristics in each of the above three variants result into nine variations. In this paper the performance of these nine variations has been studied. Moreover, we have modified the pheromone deposit calculation considering the transmission time of each successful packet(ant and incorporated this new pheromone update formula in each of the nine variants. As a result, we have obtained nine new variants of ACO. The performance of these new nine variants has been compared with previous ones with respect to the speed of execution, throughput and the number of successful packets. The experiments have been performed over two different network topologies. In one of the variant a tabu list has been incorporated. The length of the tabu list plays a vital role in improving the performance of the routing algorithm. In this paper it has been observed that the new variations of ACO have outperformed the previous ones. These new variants can perform efficient network routing in an environment having variable transmission time along the paths due to congestion or poor link quality.

  3. Histone variants and lipid metabolism

    NARCIS (Netherlands)

    Borghesan, Michela; Mazzoccoli, Gianluigi; Sheedfar, Fareeba; Oben, Jude; Pazienza, Valerio; Vinciguerra, Manlio

    2014-01-01

    Within nucleosomes, canonical histones package the genome, but they can be opportunely replaced with histone variants. The incorporation of histone variants into the nucleosome is a chief cellular strategy to regulate transcription and cellular metabolism. In pathological terms, cellular steatosis

  4. Migraine Variants And Beyond

    Directory of Open Access Journals (Sweden)

    Chakravarty A

    2002-01-01

    Full Text Available The Classic presenting features of both migraine with and without aura have been clearly defined. Occasionally however migrainous headaches are accompanied by abrupt appearance of focal and ominous neurological signs. Such attacks can be labelled as migraine variants and the diagnosis in reality is one made by exclusion of other CNS diseases. Some but not all such conditions are mentioned in the International Headache Society (IHS classification under the general heading of migraine with aura. Rarely, the focal neurological deficit may outlast the migraine attack by days and occasionally with appearance of structural brain lesions on neuroimaging. Such attacks have been labelled as complicated Migraine by the IHS. The present review deal with the clinical, radiologic and pathophysiologic aspects of both these conditions - migraine variants and complicated migraine.

  5. Variants of Uncertainty

    Science.gov (United States)

    1981-05-15

    Variants of Uncertainty Daniel Kahneman University of British Columbia Amos Tversky Stanford University DTI-C &%E-IECTE ~JUNO 1i 19 8 1j May 15, 1981... Dennett , 1979) in which different parts have ac- cess to different data, assign then different weights and hold different views of the situation...2robable and t..h1 provable. Oxford- Claredor Press, 1977. Dennett , D.C. Brainstorms. Hassocks: Harvester, 1979. Donchin, E., Ritter, W. & McCallum, W.C

  6. Variants of glycoside hydrolases

    Energy Technology Data Exchange (ETDEWEB)

    Teter, Sarah; Ward, Connie; Cherry, Joel; Jones, Aubrey; Harris, Paul; Yi, Jung

    2017-07-11

    The present invention relates to variants of a parent glycoside hydrolase, comprising a substitution at one or more positions corresponding to positions 21, 94, 157, 205, 206, 247, 337, 350, 373, 383, 438, 455, 467, and 486 of amino acids 1 to 513 of SEQ ID NO: 2, and optionally further comprising a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2 a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2, wherein the variants have glycoside hydrolase activity. The present invention also relates to nucleotide sequences encoding the variant glycoside hydrolases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  7. Variants of glycoside hydrolases

    Energy Technology Data Exchange (ETDEWEB)

    Teter, Sarah (Davis, CA); Ward, Connie (Hamilton, MT); Cherry, Joel (Davis, CA); Jones, Aubrey (Davis, CA); Harris, Paul (Carnation, WA); Yi, Jung (Sacramento, CA)

    2011-04-26

    The present invention relates to variants of a parent glycoside hydrolase, comprising a substitution at one or more positions corresponding to positions 21, 94, 157, 205, 206, 247, 337, 350, 373, 383, 438, 455, 467, and 486 of amino acids 1 to 513 of SEQ ID NO: 2, and optionally further comprising a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2 a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2, wherein the variants have glycoside hydrolase activity. The present invention also relates to nucleotide sequences encoding the variant glycoside hydrolases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  8. Chemokine gene variants in schizophrenia.

    Science.gov (United States)

    Dasdemir, Selcuk; Kucukali, Cem Ismail; Bireller, Elif Sinem; Tuzun, Erdem; Cakmakoglu, Bedia

    2016-08-01

    Background Chemokines are known to play a major role in driving inflammation and immune responses in several neuroinflammatory diseases, including multiple sclerosis, Alzheimer's disease and Parkinson's disease. Inflammation has also been implicated in the pathogenesis of schizophrenia. Aim We aimed to investigate a potential link between chemokines and schizophrenia and analyze the role of MCP-1-A2518G, SDF-1-3'A, CCR5-delta32, CCR5-A55029G, CXCR4-C138T and CCR2-V64I gene polymorphisms in the Turkish population. Methods Genotyping was conducted by PCR-RFLP based on 140 patients and 123 unrelated healthy controls to show the relation between chemokine gene variants and schizophrenia risk. Results Frequencies of CCR5-A55029G A genotypes and CCR5-A55029G AG genotypes were found higher in patients than the controls and even also CCR2-V64I WT: CCR5-A55029G A and CCR2-V64I 64I: CCR5-A55029G A haplotypes significantly associated according to Bonferroni correction. However, no significant association was found for any of the other polymorphisms with the risk of schizophrenia. Conclusions Our findings suggest that CCR5-A55029G polymorphisms and CCR2-V64I WT: CCR5-A55029G A and CCR2-V64I 64I: CCR5-A55029G A haplotypes might have association with schizophrenia pathogenesis.

  9. Genomic structural variants are linked with intellectual disability

    NARCIS (Netherlands)

    Bulayeva, Kazima; Lesch, Klaus-Peter; Bulayev, Oleg; Walsh, Christopher; Glatt, Stephen; Gurgenova, Farida; Omarova, Jamilja; Berdichevets, Irina; Thompson, Paul M

    2015-01-01

    Mutations in more than 500 genes have been associated with intellectual disability (ID) and related disorders of cognitive function, such as autism and schizophrenia. Here we aimed to unravel the molecular epidemiology of non-specific ID in a genetic isolate using a combination of population and mol

  10. Communication Links

    OpenAIRE

    2003-01-01

    This interactive tutorial helps learners to: Identify key upward, lateral, downward, and informal communication links in their organizations. , Reflect on the benefits, control, satisfaction, information filters, and feedback mechanism of various communication links in the organizations. OCL1000 Communicating Change in Complex Organizations

  11. Operative links

    DEFF Research Database (Denmark)

    Wistoft, Karen

    2010-01-01

    as networks: second, a semantic perspective on discourses and concepts of health, and, third, a health pedagogical perspective on participation, intervention, and roles. This paper argues for the importance of 'operative links' between different levels in health strategies. It is proposed that such links...

  12. Product Variant Master as a Means to Handle Variant Design

    DEFF Research Database (Denmark)

    Hildre, Hans Petter; Mortensen, Niels Henrik; Andreasen, Mogens Myrup

    1996-01-01

    The overall time requiered to design a new product variant relies on two factor: how good the methods to design the new variant are and how good these method are supported by computers.It has been estimated that 80% of all design tasks are variational in that the goal of the design is to adapt an...

  13. 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.

  14. Histone variants and lipid metabolism

    NARCIS (Netherlands)

    Borghesan, Michela; Mazzoccoli, Gianluigi; Sheedfar, Fareeba; Oben, Jude; Pazienza, Valerio; Vinciguerra, Manlio

    2014-01-01

    Within nucleosomes, canonical histones package the genome, but they can be opportunely replaced with histone variants. The incorporation of histone variants into the nucleosome is a chief cellular strategy to regulate transcription and cellular metabolism. In pathological terms, cellular steatosis i

  15. Link Analysis

    Science.gov (United States)

    Donoho, Steve

    Link analysis is a collection of techniques that operate on data that can be represented as nodes and links. This chapter surveys a variety of techniques including subgraph matching, finding cliques and K-plexes, maximizing spread of influence, visualization, finding hubs and authorities, and combining with traditional techniques (classification, clustering, etc). It also surveys applications including social network analysis, viral marketing, Internet search, fraud detection, and crime prevention.

  16. Mouse tissues express multiple splice variants of prominin-1.

    Directory of Open Access Journals (Sweden)

    Kristel Kemper

    Full Text Available Prominin-1, a heavily glycosylated pentaspan membrane protein, is mainly known for its function as a marker for (cancer stem cells, although it can also be detected on differentiated cells. Mouse prominin-1 expression is heavily regulated by splicing in eight different variants. The function or the expression pattern of prominin-1 and its splice variants (SVs is thus far unknown. In this study, we analyzed the expression of the prominin-1 splice variants on mRNA level in several mouse tissues and found a broad tissue expression of the majority of SVs, but a specific set of SVs had a much more restricted expression profile. For instance, the testis expressed only SV3 and SV7. Moreover, SV8 was solely detected in the eye. Intriguingly, prominin-1 knockout mice do not suffer from gross abnormalities, but do show signs of blindness, which suggest that SV8 has a specific function in this tissue. In addition, databases searches for putative promoter regions in the mouse prominin-1 gene revealed three potential promoter regions that could be linked to specific SVs. Interestingly, for both SV7 and SV8, a specific potential promoter region could be identified. To conclude, the majority of mouse prominin-1 splice variants are widely expressed in mouse tissues. However, specific expression of a few variants, likely driven by specific promoters, suggests distinct regulation and a potential important function for these variants in certain tissues.

  17. Cellobiohydrolase variants and polynucleotides encoding same

    Energy Technology Data Exchange (ETDEWEB)

    Wogulis, Mark

    2017-04-04

    The present invention relates to variants of a parent cellobiohydrolase II. The present invention also relates to polynucleotides encoding the variants; nucleic acid constructs, vectors, and host cells comprising the polynucleotides; and methods of using the variants.

  18. Certain variants of multipermutohedron ideals

    Indian Academy of Sciences (India)

    AJAY KUMAR; CHANCHAL KUMAR

    2016-10-01

    Multipermutohedron ideals have rich combinatorial properties. An explicit combinatorial formula for the multigraded Betti numbers of a multipermutohedron ideal and their Alexander duals are known. Also, the dimension of the Artinian quotient of an Alexander dual of a multipermutohedron ideal is the number of generalized parking functions. In this paper, monomial ideals which are certain variants of multipermutohedron ideals are studied. Multigraded Betti numbers of these variant monomial ideals and their Alexander duals are obtained. Further, many interesting combinatorial properties of multipermutohedron ideals are extended to these variant monomial ideals.

  19. Gene Variants Reduce Opioid Risks

    Science.gov (United States)

    ... Opioids Prescription Drugs & Cold Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/Nicotine ... variant of the gene for the μ-opioid receptor (OPRM1) with a decreased risk for addiction to ...

  20. 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

  1. Connected speech production in three variants of primary progressive aphasia.

    Science.gov (United States)

    Wilson, Stephen M; Henry, Maya L; Besbris, Max; Ogar, Jennifer M; Dronkers, Nina F; Jarrold, William; Miller, Bruce L; Gorno-Tempini, Maria Luisa

    2010-07-01

    linked with atrophy to a wide range of both anterior and posterior language regions, but specific deficits had more circumscribed anatomical correlates. Frontal regions were associated with motor speech and syntactic processes, anterior and inferior temporal regions with lexical retrieval, and posterior temporal regions with phonological errors and several other types of disruptions to fluency. These findings demonstrate that a multidimensional quantification of connected speech production is necessary to characterize the differences between the speech patterns of each primary progressive aphasic variant adequately, and to reveal associations between particular aspects of connected speech and specific components of the neural network for speech production.

  2. Transatlantic link

    Science.gov (United States)

    (left) European Geophysical Society (EGS) President Rolf Meissner at AGU Headquarters with (center) Executive Director Fred Spilhaus and (right) Foreign Secretary Juan Roederer. Meissner attended the meeting of AGU's Committee on International Participation (CIP) on February 26, 1988. At that meeting, specific ways of fostering close links between AGU and EGS were discussed.A few weeks later, Roederer and AGU staff, working with EGS Secretary-General Arne Richter at the EGS meeting in Bologna, Italy, March 21-25, planned details of the establishment of an AGU office in Europe. The Copernicus Gesellschaft, a new entity located on the premises of the Max Planck Institute for Aeronomy in Lindau, Federal Republic of Germany, will provide the administrative staff and handle logistics.

  3. Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis.

    Science.gov (United States)

    van Es, Michael A; Schelhaas, Helenius J; van Vught, Paul W J; Ticozzi, Nicola; Andersen, Peter M; Groen, Ewout J N; Schulte, Claudia; Blauw, Hylke M; Koppers, Max; Diekstra, Frank P; Fumoto, Katsumi; LeClerc, Ashley Lyn; Keagle, Pamela; Bloem, Bastiaan R; Scheffer, Hans; van Nuenen, Bart F L; van Blitterswijk, Marka; van Rheenen, Wouter; Wills, Anne-Marie; Lowe, Patrick P; Hu, Guo-fu; Yu, Wenhao; Kishikawa, Hiroko; Wu, David; Folkerth, Rebecca D; Mariani, Claudio; Goldwurm, Stefano; Pezzoli, Gianni; Van Damme, Philip; Lemmens, Robin; Dahlberg, Caroline; Birve, Anna; Fernández-Santiago, Rubén; Waibel, Stefan; Klein, Christine; Weber, Markus; van der Kooi, Anneke J; de Visser, Marianne; Verbaan, Dagmar; van Hilten, Jacobus J; Heutink, Peter; Hennekam, Eric A M; Cuppen, Edwin; Berg, Daniela; Brown, Robert H; Silani, Vincenzo; Gasser, Thomas; Ludolph, Albert C; Robberecht, Wim; Ophoff, Roel A; Veldink, Jan H; Pasterkamp, R Jeroen; de Bakker, Paul I W; Landers, John E; van de Warrenburg, Bart P; van den Berg, Leonard H

    2011-12-01

    Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD. We reviewed all previous studies on ANG in ALS and performed sequence experiments on additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers (13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the Mantel-Haenszel procedure was used to estimate odds ratios. Analysis of sequence data from 17,258 individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared to control subjects (p = 9.3 × 10(-6) for ALS and p = 4.3 × 10(-5) for PD). The odds ratio for any ANG variant in patients versus controls was 9.2 for ALS and 6.7 for PD. The data from this multicenter study demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between ALS and PD. Copyright © 2011 American Neurological Association.

  4. Novel variants in GNAI3 associated with auriculocondylar syndrome strengthen a common dominant negative effect

    OpenAIRE

    2014-01-01

    Auriculocondylar syndrome is a rare craniofacial disorder comprising core features of micrognathia, condyle dysplasia and question mark ear. Causative variants have been identified in PLCB4, GNAI3 and EDN1, which are predicted to function within the EDN1–EDNRA pathway during early pharyngeal arch patterning. To date, two GNAI3 variants in three families have been reported. Here we report three novel GNAI3 variants, one segregating with affected members in a family previously linked to 1p21.1-...

  5. Variant Creutzfeldt-Jakob disease

    NARCIS (Netherlands)

    E.A. Croes (Esther); C.M. van Duijn (Cock)

    2003-01-01

    textabstractA variant form of Creutzfeldt-Jakob disease (vCJD) has had major impact in Europe during the last decade. In this article, we review the aetiology of vCJD and its relation with bovine spongiform encephalopathy. Further, treatment of the disease, the strategies focusing on prevention of t

  6. Dancing links

    CERN Document Server

    Knuth, Donald E

    2009-01-01

    The author presents two tricks to accelerate depth-first search algorithms for a class of combinatorial puzzle problems, such as tiling a tray by a fixed set of polyominoes. The first trick is to implement each assumption of the search with reversible local operations on doubly linked lists. By this trick, every step of the search affects the data incrementally. The second trick is to add a ghost square that represents the identity of each polyomino. Thus puts the rule that each polyomino be used once on the same footing as the rule that each square be covered once. The coding simplifies to a more abstract form which is equivalent to 0-1 integer programming. More significantly for the total computation time, the search can naturally switch between placing a fixed polyomino or covering a fixed square at different stages, according to a combined heuristic. Finally the author reports excellent performance for his algorithm for some familiar puzzles. These include tiling a hexagon by 19 hexiamonds and the N queen...

  7. Swine Influenza/Variant Influenza Viruses

    Science.gov (United States)

    ... Address What's this? Submit What's this? Submit Button Influenza Types Seasonal Avian Swine Variant Other Information on Swine Influenza/Variant Influenza Virus Language: English (US) Español ...

  8. Phenotypic diversification in vivo: Pseudomonas aeruginosa gacS- strains generate small colony variants in vivo that are distinct from in vitro variants.

    Science.gov (United States)

    Nelson, Lisa K; Stanton, M Mark; Elphinstone, Robyn E A; Helwerda, Janessa; Turner, Raymond J; Ceri, Howard

    2010-12-01

    Pseudomonas aeruginosa has long been known to produce phenotypic variants during chronic mucosal surface infections. These variants are thought to be generated to ensure bacterial survival against the diverse challenges in the mucosal environment. Studies have begun to elucidate the mechanisms by which these variants emerge in vitro; however, too little information exists on phenotypic variation in vivo to draw any links between variants generated in vitro and in vivo. Consequently, in this study, the P. aeruginosa gacS gene, which has previously been linked to the generation of small colony variants (SCVs) in vitro, was studied in an in vivo mucosal surface infection model. More specifically, the rat prostate served as a model mucosal surface to test for the appearance of SCVs in vivo following infections with P. aeruginosa gacS(-) strains. As in in vitro studies, deletion of the gacS gene led to SCV production in vivo. The appearance of these in vivo SCVs was important for the sustainability of a chronic infection. In the subset of rats in which P. aeruginosa gacS(-) did not convert to SCVs, clearance of the bacteria took place and healing of the tissue ensued. When comparing the SCVs that arose at the mucosal surface (MS-SCVs) with in vitro SCVs (IV-SCVs) from the same gacS(-) parent, some differences between the phenotypic variants were observed. Whereas both MS-SCVs and IV-SCVs formed dense biofilms, MS-SCVs exhibited a less diverse resistance profile to antimicrobial agents than IV-SCVs. Additionally, MS-SCVs were better suited to initiate an infection in the rat model than IV-SCVs. Together, these observations suggest that phenotypic variation in vivo can be important for maintenance of infection, and that in vivo variants may differ from in vitro variants generated from the same genetic parent.

  9. Resistance of Abaca Somaclonal Variant Against Fusarium

    OpenAIRE

    RULLY DYAH PURWATI; SUDARSONO

    2007-01-01

    The objectives of this study were (i) to evaluate responses against F. oxysporum f.sp. cubense (Foc) infection of abaca variants regenerated using four different methods, (ii) to determine initial root length and plant height effects on survival of inoculated abaca variants, and (iii) to identify Foc resistance abaca variants. In the previous experiment, four abaca variant lines were regenerated from (i) embryogenic calli (TC line), (ii) ethyl methyl sulphonate (EMS) treated embryogenic calli...

  10. High-resolution melting analysis using unlabeled probe and amplicon scanning simultaneously detects several lactase persistence variants

    DEFF Research Database (Denmark)

    Janukonyté, Jurgita; Vestergaard, Else M; Ladefoged, Søren A

    2010-01-01

    Lactase persistence and thereby tolerance to lactose is a common trait in people of Northern European descent. It is linked to the LCT -13910C>T variant located in intron 13 of the MCM6 gene 13.9 kb upstream of the lactase (LCT) gene. In people of African and Middle Eastern descent, lactase...... persistence can be associated with other variants nearby the -13910C>T variant, limiting the use of the -13910C>T-based SNP analysis, e.g. TaqMan assays for the diagnosis of lactose intolerance. Using high-resolution melting analysis, we identified five samples that were heterozygous for the -13915T>G variant...... the -13910C>T and -13915T>G variants in addition to rarer variants surrounding the -13910 site. This new method may contribute to improve the diagnostic performance of the genetic analysis for lactose intolerance....

  11. Variant Humicola grisea CBH1.1

    Energy Technology Data Exchange (ETDEWEB)

    Goedegebuur, Frits; Gualfetti, Peter; Mitchinson, Colin; Larenas, Edmund

    2017-05-09

    Disclosed are variants of Humicola grisea CeI7A (CBH1.1), H. jecorina CBH1 variant or S. thermophilium CBH1, nucleic acids encoding the same and methods for producing the same. The variant cellulases have the amino acid sequence of a glycosyl hydrolase of family 7A wherein one or more amino acid residues are substituted.

  12. DHAD variants and methods of screening

    Energy Technology Data Exchange (ETDEWEB)

    Kelly, Kristen J.; Ye, Rick W.

    2017-02-28

    Methods of screening for dihydroxy-acid dehydratase (DHAD) variants that display increased DHAD activity are disclosed, along with DHAD variants identified by these methods. Such enzymes can result in increased production of compounds from DHAD requiring biosynthetic pathways. Also disclosed are isolated nucleic acids encoding the DHAD variants, recombinant host cells comprising the isolated nucleic acid molecules, and methods of producing butanol.

  13. A FRMD7 variant in a Japanese family causes congenital nystagmus.

    Science.gov (United States)

    Kohmoto, Tomohiro; Okamoto, Nana; Satomura, Shigeko; Naruto, Takuya; Komori, Takahide; Hashimoto, Toshiaki; Imoto, Issei

    2015-01-01

    Idiopathic congenital nystagmus (ICN) is a genetically heterogeneous eye movement disorder that causes a large proportion of childhood visual impairment. Here we describe a missense variant (p.L292P) within a mutation-rich region of FRMD7 detected in three affected male siblings in a Japanese family with X-linked ICN. Combining sequence analysis and results from structural and functional predictions, we report p.L292P as a variant potentially disrupting FRMD7 function associated with X-linked ICN.

  14. Clinical variants of lichen planus.

    Science.gov (United States)

    Wagner, Gunnar; Rose, Christian; Sachse, Michael Max

    2013-04-01

    Lichen planus is characterized by lichenoid, polygonal papules with fine white lines, called Wickham striae. Lesions most commonly occur on the limbs and on the dorsal aspect of the trunk. At the same time often leukoplakia of mucous membranes as well as nail disorders are seen. There are numerous variants of lichen planus which can be distinguished from the classical form on the basis of morphology and distribution of the lesions. The typical primary lesion of lichen planus may be replaced by other forms, such as patches, hyperkeratoses, ulcerations, or bullous lesions. Moreover, distribution patterns of these lesions may vary and include erythrodermic, inverse or linear arrangements. In contrast to these numerous clinical features, histologic findings remain characteristic in the variants, so that the diagnosis can be made securely. Differential diagnoses of lichen planus include diverse dermatoses such as bullous pemphigoid or paronychia.

  15. Coronary artery anatomy and variants

    Energy Technology Data Exchange (ETDEWEB)

    Malago, Roberto; Pezzato, Andrea; Barbiani, Camilla; Alfonsi, Ugolino; Nicoli, Lisa; Caliari, Giuliana; Pozzi Mucelli, Roberto [Policlinico G.B. Rossi, University of Verona, Department of Radiology, Verona (Italy)

    2011-12-15

    Variants and congenital anomalies of the coronary arteries are usually asymptomatic, but may present with severe chest pain or cardiac arrest. The introduction of multidetector CT coronary angiography (MDCT-CA) allows the detection of significant coronary artery stenosis. Improved performance with isotropic spatial resolution and higher temporal resolution provides a valid alternative to conventional coronary angiography (CCA) in many patients. MDCT-CA is now considered the ideal tool for three-dimensional visualization of the complex and tortuous anatomy of the coronary arteries. With multiplanar and volume-rendered reconstructions, MDCT-CA may even outperform CCA in determining the relative position of vessels, thus providing a better view of the coronary vascular anatomy. The purpose of this review is to describe the normal anatomy of the coronary arteries and their main variants based on MDCT-CA with appropriate reconstructions. (orig.)

  16. [Mirizzi syndrome and its variants].

    Science.gov (United States)

    Meyer, G J; Runge, D; Gebhardt, J

    1990-04-01

    Between 1981 and 1987 5434 patients were studied by ERCP in Allgemeines Krankenhaus Hamburg-Barmbeck. 26 (i.e. 0.43%) suffered from Mirizze syndrome with the triad of cholelithiasis, cholecystitis and obstructive biliary disease. They were classified in four different types according to the variable localisation and origin of the biliary obstruction. 16 patients corresponded to the classical type (I and II) with compression, penetration, and obturation by the concrement, five patients matched borderline with infiltration (III) and five patients were classified as variants of this syndrome. A mild elevation of serum bilirubine and alkaline phosphatase indicated more likely the benign etiology of type I to III, however, a marked elevation of alkaline phosphatase in the variants suggested more likely a malignant underlying disease. The diagnosis was ascertained in all cases by ERC and sonography preoperatively and was verified by laparotomy (n = 18) and follow-up (n = 6).

  17. 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.

  18. Unusual variant of Cantrell's pentalogy?

    OpenAIRE

    Kumar, Basant; Sharma, S.B.; Kandpal, Deepak K.; Agrawal, L. D.

    2008-01-01

    A 12-hour-old male infant presented with prolapsed abdominal content through a defect on left side of chest wall with respiratory distress. A thorough clinical examination suggested absence of ectopia cordis, abdominal wall defect, and any bony anomaly. The child expired after 6 hours of admission because of respiratory distress and electrolyte imbalance. Is congenital defect of chest wall associated with diaphragmatic hernia without ectopia cordis and omphalocele, an unusual variant of Cantr...

  19. Hypercubic smeared links for dynamical fermions

    Energy Technology Data Exchange (ETDEWEB)

    Hasenfratz, A.; Hoffmann, R. [Colorado Univ., Boulder, CO (United States). Dept. of Physics; Schaefer, S. [Deutsches Elektronen-Synchrotron (DESY), Zeuthen (Germany). John von Neumann-Inst. fuer Computing NIC

    2007-02-15

    We investigate a variant of hypercubic gauge link smearing where the SU(3) projection is replaced with a normalization to the corresponding unitary group. This smearing is differentiable and thus suitable for use in dynamical fermion simulations using molecular dynamics type algorithms. We show that this smearing is as efficient as projected hypercubic smearing in removing ultraviolet noise from the gauge fields. We test the normalized hypercubic smearing in dynamical improved (clover) Wilson and valence overlap simulations. (orig.)

  20. Dorsal variant blister aneurysm repair.

    Science.gov (United States)

    Couldwell, William T; Chamoun, Roukoz

    2012-01-01

    Dorsal variant proximal carotid blister aneurysms are treacherous lesions to manage. It is important to recognize this variant on preoperative angiographic imaging, in anticipation of surgical strategies for their treatment. Strategies include trapping the involved segment and revascularization if necessary. Other options include repair of the aneurysm rupture site directly. Given that these are not true berry aneurysms, repair of the rupture site involves wrapping or clip-grafting techniques. The case presented here was a young woman with a subarachnoid hemorrhage from a ruptured dorsal variant blister aneurysm. The technique used is demonstrated in the video and is a modified clip-wrap technique using woven polyester graft material. The patient was given aspirin preoperatively as preparation for the clip-wrap technique. It is the authors' current protocol to attempt a direct repair with clip-wrapping and leaving artery sacrifice with or without bypass as a salvage therapy if direct repair is not possible. Assessment of vessel patency after repair is performed by intraoperative Doppler and indocyanine green angiography. Intraoperative somatosensory and motor evoked potential monitoring is performed in all cases. The video can be found here: http://youtu.be/crUreWGQdGo.

  1. Microcystic Variant of Urothelial Carcinoma

    Directory of Open Access Journals (Sweden)

    Anthony Kodzo-Grey Venyo

    2013-01-01

    Full Text Available Background. Microcystic variant of urothelial carcinoma is one of the new variants of urothelial carcinoma that was added to the WHO classification in 2004. Aims. To review the literature on microcystic variant of urothelial carcinoma. Methods. Various internet search engines were used to identify reported cases of the tumour. Results. Microscopic features of the tumour include: (i Conspicuous intracellular and intercellular lumina/microcysts encompassed by malignant urothelial or squamous cells. (ii The lumina are usually empty; may contain granular eosinophilic debris, mucin, or necrotic cells. (iii The cysts may be variable in size; round, or oval, up to 2 mm; lined by urothelium which are either flattened cells or low columnar cells however, they do not contain colonic epithelium or goblet cells; are infiltrative; invade the muscularis propria; mimic cystitis cystica and cystitis glandularis; occasionally exhibit neuroendocrine differentiation. (iv Elongated and irregular branching spaces are usually seen. About 17 cases of the tumour have been reported with only 2 patients who have survived. The tumour tends to be of high-grade and high-stage. There is no consensus opinion on the best option of treatment of the tumour. Conclusions. It would prove difficult at the moment to be dogmatic regarding its prognosis but it is a highly aggressive tumour. New cases of the tumour should be reported in order to document its biological behaviour.

  2. Sex-linked dominant

    Science.gov (United States)

    Inheritance - sex-linked dominant; Genetics - sex-linked dominant; X-linked dominant; Y-linked dominant ... can be either an autosomal chromosome or a sex chromosome. It also depends on whether the trait ...

  3. Blood type, ABO genetic variants, and ovarian cancer survival.

    Science.gov (United States)

    Cozzi, Gabriella D; Levinson, Rebecca T; Toole, Hilary; Snyder, Malcolm-Robert; Deng, Angie; Crispens, Marta A; Khabele, Dineo; Beeghly-Fadiel, Alicia

    2017-01-01

    Blood type A and the A1 allele have been associated with increased ovarian cancer risk. With only two small studies published to date, evidence for an association between ABO blood type and ovarian cancer survival is limited. We conducted a retrospective cohort study of Tumor Registry confirmed ovarian cancer cases from the Vanderbilt University Medical Center with blood type from linked laboratory reports and ABO variants from linked Illumina Exome BeadChip data. Associations with overall survival (OS) were quantified by hazard ratios (HR) and confidence intervals (CI) from proportional hazards regression models; covariates included age, race, stage, grade, histologic subtype, and year of diagnosis. ABO phenotype (N = 694) and/or genotype (N = 154) data were available for 713 predominantly Caucasian (89.3%) cases. In multivariable models, blood type A had significantly better OS compared to either O (HR: 0.75, 95% CI: 0.60-0.93) or all non-A (HR: 0.77, 95% CI: 0.63-0.94) cases. Similarly, missense rs1053878 minor allele carriers (A2) had better OS (HR: 0.50, 95% CI: 0.25-0.99). Among Caucasians, this phenotype association was strengthened, but the genotype association was attenuated; instead, four variants sharing moderate linkage disequilibrium with the O variant were associated with better OS (HR: 0.62, 95% CI: 0.39-0.99) in unadjusted models. Blood type A was significantly associated with longer ovarian cancer survival in the largest such study to date. This finding was supported by genetic analysis, which implicated the A2 allele, although O related variants also had suggestive associations. Further research on ABO and ovarian cancer survival is warranted.

  4. Predicting missing links via correlation between nodes

    CERN Document Server

    Liao, Hao; Zhang, Yi-Cheng

    2014-01-01

    As a fundamental problem in many different fields, link prediction aims to estimate the likelihood of an existing link between two nodes based on the observed information. Since this problem is related to many applications ranging from uncovering missing data to predicting the evolution of networks, link prediction has been intensively investigated recently and many methods have been proposed so far. The essential challenge of link prediction is to estimate the similarity between nodes. Most of the existing methods are based on the common neighbor index and its variants. In this paper, we propose to calculate the similarity between nodes by the correlation coefficient. This method is found to be very effective when applied to calculate similarity based on high order paths. We finally fuse the correlation-based method with the resource allocation method, and find that the combined method can substantially outperform the existing methods, especially in sparse networks.

  5. 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.

  6. Linked alternating forms and linked symplectic Grassmannians

    CERN Document Server

    Osserman, Brian

    2011-01-01

    Motivated by applications to higher-rank Brill-Noether theory and the Bertram-Feinberg-Mukai conjecture, we introduce the concepts of linked alternating and linked symplectic forms on a chain of vector bundles, and show that the linked symplectic Grassmannians parametrizing chains of subbundles isotropic for a given linked symplectic form has good dimensional behavior analogous to that of the classical symplectic Grassmannian.

  7. Association Between IL-4 and IL-6 Expression Variants and Gastric Cancer Among Portuguese Population

    Directory of Open Access Journals (Sweden)

    Ana Maria Sampaio

    2015-07-01

    Conclusion: IL-6 and IL-4 expression variants seem to have an important role in GC risk mechanisms. This study provides preliminary evidence that IL-4 and IL-6 polymorphisms, although not directly linked to the disease, may be useful tools in the study of this multifactorial disease.

  8. Hybrid Monte Carlo with Fat Link Fermion Actions

    CERN Document Server

    Kamleh, W; Williams, A G; Kamleh, Waseem; Leinweber, Derek B.; Williams, Anthony G.

    2004-01-01

    The use of APE smearing or other blocking techniques in lattice fermion actions can provide many advantages. There are many variants of these fat link actions in lattice QCD currently, such as FLIC fermions. The FLIC fermion formalism makes use of the APE blocking technique in combination with a projection of the blocked links back into the special unitary group. This reunitarisation is often performed using an iterative maximisation of a gauge invariant measure. This technique is not differentiable with respect to the gauge field and thus prevents the use of standard Hybrid Monte Carlo simulation algorithms. The use of an alternative projection technique circumvents this difficulty and allows the simulation of dynamical fat link fermions with standard HMC and its variants. The necessary equations of motion for FLIC fermions are derived, and some initial simulation results are presented. The technique is more general however, and is straightforwardly applicable to other smearing techniques or fat link actions...

  9. Hybrid Monte Carlo algorithm with fat link fermion actions

    CERN Document Server

    Kamleh, Waseem; Williams, Anthony G; 10.1103/PhysRevD.70.014502

    2004-01-01

    The use of APE smearing or other blocking techniques in lattice fermion actions can provide many advantages. There are many variants of these fat link actions in lattice QCD currently, such as flat link irrelevant clover (FLIC) fermions. The FLIC fermion formalism makes use of the APE blocking technique in combination with a projection of the blocked links back into the special unitary group. This reunitarization is often performed using an iterative maximization of a gauge invariant measure. This technique is not differentiable with respect to the gauge field and thus prevents the use of standard Hybrid Monte Carlo simulation algorithms. The use of an alternative projection technique circumvents this difficulty and allows the simulation of dynamical fat link fermions with standard HMC and its variants. The necessary equations of motion for FLIC fermions are derived, and some initial simulation results are presented. The technique is more general however, and is straightforwardly applicable to other smearing ...

  10. Identification of POMC exonic variants associated with substance dependence and body mass index.

    Directory of Open Access Journals (Sweden)

    Fan Wang

    Full Text Available BACKGROUND: Risk of substance dependence (SD and obesity has been linked to the function of melanocortin peptides encoded by the proopiomelanocortin gene (POMC. METHODS AND RESULTS: POMC exons were Sanger sequenced in 280 African Americans (AAs and 308 European Americans (EAs. Among them, 311 (167 AAs and 114 EAs were affected with substance (alcohol, cocaine, opioid and/or marijuana dependence and 277 (113 AAs and164 EAs were screened controls. We identified 23 variants, including two common polymorphisms (rs10654394 and rs1042571 and 21 rare variants; 12 of which were novel. We used logistic regression to analyze the association between the two common variants and SD or body mass index (BMI, with sex, age, and ancestry proportion as covariates. The common variant rs1042571 in the 3'UTR was significantly associated with BMI in EAs (Overweight: P(adj = 0.005; Obese: P(adj = 0.018; Overweight+Obese: P(adj = 0.002 but not in AAs. The common variant, rs10654394, was not associated with BMI and neither common variant was associated with SD in either population. To evaluate the association between the rare variants and SD or BMI, we collapsed rare variants and tested their prevalence using Fisher's exact test. In AAs, rare variants were nominally associated with SD overall and with specific SD traits (SD: P(FET,1df = 0.026; alcohol dependence: P(FET,1df = 0.027; cocaine dependence: P(FET,1df = 0.007; marijuana dependence: P(FET,1df = 0.050 (the P-value from cocaine dependence analysis survived Bonferroni correction. There was no such effect in EAs. Although the frequency of the rare variants did not differ significantly between the normal-weight group and the overweight or obese group in either population, certain rare exonic variants occurred only in overweight or obese subjects without SD. CONCLUSION: These findings suggest that POMC exonic variants may influence risk for both SD and elevated BMI, in a population-specific manner. However, common

  11. PLS3 sequencing in childhood-onset primary osteoporosis identifies two novel disease-causing variants.

    Science.gov (United States)

    Kämpe, A J; Costantini, A; Mäkitie, R E; Jäntti, N; Valta, H; Mäyränpää, M; Kröger, H; Pekkinen, M; Taylan, F; Jiao, H; Mäkitie, O

    2017-07-26

    Altogether 95 children with primary bone fragility were screened for variants in PLS3, the gene underlying X-linked osteoporosis. Two children with multiple peripheral and spinal fractures and low BMD had novel disease-causing PLS3 variants. Children with milder phenotypes had no pathogenic variants. PLS3 screening is indicated in childhood-onset primary osteoporosis. The study aimed to determine the role of pathogenic PLS3 variants in children's bone fragility and to elucidate the associated phenotypic features. Two cohorts of children with bone fragility were screened for variants in PLS3, the gene underlying X-linked osteoporosis. Cohort I comprised 31 patients with childhood-onset primary osteoporosis of unknown etiology. Cohort II comprised 64 children who had sustained multiple fractures but were otherwise healthy. Clinical and radiological data were reviewed. Peripheral blood DNA was Sanger sequenced for coding exons and flanking intronic regions of PLS3. In two patients of cohort I, where other common genetic causes had been excluded, we identified two novel disease-causing PLS3 variants. Patient 1 was a male with bilateral femoral fractures at 10 years, low BMD (Z-score -4.1; 18 years), and multiple vertebral compression fractures. He had a novel nonsense variant in PLS3. Patient 2 was a girl with multiple long bone and vertebral fractures and low BMD (Z-score -6.6 at 6 years). She had a de novo missense variant in PLS3; whole exome sequencing and array-CGH identified no other genetic causes. Iliac crest bone biopsies confirmed low-turnover osteoporosis in both patients. In cohort II, no pathogenic PLS3 variants were identified in any of the subjects. Two novel disease-causing variants in PLS3 were identified in a boy and a girl with multiple peripheral and spinal fractures and very low BMD while no pathogenic variants were identified in children with less severe skeletal fragility. PLS3 screening is warranted in male and female patients with childhood

  12. X-Linked and Autosomal Recessive Alport Syndrome

    DEFF Research Database (Denmark)

    Savige, Judith; Storey, Helen; Il Cheong, Hae

    2016-01-01

    Alport syndrome results from mutations in the COL4A5 (X-linked) or COL4A3/COL4A4 (recessive) genes. This study examined 754 previously- unpublished variants in these genes from individuals referred for genetic testing in 12 accredited diagnostic laboratories worldwide, in addition to all publishe...

  13. PLS3 mutations in X-linked osteoporosis with fractures

    NARCIS (Netherlands)

    Dijk, F.S. Van; Zillikens, M.C.; Micha, D.; Riessland, M.; Marcelis, C.L.M.; Die-Smulders, C.E.M. de; Milbradt, J.; Franken, A.A.; Harsevoort, A.J.; Lichtenbelt, K.D.; Pruijs, H.E.; Rubio-Gozalbo, M.E.; Zwertbroek, R.; Moutaouakil, Y.; Egthuijsen, J.; Hammerschmidt, M.; Bijman, R.; Semeins, C.M.; Bakker, A.D.; Everts, V.; Klein-Nulend, J.; Campos-Obando, N.; Hofman, A.; Meerman, G.J. te; Verkerk, A.J.; Uitterlinden, A.G.; Maugeri, A.; Sistermans, E.A.; Waisfisz, Q.; Meijers-Heijboer, H.; Wirth, B.; Simon, M.E.; Pals, G.

    2013-01-01

    Plastin 3 (PLS3), a protein involved in the formation of filamentous actin (F-actin) bundles, appears to be important in human bone health, on the basis of pathogenic variants in PLS3 in five families with X-linked osteoporosis and osteoporotic fractures that we report here. The bone-regulatory prop

  14. Resistance of Abaca Somaclonal Variant Against Fusarium

    Directory of Open Access Journals (Sweden)

    RULLY DYAH PURWATI

    2007-12-01

    Full Text Available The objectives of this study were (i to evaluate responses against F. oxysporum f.sp. cubense (Foc infection of abaca variants regenerated using four different methods, (ii to determine initial root length and plant height effects on survival of inoculated abaca variants, and (iii to identify Foc resistance abaca variants. In the previous experiment, four abaca variant lines were regenerated from (i embryogenic calli (TC line, (ii ethyl methyl sulphonate (EMS treated embryogenic calli (EMS line, (iii EMS treated embryogenic calli, followed by in vitro selection on Foc culture filtrate (EMS+CF line, and (iv EMS treated embryogenic calli, followed by in vitro selection on fusaric acid (EMS+FA line. All abaca variants were grown in a glasshouse and inoculated with Banyuwangi isolate of Foc (Foc Bw. Initial root length (RL and plant height (PH of the abaca variants were recorded before inoculation, while scores of plant damage (SPD, and their survival were recorded at 60 days after inoculation (DAI. The results showed that the initial RL and PH did not affect survival of the tested abaca variants. Regardless of their initial RL and PH, susceptible abaca variants died before 60 DAI while resistance ones still survived. Abaca variants regenerated from single clump of embryogenic callus showed an array of responses against Foc Bw infection, indicating the existence of a mix cells population. The Foc Bw resistance abaca variants were successfully identified from four tested abaca variant lines, although with different frequencies. However, more Foc Bw resistance abaca plants were identified from EMS+CF line than the others. Using the developed procedures, 8 resistance abaca plants were identified from abaca cv. Tangongon and 12 from abaca cv. Sangihe-1.

  15. The rs3857059 variant of the SNCA gene is associated with Parkinson’s disease in Mexican Mestizos

    OpenAIRE

    2016-01-01

    ABSTRACT Among the candidate genes for Parkinson’s disease (PD), SNCA has replicated association in different populations. Besides other known mutations in the SNCA gene, the rs3857059 variant has also been linked to various neurodegenerative disorders. Therefore, the aim of the present study was to search for association of this variant and sporadic PD in Mexican Mestizo patients. A case-control study was performed including 241 individuals, 106 patients, and 135 healthy controls. Geno...

  16. Allele-specific methylation occurs at genetic variants associated with complex disease.

    Directory of Open Access Journals (Sweden)

    John N Hutchinson

    Full Text Available We hypothesize that the phenomenon of allele-specific methylation (ASM may underlie the phenotypic effects of multiple variants identified by Genome-Wide Association studies (GWAS. We evaluate ASM in a human population and document its genome-wide patterns in an initial screen at up to 380,678 sites within the genome, or up to 5% of the total genomic CpGs. We show that while substantial inter-individual variation exists, 5% of assessed sites show evidence of ASM in at least six samples; the majority of these events (81% are under genetic influence. Many of these cis-regulated ASM variants are also eQTLs in peripheral blood mononuclear cells and monocytes and/or in high linkage-disequilibrium with variants linked to complex disease. Finally, focusing on autoimmune phenotypes, we extend this initial screen to confirm the association of cis-regulated ASM with multiple complex disease-associated variants in an independent population using next-generation bisulfite sequencing. These four variants are implicated in complex phenotypes such as ulcerative colitis and AIDS progression disease (rs10491434, Celiac disease (rs2762051, Crohn's disease, IgA nephropathy and early-onset inflammatory bowel disease (rs713875 and height (rs6569648. Our results suggest cis-regulated ASM may provide a mechanistic link between the non-coding genetic changes and phenotypic variation observed in these diseases and further suggests a route to integrating DNA methylation status with GWAS results.

  17. Semantic prioritization of novel causative genomic variants

    KAUST Repository

    Boudellioua, Imane

    2017-04-17

    Discriminating the causative disease variant(s) for individuals with inherited or de novo mutations presents one of the main challenges faced by the clinical genetics community today. Computational approaches for variant prioritization include machine learning methods utilizing a large number of features, including molecular information, interaction networks, or phenotypes. Here, we demonstrate the PhenomeNET Variant Predictor (PVP) system that exploits semantic technologies and automated reasoning over genotype-phenotype relations to filter and prioritize variants in whole exome and whole genome sequencing datasets. We demonstrate the performance of PVP in identifying causative variants on a large number of synthetic whole exome and whole genome sequences, covering a wide range of diseases and syndromes. In a retrospective study, we further illustrate the application of PVP for the interpretation of whole exome sequencing data in patients suffering from congenital hypothyroidism. We find that PVP accurately identifies causative variants in whole exome and whole genome sequencing datasets and provides a powerful resource for the discovery of causal variants.

  18. Fundamental Characteristics of Industrial Variant Specification Systems

    DEFF Research Database (Denmark)

    Hansen, Benjamin Loer; Hvam, Lars

    2004-01-01

    fundamental concepts related to this task, which are relevant to understand for academia and practitioners working with the subject. This is done through a description of variant specification tasks and typical aspects of system solutions. To support the description of variant specification tasks and systems...

  19. Beta-glucosidase I variants with improved properties

    Energy Technology Data Exchange (ETDEWEB)

    Bott, Richard R.; Kaper, Thijs; Kelemen, Bradley; Goedegebuur, Frits; Hommes, Ronaldus Wilhelmus; Kralj, Slavko; Kruithof, Paulien; Nikolaev, Igor; Van Der Kley, Wilhelmus Antonious Hendricus; Van Lieshout, Johannes Franciscus Thomas; Van Stigt Thans, Sander

    2016-09-20

    The present disclosure is generally directed to enzymes and in particular beta-glucosidase variants. Also described are nucleic acids encoding beta-glucosidase variants, compositions comprising beta-glucosidase variants, methods of using beta-glucosidase variants, and methods of identifying additional useful beta-glucosidase variants.

  20. 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.

  1. Histones in functional diversification. Core histone variants.

    Science.gov (United States)

    Pusarla, Rama-Haritha; Bhargava, Purnima

    2005-10-01

    Recent research suggests that minor changes in the primary sequence of the conserved histones may become major determinants for the chromatin structure regulating gene expression and other DNA-related processes. An analysis of the involvement of different core histone variants in different nuclear processes and the structure of different variant nucleosome cores shows that this may indeed be so. Histone variants may also be involved in demarcating functional regions of the chromatin. We discuss in this review why two of the four core histones show higher variation. A comparison of the status of variants in yeast with those from higher eukaryotes suggests that histone variants have evolved in synchrony with functional requirement of the cell.

  2. 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 funda...... 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.......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...

  3. Genetic variants of the DNA repair genes from Exome Aggregation Consortium (EXAC) database: significance in cancer.

    Science.gov (United States)

    Das, Raima; Ghosh, Sankar Kumar

    2017-04-01

    DNA repair pathway is a primary defense system that eliminates wide varieties of DNA damage. Any deficiencies in them are likely to cause the chromosomal instability that leads to cell malfunctioning and tumorigenesis. Genetic polymorphisms in DNA repair genes have demonstrated a significant association with cancer risk. Our study attempts to give a glimpse of the overall scenario of the germline polymorphisms in the DNA repair genes by taking into account of the Exome Aggregation Consortium (ExAC) database as well as the Human Gene Mutation Database (HGMD) for evaluating the disease link, particularly in cancer. It has been found that ExAC DNA repair dataset (which consists of 228 DNA repair genes) comprises 30.4% missense, 12.5% dbSNP reported and 3.2% ClinVar significant variants. 27% of all the missense variants has the deleterious SIFT score of 0.00 and 6% variants carrying the most damaging Polyphen-2 score of 1.00, thus affecting the protein structure and function. However, as per HGMD, only a fraction (1.2%) of ExAC DNA repair variants was found to be cancer-related, indicating remaining variants reported in both the databases to be further analyzed. This, in turn, may provide an increased spectrum of the reported cancer linked variants in the DNA repair genes present in ExAC database. Moreover, further in silico functional assay of the identified vital cancer-associated variants, which is essential to get their actual biological significance, may shed some lights in the field of targeted drug development in near future. Copyright © 2017. Published by Elsevier B.V.

  4. Recurrent somatic JAK-STAT pathway variants within a RUNX1-mutated pedigree.

    Science.gov (United States)

    Tawana, Kiran; Wang, Jun; Király, Péter A; Kállay, Krisztián; Benyó, Gábor; Zombori, Marianna; Csomor, Judit; Al Seraihi, Ahad; Rio-Machin, Ana; Matolcsy, András; Chelala, Claude; Cavenagh, Jamie; Fitzgibbon, Jude; Bödör, Csaba

    2017-08-01

    Germline variants within the transcription factor RUNX1 are associated with familial platelet disorder and acute leukemia in over 40% of carriers. At present, the somatic events triggering leukemic transformation appear heterogeneous and profiles of leukemia initiation across family members are poorly defined. We report a new RUNX1 family where three sisters harboring a germline nonsense RUNX1 variant, c.601C>T (p.(Arg201*)), developed acute myelomonocytic leukemia (AML) at 5 years of age. Whole-exome sequencing of tumor samples revealed all three siblings independently acquired variants within the JAK-STAT pathway, specifically targeting JAK2 and SH2B3 (a negative regulator of JAK2), while also sharing the 46/1 haplotype linked with sporadic JAK2-positive myeloproliferative neoplasms. In-depth chromosomal characterization of tumors revealed acquired copy number gains and uniparental disomy amplifying RUNX1, JAK2 and SH2B3 variants, highlighting the significance of co-operation between these disrupted pathways. One sibling, presenting with myelodysplasia at 14 years, had no evidence of clonal or subclonal JAK2 or SH2B3 variants, suggesting the latter were specifically associated with leukemic transformation in her sisters. Collectively, the clinical and molecular homogeneity across these three young siblings provides the first notable example of convergent AML evolution in a RUNX1 pedigree, with the recurrent acquisition of JAK-STAT pathway variants giving rise to high-risk AML, characterized by chemotherapy resistance and relapse.

  5. Classification and Clinical Management of Variants of Uncertain Significance in High Penetrance Cancer Predisposition Genes.

    Science.gov (United States)

    Moghadasi, Setareh; Eccles, Diana M; Devilee, Peter; Vreeswijk, Maaike P G; van Asperen, Christi J

    2016-04-01

    In 2008, the International Agency for Research on Cancer (IARC) proposed a system for classifying sequence variants in highly penetrant breast and colon cancer susceptibility genes, linked to clinical actions. This system uses a multifactorial likelihood model to calculate the posterior probability that an altered DNA sequence is pathogenic. Variants between 5%-94.9% (class 3) are categorized as variants of uncertain significance (VUS). This interval is wide and might include variants with a substantial difference in pathogenicity at either end of the spectrum. We think that carriers of class 3 variants would benefit from a fine-tuning of this classification. Classification of VUS to a category with a defined clinical significance is very important because for carriers of a pathogenic mutation full surveillance and risk-reducing surgery can reduce cancer incidence. Counselees who are not carriers of a pathogenic mutation can be discharged from intensive follow-up and avoid unnecessary risk-reducing surgery. By means of examples, we show how, in selected cases, additional data can lead to reclassification of some variants to a different class with different recommendations for surveillance and therapy. To improve the clinical utility of this classification system, we suggest a pragmatic adaptation to clinical practice.

  6. Linked data management

    CERN Document Server

    Hose, Katja; Schenkel, Ralf

    2014-01-01

    Linked Data Management presents techniques for querying and managing Linked Data that is available on today’s Web. The book shows how the abundance of Linked Data can serve as fertile ground for research and commercial applications. The text focuses on aspects of managing large-scale collections of Linked Data. It offers a detailed introduction to Linked Data and related standards, including the main principles distinguishing Linked Data from standard database technology. Chapters also describe how to generate links between datasets and explain the overall architecture of data integration systems based on Linked Data. A large part of the text is devoted to query processing in different setups. After presenting methods to publish relational data as Linked Data and efficient centralized processing, the book explores lookup-based, distributed, and parallel solutions. It then addresses advanced topics, such as reasoning, and discusses work related to read-write Linked Data for system interoperation. Desp...

  7. Common variants at 12q15 and 12q24 are associated with infant head circumference

    DEFF Research Database (Denmark)

    Taal, H Rob; St Pourcain, Beate; Thiering, Elisabeth

    2012-01-01

    q21 signal have shown genome-wide association with adult intracranial volume, Parkinson's disease and other neurodegenerative diseases, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.......To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication...

  8. 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.

  9. Histological variants of cutaneous Kaposi sarcoma

    Directory of Open Access Journals (Sweden)

    Pantanowitz Liron

    2008-07-01

    Full Text Available Abstract This review provides a comprehensive overview of the broad clinicopathologic spectrum of cutaneous Kaposi sarcoma (KS lesions. Variants discussed include: usual KS lesions associated with disease progression (i.e. patch, plaque and nodular stage; morphologic subtypes alluded to in the older literature such as anaplastic and telangiectatic KS, as well as several lymphedematous variants; and numerous recently described variants including hyperkeratotic, keloidal, micronodular, pyogenic granuloma-like, ecchymotic, and intravascular KS. Involuting lesions as a result of treatment related regression are also presented.

  10. Ultrasonographic imaging of papillary thyroid carcinoma variants

    Energy Technology Data Exchange (ETDEWEB)

    Shin, Jung Hee [Dept. of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2017-04-15

    Ultrasonography (US) is routinely used to evaluate thyroid nodules. The US features of papillary thyroid carcinoma (PTC), the most common thyroid malignancy, include hypoechogenicity, spiculated/microlobulated margins, microcalcifications, and a nonparallel orientation. However, many PTC variants have been identified, some of which differ from the classic type of PTC in terms of biological behavior and clinical outcomes. This review describes the US features and clinical implications of the variants of PTC. With the introduction of active surveillance replacing immediate biopsy or surgical treatment of indolent, small PTCs, an understanding of the US characteristics of PTC variants will facilitate the individualized management of patients with PTC.

  11. A nondegenerate code of deleterious variants in Mendelian loci contributes to complex disease risk.

    Science.gov (United States)

    Blair, David R; Lyttle, Christopher S; Mortensen, Jonathan M; Bearden, Charles F; Jensen, Anders Boeck; Khiabanian, Hossein; Melamed, Rachel; Rabadan, Raul; Bernstam, Elmer V; Brunak, Søren; Jensen, Lars Juhl; Nicolae, Dan; Shah, Nigam H; Grossman, Robert L; Cox, Nancy J; White, Kevin P; Rzhetsky, Andrey

    2013-09-26

    Although countless highly penetrant variants have been associated with Mendelian disorders, the genetic etiologies underlying complex diseases remain largely unresolved. By mining the medical records of over 110 million patients, we examine the extent to which Mendelian variation contributes to complex disease risk. We detect thousands of associations between Mendelian and complex diseases, revealing a nondegenerate, phenotypic code that links each complex disorder to a unique collection of Mendelian loci. Using genome-wide association results, we demonstrate that common variants associated with complex diseases are enriched in the genes indicated by this "Mendelian code." Finally, we detect hundreds of comorbidity associations among Mendelian disorders, and we use probabilistic genetic modeling to demonstrate that Mendelian variants likely contribute nonadditively to the risk for a subset of complex diseases. Overall, this study illustrates a complementary approach for mapping complex disease loci and provides unique predictions concerning the etiologies of specific diseases. Copyright © 2013 Elsevier Inc. All rights reserved.

  12. A Non-Degenerate Code of Deleterious Variants in Mendelian Loci Contributes to Complex Disease Risk

    Science.gov (United States)

    Blair, David R.; Lyttle, Christopher S.; Mortensen, Jonathan M.; Bearden, Charles F.; Jensen, Anders Boeck; Khiabanian, Hossein; Melamed, Rachel; Rabadan, Raul; Bernstam, Elmer V.; Brunak, Søren; Jensen, Lars Juhl; Nicolae, Dan; Shah, Nigam H.; Grossman, Robert L.; Cox, Nancy J.; White, Kevin P.; Rzhetsky, Andrey

    2013-01-01

    Summary Whereas countless highly penetrant variants have been associated with Mendelian disorders, the genetic etiologies underlying complex diseases remain largely unresolved. Here, we examine the extent to which Mendelian variation contributes to complex disease risk by mining the medical records of over 110 million patients. We detect thousands of associations between Mendelian and complex diseases, revealing a non-degenerate, phenotypic code that links each complex disorder to a unique collection of Mendelian loci. Using genome-wide association results, we demonstrate that common variants associated with complex diseases are enriched in the genes indicated by this “Mendelian code.” Finally, we detect hundreds of comorbidity associations among Mendelian disorders, and we use probabilistic genetic modeling to demonstrate that Mendelian variants likely contribute non-additively to the risk for a subset of complex diseases. Overall, this study illustrates a complementary approach for mapping complex disease loci and provides unique predictions concerning the etiologies of specific diseases. PMID:24074861

  13. A Nondegenerate Code of Deleterious Variants in Mendelian Loci Contributes to Complex Disease Risk

    DEFF Research Database (Denmark)

    Blair, David R.; Lyttle, Christopher S.; Mortensen, Jonathan M.

    2013-01-01

    with complex diseases are enriched in the genes indicated by this ‘‘Mendelian code.’’ Finally, we detect hundreds of comorbidity associations among Mendelian disorders, and we use probabilistic genetic modeling to demonstrate that Mendelian variants likely contribute nonadditively to the risk for a subset......Although countless highly penetrant variants have been associated with Mendelian disorders, the genetic etiologies underlying complex diseases remain largely unresolved. By mining the medical records of over 110 million patients, we examine the extent to which Mendelian variation contributes...... to complex disease risk. We detect thousands of associations between Mendelian and complex diseases, revealing a nondegenerate, phenotypic code that links each complex disorder to a unique collection of Mendelian loci. Using genome-wide association results, we demonstrate that common variants associated...

  14. Medical genomics: The intricate path from genetic variant identification to clinical interpretation

    Directory of Open Access Journals (Sweden)

    B. Quintáns

    2014-09-01

    A plethora of automated analysis software tools is being developed that will enhance efficiency and accuracy. However a risk of misinterpretation could derive from biased biorepository content, facilitated by annotation of variant functional consequences using previous datasets stored in the same or linked repositories. In order to improve variant interpretation and avoid an exponential accumulation of confounding noise in the medical literature, the use of terms in a standard way should be sought and requested when reporting genetic variants and their consequences. Generally, stepwise and linear interpretation processes are likely to overrate some pieces of evidence while underscoring others. Algorithms are needed that allow a multidimensional, parallel analysis of diverse lines of evidence to be carried out by expert teams for specific genes, cellular pathways or disorders.

  15. Expanding the phenotypic spectrum of PORCN variants in two males with syndromic microphthalmia.

    Science.gov (United States)

    Brady, Paul D; Van Esch, Hilde; Fieremans, Nathalie; Froyen, Guy; Slavotinek, Anne; Deprest, Jan; Devriendt, Koenraad; Vermeesch, Joris R

    2015-04-01

    Variants in PORCN are a cause of Goltz-Gorlin syndrome or Focal Dermal Hypoplasia, an X-linked dominant disorder affecting heterozygous females and until now considered to be embryonic lethal in males. Exome sequencing was performed in a family in which two male siblings were characterized by microphthalmia and additional congenital anomalies including diaphragmatic hernia, spina bifida and cardiac defects. Surprisingly, we identified a maternally inherited variant in PORCN present in both males as well as in two female siblings. This represents the first finding of a PORCN variant in non-mosaic males affected with Goltz-Gorlin syndrome. The apparently asymptomatic mother showed extreme skewing of X-inactivation (90%), an asymptomatic female sibling showed skewing of 88%, and the second female sibling affected with cutis aplasia of the scalp showed X-inactivation considered within the normal range.

  16. 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.

  17. Variant profiling of evolving prokaryotic populations

    Science.gov (United States)

    Zojer, Markus; Schuster, Lisa N.; Schulz, Frederik; Pfundner, Alexander; Horn, Matthias

    2017-01-01

    Genomic heterogeneity of bacterial species is observed and studied in experimental evolution experiments and clinical diagnostics, and occurs as micro-diversity of natural habitats. The challenge for genome research is to accurately capture this heterogeneity with the currently used short sequencing reads. Recent advances in NGS technologies improved the speed and coverage and thus allowed for deep sequencing of bacterial populations. This facilitates the quantitative assessment of genomic heterogeneity, including low frequency alleles or haplotypes. However, false positive variant predictions due to sequencing errors and mapping artifacts of short reads need to be prevented. We therefore created VarCap, a workflow for the reliable prediction of different types of variants even at low frequencies. In order to predict SNPs, InDels and structural variations, we evaluated the sensitivity and accuracy of different software tools using synthetic read data. The results suggested that the best sensitivity could be reached by a union of different tools, however at the price of increased false positives. We identified possible reasons for false predictions and used this knowledge to improve the accuracy by post-filtering the predicted variants according to properties such as frequency, coverage, genomic environment/localization and co-localization with other variants. We observed that best precision was achieved by using an intersection of at least two tools per variant. This resulted in the reliable prediction of variants above a minimum relative abundance of 2%. VarCap is designed for being routinely used within experimental evolution experiments or for clinical diagnostics. The detected variants are reported as frequencies within a VCF file and as a graphical overview of the distribution of the different variant/allele/haplotype frequencies. The source code of VarCap is available at https://github.com/ma2o/VarCap. In order to provide this workflow to a broad community

  18. Bisalbuminemia. A new molecular variant, albumin Vancouver.

    Science.gov (United States)

    Frohlich, J; Kozier, J; Campbell, D J; Curnow, J V; Tárnoky, A L

    1978-11-01

    Of 18 members of a Fiji Indian family investigated, eight of the 12 males and two of the six females had an electrophoretically slow-type bisalbuminemia (alloalbuminemia). The albumin was characterized by the hiterto unique ratio of the two bands (Al A 35%: variant 65%), and by dye-binding studies and electrophoretic mobility in different media. The data suggest that this is a new variant, which we propose to call albumin Vancouver (Al Va).

  19. Another new variant of Bouveret's syndrome

    Institute of Scientific and Technical Information of China (English)

    Seong-Heum Park; Sang-Woo Lee; Tae-Jin Song

    2009-01-01

    Although Bouveret's syndrome, i.e. gastric outlet obstruction by a large gallstone impacted in the proximal duodenum secondary to a cholecystoduodenal fistula,is rare, its pathogenesis and clinical features are well characterized. However, existence of variant forms of the syndrome are not well known, and as far as we have been described in the English-language literature.We present a case of another new variant of Bouveret's syndrome in a 54-year-old Korean woman.

  20. Brief Analysis of Regional Variants in English%Brief Analysis of Regional Variants in Enghsh

    Institute of Scientific and Technical Information of China (English)

    张炳科

    2008-01-01

    It is universally acknowledged that regional variants exist in each language, for it is impossible that people always employ the same pronunciation or vocabulary or even grammar to express the same meaning no matter how large the scope in which a language is used may be. The author of this paper is just to exemplify some regional variants in English and to analyze the factors that account for the variants ,with the purpose of teaching English well in the most efficient way.

  1. Weierstrass polynomials for links

    DEFF Research Database (Denmark)

    Hansen, Vagn Lundsgaard

    1997-01-01

    There is a natural way of identifying links in3-space with polynomial covering spaces over thecircle. Thereby any link in 3-space can be definedby a Weierstrass polynomial over the circle. Theequivalence relation for covering spaces over thecircle is, however, completely different from...... that for links in 3-space. This paper initiates a study of the connections between polynomial covering spaces over the circle and links in 3-space....

  2. Analysis of non-synonymous-coding variants of Parkinson's disease-related pathogenic and susceptibility genes in East Asian populations.

    Science.gov (United States)

    Foo, Jia Nee; Tan, Louis C; Liany, Herty; Koh, Tat Hung; Irwan, Ishak D; Ng, Yen Yek; Ahmad-Annuar, Azlina; Au, Wing-Lok; Aung, Tin; Chan, Anne Y Y; Chong, Siow-Ann; Chung, Sun Ju; Jung, Yusun; Khor, Chiea Chuen; Kim, Juyeon; Lee, Jimmy; Lim, Shen-Yang; Mok, Vincent; Prakash, Kumar-M; Song, Kyuyoung; Tai, E-Shyong; Vithana, Eranga N; Wong, Tien-Yin; Tan, Eng-King; Liu, Jianjun

    2014-07-15

    To evaluate the contribution of non-synonymous-coding variants of known familial and genome-wide association studies (GWAS)-linked genes for Parkinson's disease (PD) to PD risk in the East Asian population, we sequenced all the coding exons of 39 PD-related disease genes and evaluated the accumulation of rare non-synonymous-coding variants in 375 early-onset PD cases and 399 controls. We also genotyped 782 non-synonymous-coding variants of these genes in 710 late-onset PD cases and 9046 population controls. Significant enrichment of LRRK2 variants was observed in both early- and late-onset PD (odds ratio = 1.58; 95% confidence interval = 1.29-1.93; P = 8.05 × 10(-6)). Moderate enrichment was also observed in FGF20, MCCC1, GBA and ITGA8. Half of the rare variants anticipated to cause loss of function of these genes were present in healthy controls. Overall, non-synonymous-coding variants of known familial and GWAS-linked genes appear to make a limited contribution to PD risk, suggesting that clinical sequencing of these genes will provide limited information for risk prediction and molecular diagnosis.

  3. Genetic susceptibility variants associated with colorectal cancer prognosis.

    Science.gov (United States)

    Abulí, Anna; Lozano, Juan José; Rodríguez-Soler, María; Jover, Rodrigo; Bessa, Xavier; Muñoz, Jenifer; Esteban-Jurado, Clara; Fernández-Rozadilla, Ceres; Carracedo, Angel; Ruiz-Ponte, Clara; Cubiella, Joaquín; Balaguer, Francesc; Bujanda, Luis; Reñé, Josep M; Clofent, Juan; Morillas, Juan Diego; Nicolás-Pérez, David; Xicola, Rosa M; Llor, Xavier; Piqué, Josep M; Andreu, Montserrat; Castells, Antoni; Castellví-Bel, Sergi

    2013-10-01

    Colorectal cancer (CRC) is the second leading cause of cancer-related death among men and women in Western countries. Once a tumour develops, a differentiated prognosis could be determined by lifestyle habits or inherited and somatic genetic factors. Finding such prognostic factors will be helpful in order to identify cases with a shorter survival or at a higher risk of recurrence that may benefit from more intensive treatment and follow-up surveillance. Sixteen CRC genetic susceptibility variants were directly genotyped in a cohort of 1235 CRC patients recruited by the EPICOLON Spanish consortium. Univariate Cox and multivariate regression analyses were performed taking as primary outcomes overall survival (OS), disease-free survival and recurrence-free interval. Genetic variants rs9929218 at 16q22.1 and rs10795668 at 10p14 may have an effect on OS. The G allele of rs9929218 was linked with a better OS [GG genotype, genotypic model: hazard ratio (HR) = 0.65, 95% confidence interval (CI) 0.45-0.93, P = 0.0179; GG/GA genotypes, dominant model: HR = 0.66, 95% CI 0.47-0.94, P = 0.0202]. Likewise, the G allele of rs10795668 was associated with better clinical outcome (GG genotype, genotypic model: HR = 0.73, 95% CI 0.53-1.01, P = 0.0570; GA genotype, genotypic model: HR = 0.66, 95% CI 0.47-0.92, P = 0.0137; GG/GA genotypes, dominant model: HR = 0.68, 95% CI 0.50-0.94, P = 0.0194). In conclusion, CRC susceptibility variants rs9929218 and rs10795668 may exert some influence in modulating patient's survival and they deserve to be further tested in additional CRC cohorts in order to confirm their potential as prognosis or predictive biomarkers.

  4. Selective linking from social platforms to university websites: a case study of the Spanish academic system

    CERN Document Server

    Orduna-Malea, Enrique

    2013-01-01

    Mention indicators have frequently been used in Webometric studies because they provide a powerful tool for determining the degree of visibility and impact of web resources. Among mention indicators, hypertextual links were a central part of many studies until Yahoo discontinued the linkdomain command in 2011. Selective links constitute a variant of external links where both the source and target of the link can be selected. This paper intends to study the influence of social platforms (measured through the number of selective external links) on academic environments, in order to ascertain both the percentage that they constitute and whether some of them can be used as substitutes of total external links. For this purpose, 141 URLs belonging to 76 Spanish universities were compiled in 2010 (before Yahoo! stopped their link services), and the number of links from 13 selected social platforms to these universities were calculated. Results confirm a good correlation between total external links and links that co...

  5. The rs3857059 variant of the SNCA gene is associated with Parkinson's disease in Mexican Mestizos.

    Science.gov (United States)

    García, S; Chavira-Hernández, G; Gallegos-Arreola, M P; Dávila-Maldonado, L; García Martínez, F; Montes Almanza, L A; Palma-Flores, C; Mondragón-Terán, P; Alcaraz Estrada, S L; López-Hernández, L B

    2016-06-01

    Among the candidate genes for Parkinson's disease (PD), SNCA has replicated association in different populations. Besides other known mutations in the SNCA gene, the rs3857059 variant has also been linked to various neurodegenerative disorders. Therefore, the aim of the present study was to search for association of this variant and sporadic PD in Mexican Mestizo patients. A case-control study was performed including 241 individuals, 106 patients, and 135 healthy controls. Genotyping was performed using real-time PCR. The rs3857059 variant demonstrated an association with PD in Mexican Mestizos (OR = 2.40, CI, 1.1 to 5.1, p = 0.02) under the recessive model. In addition, a gender effect was found for the GG genotype in females (OR = 1.31, CI, 1.01 to 1.7, p = 0.037). This is the first study to confirm an association of the rs3857059 variant with PD and also to show a gender effect. Our data contribute to the elucidation of the link between rs3857059 and susceptibility to PD observed in the Mexican Mestizo population.

  6. Super Spy variants implicate flexibility in chaperone action.

    Science.gov (United States)

    Quan, Shu; Wang, Lili; Petrotchenko, Evgeniy V; Makepeace, Karl At; Horowitz, Scott; Yang, Jianyi; Zhang, Yang; Borchers, Christoph H; Bardwell, James Ca

    2014-01-01

    Experimental study of the role of disorder in protein function is challenging. It has been proposed that proteins utilize disordered regions in the adaptive recognition of their various binding partners. However apart from a few exceptions, defining the importance of disorder in promiscuous binding interactions has proven to be difficult. In this paper, we have utilized a genetic selection that links protein stability to antibiotic resistance to isolate variants of the newly discovered chaperone Spy that show an up to 7 fold improved chaperone activity against a variety of substrates. These "Super Spy" variants show tighter binding to client proteins and are generally more unstable than is wild type Spy and show increases in apparent flexibility. We establish a good relationship between the degree of their instability and the improvement they show in their chaperone activity. Our results provide evidence for the importance of disorder and flexibility in chaperone function. DOI: http://dx.doi.org/10.7554/eLife.01584.001.

  7. New polymorphic variants of human blood clotting factor IX

    Energy Technology Data Exchange (ETDEWEB)

    Surin, V.L.; Luk`yanenko, A.V.; Tagiev, A.F.; Smirnova, O.V. [Hematological Research Center, Moscow (Russian Federation); Plutalov, O.V.; Berlin, Yu.A. [Shemyakin Institute of Bioorganic Chemistry, Moscow (Russian Federation)

    1995-04-01

    The polymorphism of Alu-repeats, which are located in the introns of the human factor IX gene (copies 1-3), was studied. To identify polymorphic variants, direct sequencing of PCR products that contained appropriate repeats was used. In each case, 20 unrelated X chromosomes were studied. A polymorphic Dra I site was found near the 3{prime}-end of Alu copy 3 within the region of the polyA tract. A PCR-based testing system with internal control of restriction hydrolysis was suggested. Testing 81 unrelated X chromosomes revealed that the frequency of the polymorphic Dra I site is 0.23. Taq I polymorphism, which was revealed in Alu copy 4 of factor IX gene in our previous work, was found to be closely linked to Dra I polymorphism. Studies in linkage between different types of polymorphisms of the factor IX gene revealed the presence of a rare polymorphism in intron a that was located within the same minisatellite region as the known polymorphic insertion 50 bp/Dde I. However, the size of the insertion in our case was 26 bp. Only one polymorphic variant was found among over 150 unrelated X chromosomes derived from humans from Moscow and its vicinity. 10 refs., 4 figs., 1 tab.

  8. Antigenic Relatedness of Norovirus GII.4 Variants Determined by Human Challenge Sera.

    Directory of Open Access Journals (Sweden)

    Ying-Chun Dai

    Full Text Available The GII.4 noroviruses (NoVs are a single genotype that is responsible for over 50% of NoV gastroenteritis epidemics worldwide. However, GII.4 NoVs have been found to undergo antigenic drifts, likely selected by host herd immunity, which raises an issue for vaccine strategies against NoVs. We previously characterized GII.4 NoV antigenic variations and found significant levels of antigenic relatedness among different GII.4 variants. Further characterization of the genetic and antigenic relatedness of recent GII.4 variants (2008b and 2010 cluster was performed in this study. The amino acid sequences of the receptor binding interfaces were highly conserved among all GII.4 variants from the past two decades. Using serum samples from patients enrolled in a GII.4 virus challenge study, significant cross-reactivity between major GII.4 variants from 1998 to 2012 was observed using enzyme-linked immunosorbent assays and HBGA receptor blocking assays. The overall abilities of GII.4 NoVs to bind to the A/B/H HBGAs were maintained while their binding affinities to individual ABH antigens varied. These results highlight the importance of human HBGAs in NoV evolution and how conserved antigenic types impact vaccine development against GII.4 variants.

  9. Dynamic deposition of histone variant H3.3 accompanies developmental remodeling of the Arabidopsis transcriptome.

    Directory of Open Access Journals (Sweden)

    Heike Wollmann

    Full Text Available In animals, replication-coupled histone H3.1 can be distinguished from replication-independent histone H3.3. H3.3 variants are enriched at active genes and their promoters. Furthermore, H3.3 is specifically incorporated upon gene activation. Histone H3 variants evolved independently in plants and animals, and it is unclear whether different replication-independent H3.3 variants developed similar properties in both phyla. We studied Arabidopsis H3 variants in order to find core properties of this class of histones. Here we present genome-wide maps of H3.3 and H3.1 enrichment and the dynamic changes of their profiles upon cell division arrest. We find H3.3 enrichment to positively correlate with gene expression and to be biased towards the transcription termination site. In contrast with H3.1, heterochromatic regions are mostly depleted of H3.3. We report that, in planta, dynamic changes in H3.3 profiles are associated with the extensive remodeling of the transcriptome that occurs during cell differentiation. We propose that H3.3 dynamics are linked to transcription and are involved in resetting covalent histone marks at a genomic scale during plant development. Our study suggests that H3 variants properties likely result from functionally convergent evolution.

  10. Structural and Functional Analysis of the ApolipoproteinA-I A164S Variant.

    Directory of Open Access Journals (Sweden)

    Jonathan Dalla-Riva

    Full Text Available Apolipoprotein A-I (apoA-I is the main protein involved in the formation of high-density lipoprotein (HDL, it is the principal mediator of the reverse cholesterol transfer (RCT pathway and provides cardio-protection. In addition to functional wild-type apoA-I, several variants have been shown to associate with hereditary amyloidosis. In this study we have performed biophysical and biochemical analyses of the structure and functional properties of the A164S variant of apoA-I (1:500 in the Danish general population, which is the first known mutation of apoA-I that leads to an increased risk of ischaemic heart disease (IHD, myocardial infarction and mortality without associated low HDL cholesterol levels. Despite the fact that epidemiologically IHD is associated with low plasma levels of HDL, the A164S mutation is linked to normal plasma levels of lipids, HDL and apoA-I, suggesting impaired functionality of this variant. Using biophysical techniques (e.g., circular dichroism spectroscopy and electron microscopy to determine secondary structure, stability and pro-amyloidogenic property of the lipid free A164S apoA-I variant, our observations suggest similarity in structural properties between apoA-I WT and apoA-I A164S. However, the A164S apoA-I variant exhibits lower binding affinity to lipids but forms similar sized HDL particles to those produced by WT.

  11. Sensory gating and alpha-7 nicotinic receptor gene allelic variants in schizoaffective disorder, bipolar type.

    Science.gov (United States)

    Martin, Laura F; Leonard, Sherry; Hall, Mei-Hua; Tregellas, Jason R; Freedman, Robert; Olincy, Ann

    2007-07-05

    Single nucleotide allelic variants in the promoter region of the chromosome 15 alpha-7 acetylcholine nicotinic receptor gene (CHRNA7) are associated with both schizophrenia and the P50 auditory evoked potential sensory gating deficit. The purpose of this study was to determine if CHRNA7 promoter allelic variants are also associated with abnormal P50 ratios in persons with schizoaffective disorder, bipolar type. P50 auditory evoked potentials were recorded in a paired stimulus paradigm in 17 subjects with schizoaffective disorder, bipolar type. The P50 test to conditioning ratio was used as the measure of sensory gating. Mutation screening of the CHRNA7 promoter region was performed on the subjects' DNA samples. Comparisons to previously obtained data from persons with schizophrenia and controls were made. Subjects with schizophrenia, regardless of allele status, had an abnormal mean P50 ratio. Subjects with schizoaffective disorder, bipolar type and a variant allele had an abnormal mean P50 ratio, whereas those schizoaffective subjects with the common alleles had a normal mean P50 ratio. Normal control subjects had a normal mean ratio, but controls with variant alleles had higher P50 ratios. In persons with bipolar type schizoaffective disorder, CHRNA7 promoter region allelic variants are linked to the capacity to inhibit the P50 auditory evoked potential and thus are associated with a type of illness genetically and biologically more similar to schizophrenia.

  12. Negative-dominance phenomenon with genetic variants of the cardiac sodium channel Nav1.5.

    Science.gov (United States)

    Sottas, Valentin; Abriel, Hugues

    2016-07-01

    During the past two decades, many pathological genetic variants in SCN5A, the gene encoding the pore-forming subunit of the cardiac (monomeric) sodium channel Na(v)1.5, have been described. Negative dominance is a classical genetic concept involving a "poison" mutant peptide that negatively interferes with the co-expressed wild-type protein, thus reducing its cellular function. This phenomenon has been described for genetic variants of multimeric K(+) channels, which mechanisms are well understood. Unexpectedly, several pathologic SCN5A variants that are linked to Brugada syndrome also demonstrate such a dominant-negative (DN) effect. The molecular determinants of these observations, however, are not yet elucidated. This review article summarizes recent findings that describe the mechanisms underlying the DN phenomenon of genetic variants of K(+), Ca(2+), Cl(-) and Na(+) channels, and in particular Brugada syndrome variants of Na(v)1.5. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.

  13. SV40 host-substituted variants: a new look at the monkey DNA inserts and recombinant junctions.

    Science.gov (United States)

    Singer, Maxine; Winocour, Ernest

    2011-04-10

    The available monkey genomic data banks were examined in order to determine the chromosomal locations of the host DNA inserts in 8 host-substituted SV40 variant DNAs. Five of the 8 variants contained more than one linked monkey DNA insert per tandem repeat unit and in all cases but one, the 19 monkey DNA inserts in the 8 variants mapped to different locations in the monkey genome. The 50 parental DNAs (32 monkey and 18 SV40 DNA segments) which spanned the crossover and flanking regions that participated in monkey/monkey and monkey/SV40 recombinations were characterized by substantial levels of microhomology of up to 8 nucleotides in length; the parental DNAs also exhibited direct and inverted repeats at or adjacent to the crossover sequences. We discuss how the host-substituted SV40 variants arose and the nature of the recombination mechanisms involved.

  14. Beta-glucosidase variants and polynucleotides encoding same

    Energy Technology Data Exchange (ETDEWEB)

    Wogulis, Mark; Harris, Paul; Osborn, David

    2017-06-27

    The present invention relates to beta-glucosidase variants, e.g. beta-glucosidase variants of a parent Family GH3A beta-glucosidase from Aspergillus fumigatus. The present invention also relates to polynucleotides encoding the beta-glucosidase variants; nucleic acid constructs, vectors, and host cells comprising the polynucleotides; and methods of using the beta-glucosidase variants.

  15. An Obesity-Predisposing Variant of the FTO Gene Regulates D2R-Dependent Reward Learning.

    Science.gov (United States)

    Sevgi, Meltem; Rigoux, Lionel; Kühn, Anne B; Mauer, Jan; Schilbach, Leonhard; Hess, Martin E; Gruendler, Theo O J; Ullsperger, Markus; Stephan, Klaas Enno; Brüning, Jens C; Tittgemeyer, Marc

    2015-09-09

    Variations in the fat mass and obesity-associated (FTO) gene are linked to obesity. However, the underlying neurobiological mechanisms by which these genetic variants influence obesity, behavior, and brain are unknown. Given that Fto regulates D2/3R signaling in mice, we tested in humans whether variants in FTO would interact with a variant in the ANKK1 gene, which alters D2R signaling and is also associated with obesity. In a behavioral and fMRI study, we demonstrate that gene variants of FTO affect dopamine (D2)-dependent midbrain brain responses to reward learning and behavioral responses associated with learning from negative outcome in humans. Furthermore, dynamic causal modeling confirmed that FTO variants modulate the connectivity in a basic reward circuit of meso-striato-prefrontal regions, suggesting a mechanism by which genetic predisposition alters reward processing not only in obesity, but also in other disorders with altered D2R-dependent impulse control, such as addiction. Significance statement: Variations in the fat mass and obesity-associated (FTO) gene are associated with obesity. Here we demonstrate that variants of FTO affect dopamine-dependent midbrain brain responses and learning from negative outcomes in humans during a reward learning task. Furthermore, FTO variants modulate the connectivity in a basic reward circuit of meso-striato-prefrontal regions, suggesting a mechanism by which genetic vulnerability in reward processing can increase predisposition to obesity. Copyright © 2015 the authors 0270-6474/15/3512584-09$15.00/0.

  16. Westphal variant Huntington disease and refractory catatonia: a case report.

    Science.gov (United States)

    Merida-Puga, Jorge; Ramirez-Bermudez, Jesus; Aguilar-Venegas, Luis Carlos; Fricchione, Gregory L; Espinola-Nadurille, Mariana

    2011-12-01

    A young woman with Westphal variant (juvenile) Huntington disease (HD) also developed catatonia. Catatonia is an underdiagnosed psychomotor syndrome often associated with neurological and psychiatric disorders, but it has rarely been documented in patients with HD. Catatonia usually responds to standard treatment with benzodiazepines and electroconvulsive therapy; however, this patient's catatonic syndrome did not improve until we augmented the standard treatment with amantadine and levodopa. The underlying pathophysiology and a neurochemical hypothesis of HD and catatonia can explain their comorbidity and the refractoriness of catatonia to treatment. Both conditions are linked to dysregulation of neurotransmitters in the striatocortical and corticocortical pathways. This understanding may serve as a guide for the use of nonstandard treatments. Our evidence also suggests that electroconvulsive therapy can be useful and safe in the treatment of HD.

  17. Genetic mechanisms and age-related macular degeneration: common variants, rare variants, copy number variations, epigenetics, and mitochondrial genetics

    Directory of Open Access Journals (Sweden)

    Liu Melissa M

    2012-08-01

    Full Text Available Abstract Age-related macular degeneration (AMD is a complex and multifaceted disease involving contributions from both genetic and environmental influences. Previous work exploring the genetic contributions of AMD has implicated numerous genomic regions and a variety of candidate genes as modulators of AMD susceptibility. Nevertheless, much of this work has revolved around single-nucleotide polymorphisms (SNPs, and it is apparent that a significant portion of the heritability of AMD cannot be explained through these mechanisms. In this review, we consider the role of common variants, rare variants, copy number variations, epigenetics, microRNAs, and mitochondrial genetics in AMD. Copy number variations in regulators of complement activation genes (CFHR1 and CFHR3 and glutathione S transferase genes (GSTM1 and GSTT1 have been associated with AMD, and several additional loci have been identified as regions of potential interest but require further evaluation. MicroRNA dysregulation has been linked to the retinal pigment epithelium degeneration in geographic atrophy, ocular neovascularization, and oxidative stress, all of which are hallmarks in the pathogenesis of AMD. Certain mitochondrial DNA haplogroups and SNPs in mitochondrially encoded NADH dehydrogenase genes have also been associated with AMD. The role of these additional mechanisms remains only partly understood, but the importance of their further investigation is clear to elucidate more completely the genetic basis of AMD.

  18. Maisonneuve-hyperplantarflexion variant ankle fracture.

    Science.gov (United States)

    Hinds, Richard M; Tran, Wesley H; Lorich, Dean G

    2014-11-01

    Maisonneuve fractures are rare ankle injuries, accounting for up to 7% of all ankle fractures. They consist of a proximal third fibula fracture, syndesmotic disruption, and medial ankle injury (either a deltoid ligament disruption or a medial malleolus fracture), and are often successfully managed with nonoperative treatment of the proximal fibula fracture and open reduction and internal fixation (ORIF) of the medial ankle injury and syndesmotic disruption. The hyperplantarflexion variant ankle fracture comprises approximately 7% of all ankle fractures and features dual posterior tibial lip fractures featuring a posterolateral fragment and a posteromedial fragment. Good functional results have been reported in the literature after ORIF of both the posterolateral and posteromedial fragments of this variant fracture that is not described by the Lauge-Hansen classification. In this report, the authors present the unique case of an isolated ankle fracture demonstrating characteristics of both a Maisonneuve fracture and a hyperplantarflexion variant ankle fracture. They also highlight the diagnostic imaging characteristics, including magnetic resonance imaging (MRI) and preoperative radiograph findings, surgical treatment, and postoperative clinical outcome for this patient with a Maisonneuve-hyperplantarflexion variant ankle fracture. To the authors' knowledge, this unique fracture pattern has not been reported previously in the literature. The authors conclude that although good results were seen postoperatively in this case, the importance of ORIF of both the posteromedial and posterolateral fragments of variant fractures cannot be overstated. They also found MRI to be a particularly helpful adjunct in formulating the correct diagnosis and treatment plan.

  19. 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.

  20. Gastrointestinal stromal tumors, somatic mutations and candidate genetic risk variants.

    Science.gov (United States)

    O'Brien, Katie M; Orlow, Irene; Antonescu, Cristina R; Ballman, Karla; McCall, Linda; DeMatteo, Ronald; Engel, Lawrence S

    2013-01-01

    Gastrointestinal stromal tumors (GISTs) are rare but treatable soft tissue sarcomas. Nearly all GISTs have somatic mutations in either the KIT or PDGFRA gene, but there are no known inherited genetic risk factors. We assessed the relationship between KIT/PDGFRA mutations and select deletions or single nucleotide polymorphisms (SNPs) in 279 participants from a clinical trial of adjuvant imatinib mesylate. Given previous evidence that certain susceptibility loci and carcinogens are associated with characteristic mutations, or "signatures" in other cancers, we hypothesized that the characteristic somatic mutations in the KIT and PDGFRA genes in GIST tumors may similarly be mutational signatures that are causally linked to specific mutagens or susceptibility loci. As previous epidemiologic studies suggest environmental risk factors such as dioxin and radiation exposure may be linked to sarcomas, we chose 208 variants in 39 candidate genes related to DNA repair and dioxin metabolism or response. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association between each variant and 7 categories of tumor mutation using logistic regression. We also evaluated gene-level effects using the sequence kernel association test (SKAT). Although none of the association p-values were statistically significant after adjustment for multiple comparisons, SNPs in CYP1B1 were strongly associated with KIT exon 11 codon 557-8 deletions (OR = 1.9, 95% CI: 1.3-2.9 for rs2855658 and OR = 1.8, 95% CI: 1.2-2.7 for rs1056836) and wild type GISTs (OR = 2.7, 95% CI: 1.5-4.8 for rs1800440 and OR = 0.5, 95% CI: 0.3-0.9 for rs1056836). CYP1B1 was also associated with these mutations categories in the SKAT analysis (p = 0.002 and p = 0.003, respectively). Other potential risk variants included GSTM1, RAD23B and ERCC2. This preliminary analysis of inherited genetic risk factors for GIST offers some clues about the disease's genetic origins and

  1. Gastrointestinal stromal tumors, somatic mutations and candidate genetic risk variants.

    Directory of Open Access Journals (Sweden)

    Katie M O'Brien

    Full Text Available Gastrointestinal stromal tumors (GISTs are rare but treatable soft tissue sarcomas. Nearly all GISTs have somatic mutations in either the KIT or PDGFRA gene, but there are no known inherited genetic risk factors. We assessed the relationship between KIT/PDGFRA mutations and select deletions or single nucleotide polymorphisms (SNPs in 279 participants from a clinical trial of adjuvant imatinib mesylate. Given previous evidence that certain susceptibility loci and carcinogens are associated with characteristic mutations, or "signatures" in other cancers, we hypothesized that the characteristic somatic mutations in the KIT and PDGFRA genes in GIST tumors may similarly be mutational signatures that are causally linked to specific mutagens or susceptibility loci. As previous epidemiologic studies suggest environmental risk factors such as dioxin and radiation exposure may be linked to sarcomas, we chose 208 variants in 39 candidate genes related to DNA repair and dioxin metabolism or response. We calculated adjusted odds ratios (ORs and 95% confidence intervals (CIs for the association between each variant and 7 categories of tumor mutation using logistic regression. We also evaluated gene-level effects using the sequence kernel association test (SKAT. Although none of the association p-values were statistically significant after adjustment for multiple comparisons, SNPs in CYP1B1 were strongly associated with KIT exon 11 codon 557-8 deletions (OR = 1.9, 95% CI: 1.3-2.9 for rs2855658 and OR = 1.8, 95% CI: 1.2-2.7 for rs1056836 and wild type GISTs (OR = 2.7, 95% CI: 1.5-4.8 for rs1800440 and OR = 0.5, 95% CI: 0.3-0.9 for rs1056836. CYP1B1 was also associated with these mutations categories in the SKAT analysis (p = 0.002 and p = 0.003, respectively. Other potential risk variants included GSTM1, RAD23B and ERCC2. This preliminary analysis of inherited genetic risk factors for GIST offers some clues about the disease's genetic

  2. Linking open vocabularies

    CERN Document Server

    Greifender, Elke; Seadle, Michael

    2013-01-01

    Linked Data (LD), Linked Open Data (LOD) and generating a web of data, present the new knowledge sharing frontier. In a philosophical context, LD is an evolving environment that reflects humankinds' desire to understand the world by drawing on the latest technologies and capabilities of the time. LD, while seemingly a new phenomenon did not emerge overnight; rather it represents the natural progression by which knowledge structures are developed, used, and shared. Linked Open Vocabularies is a significant trajectory of LD. Linked Open Vocabularies targets vocabularies that have traditionally b

  3. Variants of Monteggia Type Injury: Case Reports

    Directory of Open Access Journals (Sweden)

    Kamudin NAF

    2015-03-01

    Full Text Available Background: Monteggia fracture-dislocation is rare in children. Various reports attest to its rarity, while recording the many variant of this injury. It is, therefore, easy to miss the diagnosis in the absence of proper clinical examination and radiographs. Case Report : This report highlights two rare variants of Monteggia fracture-dislocation seen in children. The first case was a 12-year old girl alleged to have fallen from a 15-feet tall tree and sustaining a combined type III Monteggia injury with ipsilateral Type II Salter-Harris injury of distal end radius with a metaphyseal fracture of the distal third of the ulna. The second case was a 13-year old who had sustained a closed fracture of atypical Type I Monteggia hybrid lesion, in a road traffic accident. Conclusion: This report highlights the rare variants of Monteggia fracture dislocation which could have been missed without proper clinical examinations and radiographs.

  4. Variants of Monteggia Type Injury: Case Reports

    Science.gov (United States)

    Firdouse, M; Han, CS; M Yusof, A

    2015-01-01

    Background Monteggia fracture-dislocation is rare in children. Various reports attest to its rarity, while recording the many variant of this injury. It is, therefore, easy to miss the diagnosis in the absence of proper clinical examination and radiographs. Case Report This report highlights two rare variants of Monteggia fracture-dislocation seen in children. The first case was a 12-year old girl alleged to have fallen from a 15- feet tall tree and sustaining a combined type III Monteggia injury with ipsilateral Type II Salter-Harris injury of distal end radius with a metaphyseal fracture of the distal third of the ulna. The second case was a 13-year old who had sustained a closed fracture of atypical Type I Monteggia hybrid lesion, in a road traffic accident. Conclusion This report highlights the rare variants of Monteggia fracture dislocation which could have been missed without proper clinical examinations and radiographs. PMID:28435591

  5. 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.

  6. A case of reninoma with variant angina

    Directory of Open Access Journals (Sweden)

    Hyung Ah Jo

    2014-06-01

    Full Text Available Reninoma is a tumor of the renal juxtaglomerular cell apparatus that causes hypertension and hypokalemia because of hypersecretion of renin. We present a case of a 29-year-old female patient with reninoma and concomitant variant angina. The patient had uncontrolled hypertension and elevated plasma renin activity and aldosterone levels. Imaging studies revealed a mass in the left kidney, which was further confirmed as a renin-producing lesion via selective venous catheterization. During the evaluation, the patient had acute-onset chest pain that was diagnosed as variant angina after a provocation test. After partial nephrectomy, the plasma renin activity and plasma aldosterone levels decreased and blood pressure normalized. We report a case of reninoma with variant angina.

  7. Hemoglobin variants: biochemical properties and clinical correlates.

    Science.gov (United States)

    Thom, Christopher S; Dickson, Claire F; Gell, David A; Weiss, Mitchell J

    2013-03-01

    Diseases affecting hemoglobin synthesis and function are extremely common worldwide. More than 1000 naturally occurring human hemoglobin variants with single amino acid substitutions throughout the molecule have been discovered, mainly through their clinical and/or laboratory manifestations. These variants alter hemoglobin structure and biochemical properties with physiological effects ranging from insignificant to severe. Studies of these mutations in patients and in the laboratory have produced a wealth of information on hemoglobin biochemistry and biology with significant implications for hematology practice. More generally, landmark studies of hemoglobin performed over the past 60 years have established important paradigms for the disciplines of structural biology, genetics, biochemistry, and medicine. Here we review the major classes of hemoglobin variants, emphasizing general concepts and illustrative examples.

  8. Allele Variants of Enterotoxigenic Escherichia coli Heat-Labile Toxin Are Globally Transmitted and Associated with Colonization Factors

    KAUST Repository

    Joffré, Enrique

    2015-01-15

    Enterotoxigenic Escherichia coli (ETEC) is a significant cause of morbidity and mortality in the developing world. ETEC-mediated diarrhea is orchestrated by heat-labile toxin (LT) and heat-stable toxins (STp and STh), acting in concert with a repertoire of more than 25 colonization factors (CFs). LT, the major virulence factor, induces fluid secretion after delivery of a monomeric ADP-ribosylase (LTA) and its pentameric carrier B subunit (LTB). A study of ETEC isolates from humans in Brazil reported the existence of natural LT variants. In the present study, analysis of predicted amino acid sequences showed that the LT amino acid polymorphisms are associated with a geographically and temporally diverse set of 192 clinical ETEC strains and identified 12 novel LT variants. Twenty distinct LT amino acid variants were observed in the globally distributed strains, and phylogenetic analysis showed these to be associated with different CF profiles. Notably, the most prevalent LT1 allele variants were correlated with major ETEC lineages expressing CS1 + CS3 or CS2 + CS3, and the most prevalent LT2 allele variants were correlated with major ETEC lineages expressing CS5 + CS6 or CFA/I. LTB allele variants generally exhibited more-stringent amino acid sequence conservation (2 substitutions identified) than LTA allele variants (22 substitutions identified). The functional impact of LT1 and LT2 polymorphisms on virulence was investigated by measuring total-toxin production, secretion, and stability using GM1-enzyme-linked immunosorbent assays (GM1-ELISA) and in silico protein modeling. Our data show that LT2 strains produce 5-fold more toxin than LT1 strains (P < 0.001), which may suggest greater virulence potential for this genetic variant. Our data suggest that functionally distinct LT-CF variants with increased fitness have persisted during the evolution of ETEC and have spread globally.

  9. Cryptanalysis of SIMON Variants with Connections

    DEFF Research Database (Denmark)

    Alizadeh, Javad; Alkhzaimi, Hoda A.; Aref, Mohammad Reza

    2014-01-01

    SIMON is a family of 10 lightweight block ciphers published by Beaulieu et al. from the United States National Security Agency (NSA). A cipher in this family with K-bit key and N-bit block is called SIMONN/K. We present several linear characteristics for reduced-round SIMON32/64 that can be used...... the presented observations do not directly yield an attack, but provide a basis for further analysis for the specific SIMON variant. Finally, we exploit a connection between linear and differential characteristics for SIMON to construct linear characteristics for different variants of reduced-round SIMON. Our...

  10. Histone variants and melanoma: facts and hypotheses.

    Science.gov (United States)

    Konstantinov, Nikifor K; Ulff-Møller, Constance J; Dimitrov, Stefan

    2016-07-01

    Melanoma is the most aggressive form of skin cancer with rising incidence and morbidity. Despite advances in treatment, the 10-yr survival for patients with metastatic disease is less than 10%. During the past few years, ongoing research on different epigenomic aberrations in melanoma has catalyzed better understanding of its pathogenesis and identification of new therapeutics. In our review, we will focus on the role of histone variants, key epigenetic players in melanoma initiation and progression. Specifically, incorporation of histone variants enables additional layers of chromatin structure, and here, we will describe how alterations in this epigenetic behavior impact melanoma.

  11. Variant profiling of evolving prokaryotic populations

    Directory of Open Access Journals (Sweden)

    Markus Zojer

    2017-02-01

    Full Text Available Genomic heterogeneity of bacterial species is observed and studied in experimental evolution experiments and clinical diagnostics, and occurs as micro-diversity of natural habitats. The challenge for genome research is to accurately capture this heterogeneity with the currently used short sequencing reads. Recent advances in NGS technologies improved the speed and coverage and thus allowed for deep sequencing of bacterial populations. This facilitates the quantitative assessment of genomic heterogeneity, including low frequency alleles or haplotypes. However, false positive variant predictions due to sequencing errors and mapping artifacts of short reads need to be prevented. We therefore created VarCap, a workflow for the reliable prediction of different types of variants even at low frequencies. In order to predict SNPs, InDels and structural variations, we evaluated the sensitivity and accuracy of different software tools using synthetic read data. The results suggested that the best sensitivity could be reached by a union of different tools, however at the price of increased false positives. We identified possible reasons for false predictions and used this knowledge to improve the accuracy by post-filtering the predicted variants according to properties such as frequency, coverage, genomic environment/localization and co-localization with other variants. We observed that best precision was achieved by using an intersection of at least two tools per variant. This resulted in the reliable prediction of variants above a minimum relative abundance of 2%. VarCap is designed for being routinely used within experimental evolution experiments or for clinical diagnostics. The detected variants are reported as frequencies within a VCF file and as a graphical overview of the distribution of the different variant/allele/haplotype frequencies. The source code of VarCap is available at https://github.com/ma2o/VarCap. In order to provide this workflow to

  12. Let's "Downscale" Linked Data

    NARCIS (Netherlands)

    Gueret, Christophe; de Boer, Victor; Schlobach, Stefan

    2014-01-01

    Open data policies and linked data publication are powerful tools for increasing transparency, participatory governance, and accountability. A closer look at linked data technologies, however, proves that their design and deployment exclude the majority of the world’s population. It will take small

  13. Typed links in Webvise

    DEFF Research Database (Denmark)

    1999-01-01

    We extended the Webvise open hypermedia system with support for typed links.  The ECDL'99 paper describes these extensions.......We extended the Webvise open hypermedia system with support for typed links.  The ECDL'99 paper describes these extensions....

  14. Katakana variants yield better English pronunciation : Japanese-naive native American English speakers' perception of vowel length as stress in the recognition of Japanese borrowed English

    OpenAIRE

    Anthony, Mark

    2003-01-01

    An experiment was made to determine whether native American English speakers perceive vowel length in Japanese borrowed English words as stress. Native speakers of American English were asked to identify spoken tokens of words of both Japanese borrowed English and Japanese variants in which the vowel length had been altered. Significantly more variants were identified, establishing a perceptual link between Japanese vowel length and English stress, although identification of vowel-length vari...

  15. Il progetto Linked Heritage

    Directory of Open Access Journals (Sweden)

    Marzia Piccininno

    2013-03-01

    Full Text Available ItLinked Heritage è uno dei progetti di punta finanziati dalla Commissione europea per alimentare Europeana, il portale dei contenuti culturali digitali europei. Linked Heritage raccoglie, sotto il coordinamento dell’ICCU, un consorzio molto vasto i cui partner provengono da quasi tutti i paesi dell’Unione più Russia e Israele; essi forniranno a Europeana ben 3 milioni di risorse digitali. Oltre al tema dell’aggregazione di contenuti culturali digitali, Linked Heritage sta esplorando altri temi fondamentali per Europeana come il multilinguismo, i linked data e il rapporto con possibili partner commerciali. Linked Heritage è l’ultimo in ordine di tempo di una serie di iniziative progettuali avviate da un consorzio europeo di istituzioni che opera insieme da oltre dieci anni nell’ambito del patrimonio culturale digitale.EnLinked Heritage is one of the flagship projects funded by the European commission to feed Europeana, the portal of the European digital cultural content. Linked Heritage has a very large partnership, coordinated by ICCU, whose members come from many European countries, Russia and Israel; they will supply Europeana with 3 million digital resources. Beyond the aggregation of digital cultural content, Linked Heritage is exploring other topics which are essential for Europeana, like multilingualism, linked data and the relationship with the commercial partners. Linked Heritage is the last one in time of a series of projects made up by a European consortium of institutions that has been working for over ten years in the field of digital cultural heritage.

  16. The current state of clinical interpretation of sequence variants.

    Science.gov (United States)

    Hoskinson, Derick C; Dubuc, Adrian M; Mason-Suares, Heather

    2017-01-31

    Accurate and consistent variant classification is required for Precision Medicine. But clinical variant classification remains in its infancy. While recent guidelines put forth jointly by the American College of Medical Genetics and Genomics (ACMG) and Association of Molecular Pathology (AMP) for the classification of Mendelian variants has advanced the field, the degree of subjectivity allowed by these guidelines can still lead to inconsistent classification across clinical molecular genetic laboratories. In addition, there are currently no such guidelines for somatic cancer variants, only published institutional practices. Additional variant classification guidelines, including disease- or gene-specific criteria, along with inter-laboratory data sharing is critical for accurate and consistent variant interpretation.

  17. Human SLC26A1 Gene Variants: A Pilot Study

    Directory of Open Access Journals (Sweden)

    Paul A. Dawson

    2013-01-01

    Full Text Available Kidney stones are a global health problem, incurring massive health costs annually. Why stones recur in many patients remains unknown but likely involves environmental, physiological, and genetic factors. The solute linked carrier (SLC 26A1 gene has previously been linked to kidney stones in mice. SLC26A1 encodes the sulfate anion transporter 1 (SAT1 protein, and its loss in mice leads to hyperoxaluria and calcium oxalate renal stones. To investigate the possible involvement of SAT1 in human urolithiasis, we screened the SLC26A1 gene in a cohort of 13 individuals with recurrent calcium oxalate urolithiasis, which is the commonest type. DNA sequence analyses showed missense mutations in seven patients: one individual was heterozygous R372H; 4 individuals were heterozygous Q556R; one patient was homozygous Q556R; and one patient with severe nephrocalcinosis (requiring nephrectomy was homozygous Q556R and heterozygous M132T. The M132 amino acid in human SAT1 is conserved with 15 other species and is located within the third transmembrane domain of the predicted SAT1 protein structure, suggesting that this amino acid may be important for SAT1 function. These initial findings demonstrate genetic variants in SLC26A1 of recurrent stone formers and warrant wider independent studies of SLC26A1 in humans with recurrent calcium oxalate stones.

  18. 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.

  19. Developing consistent pronunciation models for phonemic variants

    CSIR Research Space (South Africa)

    Davel, M

    2006-09-01

    Full Text Available from a lexicon containing variants. In this paper we (the authors) address both these issues by creating ‘pseudo-phonemes’ associated with sets of ‘generation restriction rules’ to model those pronunciations that are consistently realised as two or more...

  20. Mining Process Variants: Goals and Issues

    NARCIS (Netherlands)

    Li, C.; Reichert, M.U.; Wombacher, A.

    2008-01-01

    Recently, Process-Aware Information Systems (PAIS) were introduced, which allow for dynamic process and service changes. This, in turn, has led to a large number of process model variants, which are difficult to maintain and expensive to configure. This paper deals with goals and issues related to t

  1. Splicing variants of porcine synphilin-1

    DEFF Research Database (Denmark)

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

    2015-01-01

    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 (90...

  2. 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...

  3. 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.

  4. HLogo: a parallel Haskell variant of Netlogo

    NARCIS (Netherlands)

    N. Bezirgiannis (Nikolaos); Prasetya, I.S.W.B.; Sakellariou, I.

    2016-01-01

    textabstractAgent-based Modeling (ABM) has become quite popular to the simulation community for its usability and wide area of applicability. However, speed is not usually a trait that ABM tools are characterized of attaining. This paper presents HLogo, a parallel variant of the NetLogo ABM framewor

  5. PIN1 gene variants in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Siedlecki Janusz

    2009-11-01

    Full Text Available Abstract Background Peptidyl-prolyl isomerase, NIMA-interacting 1 (PIN1 plays a significant role in the brain and is implicated in numerous cellular processes related to Alzheimer's disease (AD and other neurodegenerative conditions. There are confounding results concerning PIN1 activity in AD brains. Also PIN1 genetic variation was inconsistently associated with AD risk. Methods We performed analysis of coding and promoter regions of PIN1 in early- and late-onset AD and frontotemporal dementia (FTD patients in comparison with healthy controls. Results Analysis of eighteen PIN1 common polymorphisms and their haplotypes in EOAD, LOAD and FTD individuals in comparison with the control group did not reveal their contribution to disease risk. In six unrelated familial AD patients four novel PIN1 sequence variants were detected. c.58+64C>T substitution that was identified in three patients, was located in an alternative exon. In silico analysis suggested that this variant highly increases a potential affinity for a splicing factor and introduces two intronic splicing enhancers. In the peripheral leukocytes of one living patient carrying the variant, a 2.82 fold decrease in PIN1 expression was observed. Conclusion Our data does not support the role of PIN1 common polymorphisms as AD risk factor. However, we suggest that the identified rare sequence variants could be directly connected with AD pathology, influencing PIN1 splicing and/or expression.

  6. 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

  7. Histone Variants in Development and Diseases

    Institute of Scientific and Technical Information of China (English)

    Ping Chen; Jicheng Zhao; Guohong Li

    2013-01-01

    Eukaryotic genomic DNA is highly packaged into chromatin by histones to fit inside the nucleus.Other than the bulk packaging role of canonical histones with an expression peak at S phase and replication-coupled deposition,different histone variants have evolved distinct regulatory mechanisms for their expression,deposition and functional implications.The diversity of histone variants results in structural plasticity of chromatin and highlights functionally distinct chromosomal domain,which plays critical roles in development from a fertilized egg into a complex organism,as well as in aging and diseases.However,the mechanisms of this fundamental process are poorly understood so far.It is of particular interest to investigate how the variants are incorporated into chromatin and mark specific chromatin states to regulate gene expression,and how they are involved in development and diseases.In this review,we focus on recent progress in studies of epigenetic regulation of three extensively investigated variants including H2A.Z,macroH2A and H3.3,and their functional implications in development and diseases.

  8. A compendium of genetic variant data

    DEFF Research Database (Denmark)

    Cardoso, Joao; Schöning, Lars Yannik; Herrgard, Markus

    2014-01-01

    Laboratory strains are genetically unstable if exposed to selective pressure as encountered, for example, during molecular cloning, fermentation, or adaptive laboratory evolution experiments. This genetic variation is the consequence of an adaptation process of the microorganism to stress...... obtained from distinct experiments. This compendium of genetic variant is a critical step to develop approaches to automatically and systematically characterize mutated strains in the future....

  9. SCN5A variant that blocks fibroblast growth factor homologous factor regulation causes human arrhythmia

    Science.gov (United States)

    Musa, Hassan; Kline, Crystal F.; Sturm, Amy C.; Murphy, Nathaniel; Adelman, Sara; Wang, Chaojian; Yan, Haidun; Johnson, Benjamin L.; Csepe, Thomas A.; Kilic, Ahmet; Higgins, Robert S. D.; Janssen, Paul M. L.; Fedorov, Vadim V.; Weiss, Raul; Salazar, Christina; Hund, Thomas J.; Pitt, Geoffrey S.; Mohler, Peter J.

    2015-01-01

    Nav channels are essential for metazoan membrane depolarization, and Nav channel dysfunction is directly linked with epilepsy, ataxia, pain, arrhythmia, myotonia, and irritable bowel syndrome. Human Nav channelopathies are primarily caused by variants that directly affect Nav channel permeability or gating. However, a new class of human Nav channelopathies has emerged based on channel variants that alter regulation by intracellular signaling or cytoskeletal proteins. Fibroblast growth factor homologous factors (FHFs) are a family of intracellular signaling proteins linked with Nav channel regulation in neurons and myocytes. However, to date, there is surprisingly little evidence linking Nav channel gene variants with FHFs and human disease. Here, we provide, to our knowledge, the first evidence that mutations in SCN5A (encodes primary cardiac Nav channel Nav1.5) that alter FHF binding result in human cardiovascular disease. We describe a five*generation kindred with a history of atrial and ventricular arrhythmias, cardiac arrest, and sudden cardiac death. Affected family members harbor a novel SCN5A variant resulting in p.H1849R. p.H1849R is localized in the central binding core on Nav1.5 for FHFs. Consistent with these data, Nav1.5 p.H1849R affected interaction with FHFs. Further, electrophysiological analysis identified Nav1.5 p.H1849R as a gain-of-function for INa by altering steady-state inactivation and slowing the rate of Nav1.5 inactivation. In line with these data and consistent with human cardiac phenotypes, myocytes expressing Nav1.5 p.H1849R displayed prolonged action potential duration and arrhythmogenic afterdepolarizations. Together, these findings identify a previously unexplored mechanism for human Nav channelopathy based on altered Nav1.5 association with FHF proteins. PMID:26392562

  10. Gene variants as risk factors for gastroschisis

    Science.gov (United States)

    Yang, Wei; Schultz, Kathleen; Tom, Lauren; Lin, Bin; Carmichael, Suzan L.; Lammer, Edward J.; Shaw, Gary M.

    2016-01-01

    In a population‐based case‐control study in California of 228 infants, we investigated 75 genetic variants in 20 genes and risk of gastroschisis with regard to maternal age, race/ethnicity, vitamin use, and smoking exposure. We hypothesized that genes related to vascular compromise may interact with environmental factors to affect the risk of gastroschisis. Haplotypes were constructed for 75 gene variants using the HaploView program. Risk for gastroschisis associated with each gene variant was calculated for both the homozygotes and the heterozygotes, with the homozygous wildtypes as the referent. Risks were estimated as odds ratios (ORs) with 95% confidence intervals (CIs) by logistic regression. We found 11 gene variants with increased risk and four variants with decreased risk of gastroschisis for heterozygous (ORh) or homozygous variants (ORv) genotypes. These included NOS3 (rs1036145) ORh = 0.4 (95% CI: 0.2–0.7); NOS3 (rs10277237) ORv = 2.7 (95% CI: 1.3–6.0); ADD1 (rs12503220) ORh = 2.9 (95% CI: 1.6–5.4), GNB3 (rs5443) ORh = 0.2 (95% CI: 0.1–0.5), ORv = 0.4 (95% CI: 0.2–0.9); ICAM1 (rs281428) ORv = 6.9 (95% CI: 2.1–22.9), ICAM1 (rs3093030) ORv = 2.6 (95% CI: 1.2–5.6); ICAM4 (rs281438) ORv = 4.9 (95% CI: 1.4–16.6), ICAM5 (rs281417) ORh = 2.1 (95% CI: 1.1–4.1), ORv = 4.8 (95% CI: 1.7–13.6); ICAM5 (rs281440) ORh = 23.7 (95% CI: 5.5–102.5), ORv = 20.6 (95% CI: 3.4–124.3); ICAM5 (rs2075741) ORv = 2.2 (95% CI: 1.1–4.4); NAT1 ORv = 0.3 (95% CI: 0.1–0.9). There were additional associations between several gene variants and gastroschisis among women aged 20–24 and among mothers with and without vitamin use. NOS3, ADD1, ICAM1, ICAM4, and ICAM5 warrant further investigation in additional populations and with the interaction of additional environmental exposures. © 2016 Wiley Periodicals, Inc. PMID:27616475

  11. Scalable Text and Link Analysis with Mixed-Topic Link Models

    CERN Document Server

    Zhu, Yaojia; Getoor, Lise; Moore, Cristopher

    2013-01-01

    Many data sets contain rich information about objects, as well as pairwise relations between them. For instance, in networks of websites, scientific papers, and other documents, each node has content consisting of a collection of words, as well as hyperlinks or citations to other nodes. In order to perform inference on such data sets, and make predictions and recommendations, it is useful to have models that are able to capture the processes which generate the text at each node and the links between them. In this paper, we combine classic ideas in topic modeling with a variant of the mixed-membership block model recently developed in the statistical physics community. The resulting model has the advantage that its parameters, including the mixture of topics of each document and the resulting overlapping communities, can be inferred with a simple and scalable expectation-maximization algorithm. We test our model on three data sets, performing unsupervised topic classification and link prediction. For both task...

  12. Elevated Oestrogen Receptor Splice Variant ERαΔ5 Expression in Tumour-adjacent Hormone-responsive Tissue

    Directory of Open Access Journals (Sweden)

    Pierre L. Martin-Hirsch

    2010-11-01

    Full Text Available Susceptibility to prostate or endometrial cancer is linked with obesity, a state of oestrogen excess. Oestrogen receptor (ER splice variants may be responsible for the tissue-level of ER activity. Such micro-environmental regulation may modulate cancer initiation and/or progression mechanisms. Real-time reverse transcriptase (RT polymerase chain reaction (PCR was used to quantitatively assess the levels of four ER splice variants (ERαΔ3, ERαΔ5, ERβ2 and ERβ5, plus the full-length parent isoforms ERα and ERβ1, in high-risk [tumour-adjacent prostate (n = 10 or endometrial cancer (n = 9] vs. low-risk [benign prostate (n = 12 or endometrium (n = 9], as well as a comparison of UK (n = 12 vs. Indian (n = 15 benign prostate. All three tissue groups expressed the ER splice variants at similar levels, apart from ERαΔ5. This splice variant was markedly raised in all of the tumour-adjacent prostate samples compared to benign tissues. Immunofluorescence analysis for ERβ2 in prostate tissue demonstrated that such splice variants are present in comparable, if not greater, amounts as the parent full-length isoform. This small pilot study demonstrates the ubiquitous nature of ER splice variants in these tissue sites and suggests that ERαΔ5 may be involved in progression of prostate adenocarcinoma.

  13. Spectrum and Prevalence of CALM1-, CALM2-, and CALM3-Encoded Calmodulin (CaM) Variants in Long QT Syndrome (LQTS) and Functional Characterization of a Novel LQTS-Associated CaM Missense Variant, E141G

    Science.gov (United States)

    Calvert, Melissa L.; Tester, David J.; Kryshtal, Dmytro; Hwang, Hyun Seok; Johnson, Christopher N.; Chazin, Walter J.; Loporcaro, Christina G.; Shah, Maully; Papez, Andrew L.; Lau, Yung R.; Kanter, Ronald; Knollmann, Bjorn C.; Ackerman, Michael J.

    2016-01-01

    Background Calmodulin (CaM) is encoded by three genes, CALM1, CALM2, and CALM3, all of which harbor pathogenic variants linked to long QT syndrome (LQTS) with early and severe expressivity. These LQTS-causative variants reduce CaM affinity to Ca2+ and alter the properties of the cardiac L-type calcium channel (CaV1.2). CaM also modulates NaV1.5 and the ryanodine receptor, RyR2. All of these interactions may play a role in disease pathogenesis. Here, we determine the spectrum and prevalence of pathogenic CaM variants in a cohort of genetically elusive LQTS, and functionally characterize the novel variants. Methods and Results Thirty-nine genetically elusive LQTS cases underwent whole exome sequencing to identify CaM variants. Non-synonymous CaM variants were overrepresented significantly in this heretofore LQTS cohort (15.4%) compared to exome aggregation consortium (0.04%; p<0.0001). When the clinical sequelae of these 6 CaM-positive cases was compared to the 33 CaM-negative cases, CaM-positive cases had a more severe phenotype with an average age of onset of 8 months, an average QTc of 679 ms, and a high prevalence of cardiac arrest. Functional characterization of one novel variant, E141G-CaM, revealed an 11-fold reduction in Ca2+ binding affinity and a functionally-dominant loss of inactivation in CaV1.2, mild accentuation in NaV1.5 late current, but no effect on intracellular RyR2-mediated calcium release. Conclusions Overall, 15% of our genetically elusive LQTS cohort harbored non-synonymous variants in CaM. Genetic testing of CALM1-3 should be pursued for individuals with LQTS, especially those with early childhood cardiac arrest, extreme QT prolongation, and a negative family history. PMID:26969752

  14. Regulatory element-based prediction identifies new susceptibility regulatory variants for osteoporosis.

    Science.gov (United States)

    Yao, Shi; Guo, Yan; Dong, Shan-Shan; Hao, Ruo-Han; Chen, Xiao-Feng; Chen, Yi-Xiao; Chen, Jia-Bin; Tian, Qing; Deng, Hong-Wen; Yang, Tie-Lin

    2017-08-01

    Despite genome-wide association studies (GWASs) have identified many susceptibility genes for osteoporosis, it still leaves a large part of missing heritability to be discovered. Integrating regulatory information and GWASs could offer new insights into the biological link between the susceptibility SNPs and osteoporosis. We generated five machine learning classifiers with osteoporosis-associated variants and regulatory features data. We gained the optimal classifier and predicted genome-wide SNPs to discover susceptibility regulatory variants. We further utilized Genetic Factors for Osteoporosis Consortium (GEFOS) and three in-house GWASs samples to validate the associations for predicted positive SNPs. The random forest classifier performed best among all machine learning methods with the F1 score of 0.8871. Using the optimized model, we predicted 37,584 candidate SNPs for osteoporosis. According to the meta-analysis results, a list of regulatory variants was significantly associated with osteoporosis after multiple testing corrections and contributed to the expression of known osteoporosis-associated protein-coding genes. In summary, combining GWASs and regulatory elements through machine learning could provide additional information for understanding the mechanism of osteoporosis. The regulatory variants we predicted will provide novel targets for etiology research and treatment of osteoporosis.

  15. Nonlinear model of space manipulator joint considering time-variant stiffness and backlash

    Science.gov (United States)

    Yang, Tianfu; Yan, Shaoze; Han, Zengyao

    2015-04-01

    Modeling of space manipulator joints has been studied for years but accurate positioning control is still unsatisfactory. One of the primary reasons is that, in the past researches, effects of the high-ratio reducers in the joints have usually been neglected. In this paper, a nonlinear dynamic model of the manipulator joint with planetary gear train transmission is developed by considering time-variant joint stiffness, backlash and reduction ratio. Based on the gear parameters and meshing phase relationship, the stiffness of the joint model is presented, in which the time-variant stiffness of 2K-H planetary gear train and the backlash are taken into consideration. The backlash effect is modeled as an alternate engagement mechanism, and the transmitted torque is defined as a dead zone function. This model is simulated on a two-link space manipulator system. The results show that the time-variant stiffness effect can be simplified as a constant value in most cases when other shafting parts are flexible, while if the total stiffness is approximate to the nonlinear stiffness, the positioning accuracy is reduced if neglecting the time-variant part. On the other hand, the backlash is the main source of positioning error and impact. Minimizing backlash is the most effective way to improve positioning accuracy and avoid the impact in the gearing system.

  16. Molecular characterization of a German variant of glucose-6-phosphate dehydrogenase deficiency (G6PD Aachen).

    Science.gov (United States)

    Efferth, T; Osieka, R; Beutler, E

    2000-02-01

    Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-chromosome-linked hereditary disorder. Clinically, patients with G6PD deficiency often present with drug- or food-induced hemolytic crises or neonatal jaundice. G6PD is involved in the generation of NADPH and reduced glutathione. In contrast to American, Mediterranean, and African ancestries, only few variants are known from Middle and Northern Europe. We describe the molecular characterization of a distinct variant from the northwestern area of Germany, G6PD Aachen. The sequence of the G6PD gene from three afflicted males was found to be hemizygous at cDNA residue 1089 for a C-->G mutation with a predicted amino acid change of Asn363Lys. The 1089 C-->G point mutation is unique, but produces the identical amino acid change found in a Mexican variant of G6PD deficiency, G6PD Loma Linda. This G6PD-deficient variant is caused by a 1089 C-->A mutation. The 363-amino-acid replacement is located outside a known mutation cluster region between amino acid residues 380 and 450, but may disrupt or weaken dimer interactions of G6PD enzyme subunits. Copyright 2000 Academic Press.

  17. A pooling-based approach to mapping genetic variants associated with DNA methylation.

    Science.gov (United States)

    Kaplow, Irene M; MacIsaac, Julia L; Mah, Sarah M; McEwen, Lisa M; Kobor, Michael S; Fraser, Hunter B

    2015-06-01

    DNA methylation is an epigenetic modification that plays a key role in gene regulation. Previous studies have investigated its genetic basis by mapping genetic variants that are associated with DNA methylation at specific sites, but these have been limited to microarrays that cover map of DNA methylation. Compared to methods that do not account for ASM, our approach increases statistical power to detect associations while sharply reducing cost, effort, and experimental variability. As a proof of concept, we generated deep sequencing data from a pool of 60 human cell lines; we evaluated almost twice as many CpGs as the largest microarray studies and identified more than 2000 genetic variants associated with DNA methylation. We found that these variants are highly enriched for associations with chromatin accessibility and CTCF binding but are less likely to be associated with traits indirectly linked to DNA, such as gene expression and disease phenotypes. In summary, our approach allows genome-wide mapping of genetic variants associated with DNA methylation in any tissue of any species, without the need for individual-level genotype or methylation data.

  18. Link to paper

    Data.gov (United States)

    U.S. Environmental Protection Agency — Link to the paper. This dataset is associated with the following publication: Naile, J., A.W. Garrison, J. Avants, and J. Washington. Isomers/enantiomers of...

  19. Latest Research: Genetic Links

    Science.gov (United States)

    ... Current Issue Past Issues Feature: Vision Latest Research: Genetic Links Past Issues / Summer 2008 Table of Contents ... inside the eye is a risk factor for glaucoma. Summer 2008 Issue: Volume 3 Number 3 Page ...

  20. Computational Analysis of Breast Cancer GWAS Loci Identifies the Putative Deleterious Effect of STXBP4 and ZNF404 Gene Variants.

    Science.gov (United States)

    Masoodi, Tariq Ahmad; Banaganapalli, Babajan; Vaidyanathan, Venkatesh; Talluri, Venkateswar R; Shaik, Noor A

    2017-04-19

    The genome-wide association studies (GWAS) have enabled us in identifying different breast cancer (BC) susceptibility loci. However, majority of these are non-coding variants with no annotated biological function. We investigated such 78 noncoding genome wide associated SNPs of BC and further expanded the list to 2,162 variants with strong linkage-disequilibrium (LD, r(2) ≥0.8). Using multiple publically available algorithms such as CADD, GWAVA, and FATHAMM, we classified all these variants into deleterious, damaging, or benign categories. Out of total 2,241 variants, 23 (1.02%) variants were extreme deleterious (rank 1), 70 (3.12%) variants were deleterious (rank 2), and 1,937 (86.43%) variants were benign (rank 3). The results show 14% of lead or associated variants are under strong negative selection (GERP++ RS ≥2), and ∼22% are under balancing selection (Tajima's D score >2) in CEU population of 1KGP-the regions being positively selected (GERP++ RS <0) in mammalian evolution. The expression quantitative trait loci of highest deleteriously ranked genes were tested on relevant adipose and breast tissues, the results of which were extended for protein expression on breast tissues. From the concordance analysis of ranking system of GWAVA, CADD, and FATHMM, eQTL and protein expression, we identified the deleterious SNPs localized in STXBP4 and ZNF404 genes which might play a role in BC development by dysregulating its gene expression. This simple approach will be easier to implement and to prioritize large scale GWAS data for variety of diseases and link to the potentially unrecognized functional roles of genes. J. Cell. Biochem. 9999: 1-12, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  1. Rare variant density across the genome and across populations

    OpenAIRE

    Raska Paola; Zhu Xiaofeng

    2011-01-01

    Abstract Next-generation sequencing allows for a new focus on rare variant density for conducting analyses of association to disease and for narrowing down the genomic regions that show evidence of functionality. In this study we use the 1000 Genomes Project pilot data as distributed by Genetic Analysis Workshop 17 to compare rare variant densities across seven populations. We made the comparisons using regressions of rare variants on total variant counts per gene for each population and Taji...

  2. Combined analyses of 20 common obesity susceptibility variants

    DEFF Research Database (Denmark)

    Sandholt, Camilla Helene; Sparsø, Thomas; Grarup, Niels;

    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....

  3. Surfactant Protein-D-Encoding Gene Variant Polymorphisms Are Linked to Respiratory Outcome in Premature Infants

    DEFF Research Database (Denmark)

    Sorensen, Grith Lykke; Dahl, Marianne; Tan, Qihua

    2014-01-01

    OBJECTIVE: Associations between the genetic variation within or downstream of the surfactant protein-D-encoding gene (SFTPD), which encodes the collectin surfactant protein-D (SP-D) and may lead to respiratory distress syndrome or bronchopulmonary dysplasia, recently were reported. Our aim was to...

  4. Processing of No-Release Variants in Connected Speech

    Science.gov (United States)

    LoCasto, Paul C.; Connine, Cynthia M.

    2011-01-01

    The cross modal repetition priming paradigm was used to investigate how potential lexically ambiguous no-release variants are processed. In particular we focus on segmental regularities that affect the variant's frequency of occurrence (voicing of the critical segment) and phonological context in which the variant occurs (status of the following…

  5. Rare ADH Variant Constellations are Specific for Alcohol Dependence

    OpenAIRE

    Zuo, Lingjun; Zhang, Heping; Malison, Robert T; Li, Chiang-shan R.; Zhang, Xiang-Yang; Wang, Fei; Lu, Lingeng; Lu, Lin; Wang, Xiaoping; Krystal, John H.; Zhang, Fengyu; Deng, Hong-Wen; Luo, Xingguang

    2012-01-01

    Aims: Some of the well-known functional alcohol dehydrogenase (ADH) gene variants (e.g. ADH1B*2, ADH1B*3 and ADH1C*2) that significantly affect the risk of alcohol dependence are rare variants in most populations. In the present study, we comprehensively examined the associations between rare ADH variants [minor allele frequency (MAF)

  6. GenOVa: a computer program to generate orientational variants

    OpenAIRE

    Cayron, Cyril

    2007-01-01

    A computer program called GenOVa, written in Python, calculates the orientational variants, the operators (special types of misorientations between variants) and the composition table associated with a groupoid structure. The variants can be represented by three-dimensional shapes or by pole figures.

  7. The power of multiplexed functional analysis of genetic variants.

    Science.gov (United States)

    Gasperini, Molly; Starita, Lea; Shendure, Jay

    2016-10-01

    New technologies have recently enabled saturation mutagenesis and functional analysis of nearly all possible variants of regulatory elements or proteins of interest in single experiments. Here we discuss the past, present, and future of such multiplexed (functional) assays for variant effects (MAVEs). MAVEs provide detailed insight into sequence-function relationships, and they may prove critical for the prospective clinical interpretation of genetic variants.

  8. Processing of No-Release Variants in Connected Speech

    Science.gov (United States)

    LoCasto, Paul C.; Connine, Cynthia M.

    2011-01-01

    The cross modal repetition priming paradigm was used to investigate how potential lexically ambiguous no-release variants are processed. In particular we focus on segmental regularities that affect the variant's frequency of occurrence (voicing of the critical segment) and phonological context in which the variant occurs (status of the following…

  9. Linked Ocean Data

    Science.gov (United States)

    Leadbetter, Adam; Arko, Robert; Chandler, Cynthia; Shepherd, Adam

    2014-05-01

    "Linked Data" is a term used in Computer Science to encapsulate a methodology for publishing data and metadata in a structured format so that links may be created and exploited between objects. Berners-Lee (2006) outlines the following four design principles of a Linked Data system: Use Uniform Resource Identifiers (URIs) as names for things. Use HyperText Transfer Protocol (HTTP) URIs so that people can look up those names. When someone looks up a URI, provide useful information, using the standards (Resource Description Framework [RDF] and the RDF query language [SPARQL]). Include links to other URIs so that they can discover more things. In 2010, Berners-Lee revisited his original design plan for Linked Data to encourage data owners along a path to "good Linked Data". This revision involved the creation of a five star rating system for Linked Data outlined below. One star: Available on the web (in any format). Two stars: Available as machine-readable structured data (e.g. An Excel spreadsheet instead of an image scan of a table). Three stars: As two stars plus the use of a non-proprietary format (e.g. Comma Separated Values instead of Excel). Four stars: As three stars plus the use of open standards from the World Wide Web Commission (W3C) (i.e. RDF and SPARQL) to identify things, so that people can point to your data and metadata. Five stars: All the above plus link your data to other people's data to provide context Here we present work building on the SeaDataNet common vocabularies served by the NERC Vocabulary Server, connecting projects such as the Rolling Deck to Repository (R2R) and the Biological and Chemical Oceanography Data Management Office (BCO-DMO) and other vocabularies such as the Marine Metadata Interoperability Ontology Register and Repository and the NASA Global Change Master Directory to create a Linked Ocean Data cloud. Publishing the vocabularies and metadata in standard RDF XML and exposing SPARQL endpoints renders them five-star Linked

  10. Wham: Identifying Structural Variants of Biological Consequence.

    Science.gov (United States)

    Kronenberg, Zev N; Osborne, Edward J; Cone, Kelsey R; Kennedy, Brett J; Domyan, Eric T; Shapiro, Michael D; Elde, Nels C; Yandell, Mark

    2015-12-01

    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/.

  11. Discussing and managing hematologic germ line variants.

    Science.gov (United States)

    Kohlmann, Wendy; Schiffman, Joshua D

    2016-11-24

    With the introduction of genomic technologies, more hereditary cancer syndromes with hematologic malignancies are being described. Up to 10% of hematologic malignancies in children and adults may be the result of an underlying inherited genetic risk. Managing these patients with hereditary hematologic malignancies, including familial leukemia, remains a clinical challenge because there is little information about these relatively rare disorders. This article covers some of the issues related to the diagnosis and interpretation of variants associated with hereditary hematologic malignancies, including the importance of an accurate family history in interpreting genetic variants associated with disease. The challenges of screening other family members and offering the most appropriate early malignancy detection is also discussed. We now have a good opportunity to better define hereditary cancer syndromes with associated hematologic malignancies and contribute to clinically effective guidelines.

  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. Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants.

    Directory of Open Access Journals (Sweden)

    Mengmeng Du

    Full Text Available Genome-wide association studies (GWAS have identified many common single nucleotide polymorphisms (SNPs associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs. We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33. We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s.

  14. Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants

    Science.gov (United States)

    Gala, Manish; Abecasis, Goncalo; Bezieau, Stephane; Brenner, Hermann; Butterbach, Katja; Caan, Bette J.; Carlson, Christopher S.; Casey, Graham; Chang-Claude, Jenny; Conti, David V.; Curtis, Keith R.; Duggan, David; Gallinger, Steven; Haile, Robert W.; Harrison, Tabitha A.; Hayes, Richard B.; Hoffmeister, Michael; Hopper, John L.; Hudson, Thomas J.; Jenkins, Mark A.; Küry, Sébastien; Le Marchand, Loic; Leal, Suzanne M.; Newcomb, Polly A.; Nickerson, Deborah A.; Potter, John D.; Schoen, Robert E.; Schumacher, Fredrick R.; Seminara, Daniela; Slattery, Martha L.; Hsu, Li; Chan, Andrew T.; White, Emily; Berndt, Sonja I.; Peters, Ulrike

    2016-01-01

    Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s). PMID:27379672

  15. Unusual variant of Cantrell′s pentalogy?

    Directory of Open Access Journals (Sweden)

    Kumar Basant

    2008-01-01

    Full Text Available A 12-hour-old male infant presented with prolapsed abdominal content through a defect on left side of chest wall with respiratory distress. A thorough clinical examination suggested absence of ectopia cordis, abdominal wall defect, and any bony anomaly. The child expired after 6 hours of admission because of respiratory distress and electrolyte imbalance. Is congenital defect of chest wall associated with diaphragmatic hernia without ectopia cordis and omphalocele, an unusual variant of Cantrell′s pentalogy?

  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. Small colony variants and their clinical significance

    Directory of Open Access Journals (Sweden)

    Venkataramana Venkataramana

    2016-01-01

    Full Text Available Among the many factors that contribute to bacterial colonization, persistence and development of infection, the ability of microorganisms to form small colony variants (SCVs assumes great significance. Although bacteria require intrinsic virulence factors to cause pathogenesis, some of them regularly evolve mechanisms to evade immune mechanisms, become resistant to antibiotics, and sustain in the human/animal cells to cause chronic infections. This mini review highlights the recent advances in the study of SCVs.

  18. Unusual variant of Cantrell′s pentalogy?

    OpenAIRE

    Kumar Basant; Sharma S.; Kandpal Deepak; Agrawal L

    2008-01-01

    A 12-hour-old male infant presented with prolapsed abdominal content through a defect on left side of chest wall with respiratory distress. A thorough clinical examination suggested absence of ectopia cordis, abdominal wall defect, and any bony anomaly. The child expired after 6 hours of admission because of respiratory distress and electrolyte imbalance. Is congenital defect of chest wall associated with diaphragmatic hernia without ectopia cordis and omphalocele, an unusual variant of Cantr...

  19. Frequency of the Hemochromatosis Gene (HFE Variants in a Jordanian Arab Population and in Diabetics from the Same Region

    Directory of Open Access Journals (Sweden)

    Asem Alkhateeb

    2009-01-01

    Full Text Available Hereditary HFE-linked hemochromatosis is a frequent recessive disorder among individuals of northern European ancestry. The clinical characteristic of this disease is the gradual accumulation of iron in internal organs, which ultimately may lead to organ damage and death. Three allelic variants of HFE gene have been correlated with hereditary hemochromatosis: C282Y is significantly associated with hereditary hemochromatosis in populations of Celtic origin, H63D and S65C are associated with milder form of iron overload. In this study we performed mutation analysis to identify allele frequency of the three variants of HFE gene in Jordanian Arab population, to assess deviations of these frequencies from those detected elsewhere, and to determine if there is an increased frequency of these variants in a diabetic population (Type 2 diabetes from the same area. DNA was extracted from blood samples of 440 individuals attending King Abdullah University Hospital for ambulatory services. We used polymerase chain reaction (PCR to amplify exons 2 and 4 of the HFE gene then restriction fragment length polymorphism (RFLP method to detect the variants. There were neither homozygous nor heterozygous for C282Y variant. For the H63D variant, 0.68% were homozygous and 21.1% were heterozygous. For the S65C variant, there were no homozygous and 0.23% were heterozygous. Allelic frequencies were, 0%, 11.25%, and 0.11% for C282Y, H63D, and S65C, respectively. Our samples were subdivided into two categories of type 2 diabetic (89 cases and controls (blood donors, 204 cases and compared with regard to the H63D variant. Both groups did not have homozygous H63D variant. H63D heterozygous in diabetics were 23.60% and in blood donor controls 22.55%. Allelic frequency of the mutant H63D allele was 11.80% in diabetics and 11.27% for the blood donor controls. This is the first study to show the frequency of the three hemochromatosis gene variants in Jordan with the interesting

  20. 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.

  1. Primary Aldosteronism and ARMC5 Variants

    Science.gov (United States)

    Zilbermint, Mihail; Xekouki, Paraskevi; Faucz, Fabio R.; Berthon, Annabel; Gkourogianni, Alexandra; Schernthaner-Reiter, Marie Helene; Batsis, Maria; Sinaii, Ninet; Quezado, Martha M.; Merino, Maria; Hodes, Aaron; Abraham, Smita B.; Libé, Rossella; Assié, Guillaume; Espiard, Stéphanie; Drougat, Ludivine; Ragazzon, Bruno; Davis, Adam; Gebreab, Samson Y.; Neff, Ryan; Kebebew, Electron; Bertherat, Jérôme; Lodish, Maya B.

    2015-01-01

    Context: Primary aldosteronism is one of the leading causes of secondary hypertension, causing significant morbidity and mortality. A number of genetic defects have recently been identified in primary aldosteronism, whereas we identified mutations in ARMC5, a tumor-suppressor gene, in cortisol-producing primary macronodular adrenal hyperplasia. Objective: We investigated a cohort of 56 patients who were referred to the National Institutes of Health for evaluation of primary aldosteronism for ARMC5 defects. Methods: Patients underwent step-wise diagnosis, with measurement of serum aldosterone and plasma renin activity followed by imaging, saline suppression and/or oral salt loading tests, plus adrenal venous sampling. Cortisol secretion was also evaluated; unilateral or bilateral adrenalectomy was performed, if indicated. DNA, protein, and transfection studies in H295R cells were conducted by standard methods. Results: We identified 12 germline ARMC5 genetic alterations in 20 unrelated and two related individuals in our cohort (39.3%). ARMC5 sequence changes in 6 patients (10.7%) were predicted to be damaging by in silico analysis. All affected patients carrying a variant predicted to be damaging were African Americans (P = .0023). Conclusions: Germline ARMC5 variants may be associated with primary aldosteronism. Additional cohorts of patients with primary aldosteronism and metabolic syndrome, particularly African Americans, should be screened for ARMC5 sequence variants because these may underlie part of the known increased predisposition of African Americans to low renin hypertension. PMID:25822102

  2. Warty Carcinoma Penis: An Uncommon Variant

    Science.gov (United States)

    Ghosh, Arnab; Shrestha, Santosh; Ghartimagar, Dilasma; Narasimhan, Raghavan; Talwar, OP

    2017-01-01

    Penile carcinoma frequency varies widely in different parts of the world and comprises 1–10% of all the malignancies in males. Majority of the cases of penile carcinoma are squamous cell carcinoma of penis comprising 60% to 70% of all cases. Warty carcinoma of penis is an unusual neoplasm and a variant of penile squamous cell carcinoma comprising 5%–10% of all the variants. The other histological variants include basaloid, verrucous, papillary, sarcomatous, mixed, and adenosquamous carcinoma. The various histological entities with an exophytic papillary lesions including warty carcinoma are together referred to as the “verruciform” group of neoplasms. The warty carcinoma has to be differentiated from these lesions and is typically distinguished by histological features of hyperkeratosis, arborescent papillomatosis, acanthosis, and prominent koilocytosis with nuclear pleomorphism. We present a case of 65-year-old male with growth measuring 6 × 4 cm in the penis who underwent total penectomy and was diagnosed as warty carcinoma penis. PMID:28154768

  3. Association of genetic variants with diabetic nephropathy.

    Science.gov (United States)

    Rizvi, Saliha; Raza, Syed Tasleem; Mahdi, Farzana

    2014-12-15

    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, eNOS, 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.

  4. Genetic variants associated with Crohn's disease

    Directory of Open Access Journals (Sweden)

    Michail S

    2013-07-01

    Full Text Available Sonia Michail,1 Gilberto Bultron,1 R William DePaolo2 1The University of Southern California, Children's Hospital of Los Angeles, Los Angeles, CA, USA; 2Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Abstract: Crohn's disease is an immune-related disorder characterized by inflammation of the gastrointestinal mucosa, which can occur in any area throughout the digestive tract. This life-long disease commonly presents with abdominal pain, diarrhea, vomiting, and weight loss. While the exact etiology of this disease is largely unknown, it is thought to arise from an interaction between microbial, immunological, and environmental factors in a genetically susceptible host, whereby the immune system attacks the intestine as it cross reacts against gut microbial antigens. The study of genetic variants associated with Crohn's disease has shed light on our understanding of disease pathophysiology. A large number of genetic variants identified in Crohn's disease are related to genes targeting microbial recognition and bacterial wall sensing, the most common being NOD2/CARD15 gene. This review will discuss the recent advance in our knowledge of genetic variants of this disease and how they influence the disease course and prognosis. Keywords: Crohn's disease, genetics, autophagy

  5. Adaptive beam forming for time-variant channels with a multi-beam antenna

    Institute of Scientific and Technical Information of China (English)

    JIANG Ze; MEI Yuan-yuan; RUAN Wei

    2008-01-01

    A multi-beam adaptive antenna is investigated by considering the adaptive beam forming performance for time-variant channels on the focus of mobile to base station or reverse link. This antenna is constructed by Fresnel zone phase-correcting plane (FZP) focusing element and uniformly spaced feeds array. An estimator for the beamforming weight vector in the presence of angle spreads is derived using a code filtering approach. Owing to the time-varying nature of the channels, a recursive method for computing and tracking the above optimal weight vector solution that is easy to implement is applied. The effects of angle spread, maximum Doppler frequency, and forgetting factor are studied. Simulation results showed that this type of adaptive antenna is capable of performing adaptive beam forming for time-variant channels effectively.

  6. The Serotonin Transporter Promoter Variant, Stress, and Attentional Biases in Middle Childhood.

    Science.gov (United States)

    Kotelnikova, Yuliya; LeMoult, Joelle; Mackrell, Sarah V M; Sheikh, Haroon I; Singh, Shiva M; Joormann, Jutta; Gotlib, Ian H; Hayden, Elizabeth P

    2016-09-01

    Although evidence suggests that 5-HTTLPR variants may shape risk for depression, the influence is likely complex, and involves effects on endophenotypes. We examined associations between 5-HTTLPR and biases in attention to affective stimuli in a sample of girls and a sample of both boys and girls. Children with at least one short (S) variant of the 5-HTTLPR polymorphism had lower positive attentional bias scores in both samples. This association was qualified by an interaction with stress in one sample, such that links between the S allele and decreased positive attentional bias was significant only when life stress was elevated. This difference in findings between the two samples was explained by sex differences in samples; the GXE interaction was significant only in boys. Findings are discussed in the context of sex differences in GXE.

  7. DIXDC1 Phosphorylation and Control of Dendritic Morphology Are Impaired by Rare Genetic Variants

    Directory of Open Access Journals (Sweden)

    Vickie Kwan

    2016-11-01

    Full Text Available The development of neural connectivity is essential for brain function, and disruption of this process is associated with autism spectrum disorders (ASDs. DIX domain containing 1 (DIXDC1 has previously been implicated in neurodevelopmental disorders, but its role in postnatal brain function remains unknown. Using a knockout mouse model, we determined that DIXDC1 is a regulator of excitatory neuron dendrite development and synapse function in the cortex. We discovered that MARK1, previously linked to ASDs, phosphorylates DIXDC1 to regulate dendrite and spine development through modulation of the cytoskeletal network in an isoform-specific manner. Finally, rare missense variants in DIXDC1 were identified in ASD patient cohorts via genetic sequencing. Interestingly, the variants inhibit DIXDC1 isoform 1 phosphorylation, causing impairment to dendrite and spine growth. These data reveal that DIXDC1 is a regulator of cortical dendrite and synaptic development and provide mechanistic insight into morphological defects associated with neurodevelopmental disorders.

  8. NF-κB and androgen receptor variant expression correlate with human BPH progression

    DEFF Research Database (Denmark)

    Austin, David C; Strand, Douglas W; Love, Harold L;

    2016-01-01

    BACKGROUND: Benign prostatic hyperplasia (BPH) is a common, chronic progressive disease. Inflammation is associated with prostatic enlargement and resistance to 5α-reductase inhibitor (5ARI) therapy. Activation of the nuclear factor-kappa B (NF-κB) pathway is linked to both inflammation and ligand......-independent prostate cancer progression. METHODS: NF-κB activation and androgen receptor variant (AR-V) expression were quantified in transition zone tissue samples from patients with a wide range of AUASS from incidental BPH in patients treated for low grade, localized peripheral zone prostate cancer to advanced......-V expression as well as cellular growth and differentiation were assessed. RESULTS: Canonical NF-κB signaling was found to be upregulated in late versus early stage BPH, and to be strongly associated with non-insulin dependent diabetes mellitus. Elevated expression of AR-variant 7 (AR-V7), but not other AR...

  9. 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...... to 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...

  10. 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

  11. String Variant Alias Extraction Method using Ensemble Learner

    Directory of Open Access Journals (Sweden)

    P.Selvaperumal

    2016-02-01

    Full Text Available String variant alias names are surnames which are string variant form of the primary name. Extracting string variant aliases are important in tasks such as information retrieval, information extraction, and name resolution etc. String variant alias extraction involves candidate alias name extraction and string variant alias validation. In this paper, string variant aliases are first extracted from the web and then using seven different string similarity metrics as features, candidate aliases are validated using ensemble classifier random forest. Experiments were conducted using string variant name-alias dataset containing name-alias data for 15 persons containing 30 name-alias pairs. Experimental results show that the proposed method outperforms other similar methods in terms of accuracy.

  12. Staphylococcus aureus isolates encode variant staphylococcal enterotoxin B proteins that are diverse in superantigenicity and lethality.

    Directory of Open Access Journals (Sweden)

    Petra L Kohler

    Full Text Available Staphylococcus aureus produces superantigens (SAgs that bind and cross-link T cells and APCs, leading to activation and proliferation of immune cells. SAgs bind to variable regions of the β-chains of T cell receptors (Vβ-TCRs, and each SAg binds a unique subset of Vβ-TCRs. This binding leads to massive cytokine production and can result in toxic shock syndrome (TSS. The most abundantly produced staphylococcal SAgs and the most common causes of staphylococcal TSS are TSS toxin-1 (TSST-1, and staphylococcal enterotoxins B and C (SEB and SEC, respectively. There are several characterized variants of humans SECs, designated SEC1-4, but only one variant of SEB has been described. Sequencing the seb genes from over 20 S. aureus isolates show there are at least five different alleles of seb, encoding forms of SEB with predicted amino acid substitutions outside of the predicted immune-cell binding regions of the SAgs. Examination of purified, variant SEBs indicates that these amino acid substitutions cause differences in proliferation of rabbit splenocytes in vitro. Additionally, the SEBs varied in lethality in a rabbit model of TSS. The SEBs were diverse in their abilities to cause proliferation of human peripheral blood mononuclear cells, and differed in their activation of subsets of T cells. A soluble, high-affinity Vβ-TCR, designed to neutralize the previously characterized variant of SEB (SEB1, was able to neutralize the variant SEBs, indicating that this high-affinity peptide may be useful in treating a variety of SEB-mediated illnesses.

  13. Low density lipoprotein receptor related protein 1 and 6 gene variants and ischaemic stroke risk.

    Science.gov (United States)

    Harriott, A M; Heckman, M G; Rayaprolu, S; Soto-Ortolaza, A I; Diehl, N N; Kanekiyo, T; Liu, C-C; Bu, G; Malik, R; Cole, J W; Meschia, J F; Ross, O A

    2015-08-01

    Low density lipoprotein receptor related proteins (LRPs) 1 and 6 have been implicated in cerebral ischaemia. In addition, genetic variation in LRP1 and LRP6 has been linked with various factors that are related to risk of ischaemic stroke. The aim of this study was to examine the association of LRP1 and LRP6 gene variants with risk of ischaemic stroke as part of the Ischemic Stroke Genetics Study (ISGS). A Caucasian series (434 stroke patients, 319 controls) and an African American series (161 stroke patients, 116 controls) were included. Fourteen LRP6 variants and three LRP1 variants were genotyped and assessed for association with ischaemic stroke. In the Caucasian series, significant associations with ischaemic stroke were observed for LRP6 rs2075241 [odds ratio (OR) 0.42, P = 0.023], rs2302685 (OR 0.44, P = 0.049), rs7975614 (OR 0.07, P = 0.017), rs10492120 (OR 0.62, P = 0.036) and rs10743980 (OR 0.66, P = 0.037). Risk of ischaemic stroke was significantly lower for carriers of any of these five protective LRP6 variants (24.0% of subjects) compared to non-carriers (OR 0.57, P = 0.003). The protective association for LRP6 rs2075241 was observed at a similar magnitude across ischaemic stroke subtypes, whilst the effects of rs23022685, rs10492120 and rs10743980 were most apparent for cardioembolic and large vessel stroke. In the African American series, LRP1 rs11172113 was associated with an increased risk of stroke (OR 1.89, P = 0.006). The results of our preliminary study provide evidence that LRP6 and LRP1 variants may be associated with risk of ischaemic stroke. Validation in larger studies is warranted. © 2015 EAN.

  14. Evaluation of the role of SNCA variants in survival without neurological disease.

    Directory of Open Access Journals (Sweden)

    Michael G Heckman

    Full Text Available BACKGROUND: A variety of definitions of successful aging have been proposed, many of which relate to longevity, freedom from disease and disability, or preservation of high physical and cognitive function. Many behavioral, biomedical, and psychological factors have been linked with these various measures of successful aging, however genetic predictors are less understood. Parkinson's disease (PD is an age-related neurodegenerative disorder, and variants in the α-synuclein gene (SNCA affect susceptibility to PD. This exploratory study examined whether SNCA variants may also promote successful aging as defined by survival without neurological disease. METHODS: We utilized 769 controls without neurological disease (Mean age: 79 years, Range: 33-99 years and examined the frequency of 20 different SNCA variants across age groups using logistic regression models. We also included 426 PD cases to assess the effect of these variants on PD risk. RESULTS: There was a significant decline in the proportion of carriers of the minor allele of rs10014396 as age increased (P = 0.021, from 30% in controls younger than 60 to 14% in controls 90 years of age or older. Findings were similar for rs3775439, where the proportion of carriers of the minor allele declined from 32% in controls less than 60 years old to 19% in those 90 or older (P = 0.025. A number of SNCA variants, not including rs10014396 or rs3775439, were significantly associated with susceptibility to PD. CONCLUSIONS: In addition to its documented roles in PD and α-synucleinopathies, our results suggest that SNCA has a role in survival free of neurological disease. Acknowledging that our findings would not have withstood correction for multiple testing, validation in an independent series of aged neurologically normal controls is needed.

  15. Links between DRD4, Executive Attention, and Alphabetic Skills in a Nonclinical Sample

    Science.gov (United States)

    Kegel, Cornelia A. T.; Bus, Adriana G.

    2013-01-01

    Background: The dopamine D4 receptor gene (DRD4) has been linked to attention deficit hyperactivity disorder (ADHD) and reading disorders. In this study, we examined whether diminished anticipatory dopamine cell firing--typical of the long variant of the DRD4 allele--is related to emergent and advanced alphabetic skills, and whether executive…

  16. Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study.

    Science.gov (United States)

    Ross, Owen A; Soto-Ortolaza, Alexandra I; Heckman, Michael G; Aasly, Jan O; Abahuni, Nadine; Annesi, Grazia; Bacon, Justin A; Bardien, Soraya; Bozi, Maria; Brice, Alexis; Brighina, Laura; Van Broeckhoven, Christine; Carr, Jonathan; Chartier-Harlin, Marie-Christine; Dardiotis, Efthimios; Dickson, Dennis W; Diehl, Nancy N; Elbaz, Alexis; Ferrarese, Carlo; Ferraris, Alessandro; Fiske, Brian; Gibson, J Mark; Gibson, Rachel; Hadjigeorgiou, Georgios M; Hattori, Nobutaka; Ioannidis, John P A; Jasinska-Myga, Barbara; Jeon, Beom S; Kim, Yun Joong; Klein, Christine; Kruger, Rejko; Kyratzi, Elli; Lesage, Suzanne; Lin, Chin-Hsien; Lynch, Timothy; Maraganore, Demetrius M; Mellick, George D; Mutez, Eugénie; Nilsson, Christer; Opala, Grzegorz; Park, Sung Sup; Puschmann, Andreas; Quattrone, Aldo; Sharma, Manu; Silburn, Peter A; Sohn, Young Ho; Stefanis, Leonidas; Tadic, Vera; Theuns, Jessie; Tomiyama, Hiroyuki; Uitti, Ryan J; Valente, Enza Maria; van de Loo, Simone; Vassilatis, Demetrios K; Vilariño-Güell, Carles; White, Linda R; Wirdefeldt, Karin; Wszolek, Zbigniew K; Wu, Ruey-Meei; Farrer, Matthew J

    2011-10-01

    Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility. LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0·5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants. 121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab-Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1·43, 95% CI 1·15-1·78; p=0·0012) and Asian individuals (A419V, 2·27, 1·35-3·83; p=0·0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab-Berber series (combined odds ratio 0·82, 0·72-0·94; p=0·0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1·73, 1·20-2·49; p=0·0026), but no association was noted for R1628P (0·62, 0·36-1·07; p=0·087). In the Arab-Berber series, Y2189C showed potential evidence of risk association with

  17. Links, Exchanges, Sharing.

    Science.gov (United States)

    Shearer, James

    1992-01-01

    Describes the international activities of the Thames Valley University's Department of Information Management, including formal academic links with overseas institutions, development of short courses for practitioners, discussion meetings, staff and student visits, and enrollment of international students. Topics addressed include personnel,…

  18. Response model parameter linking

    NARCIS (Netherlands)

    Barrett, Michelle Derbenwick

    2015-01-01

    With a few exceptions, the problem of linking item response model parameters from different item calibrations has been conceptualized as an instance of the problem of equating observed scores on different test forms. This thesis argues, however, that the use of item response models does not require

  19. Linking Literacy and Movement

    Science.gov (United States)

    Pica, Rae

    2010-01-01

    There are many links between literacy and movement. Movement and language are both forms of communication and self-expression. Rhythm is an essential component of both language and movement. While people may think of rhythm primarily in musical terms, there is a rhythm to words and sentences as well. Individuals develop an internal rhythm when…

  20. Linking place and mind

    DEFF Research Database (Denmark)

    Jensen, Marie Møller

    2016-01-01

    This paper investigates the salience of vernacular Tyneside forms on the basis of theories of enregisterment and exemplar processing. On one level, exemplar theory provides a psycholinguistic account of how the link between social value and linguistic features is possible. Conversely, integrating...

  1. Link Influence Entropy

    Science.gov (United States)

    Singh, Priti; Chakraborty, Abhishek; Manoj, B. S.

    2017-01-01

    In this paper we propose a new metric, Link Influence Entropy (LInE), which describes importance of each node based on the influence of each link present in a network. Influence of a link can neither be effectively estimated using betweenness centrality nor using degree based probability measures. The proposed LInE metric which provides an effective way to estimate the influence of a link in the network and incorporates this influence to identify nodal characteristics, performs better compared to degree based entropy. We found that LInE can differentiate various network types which degree-based or betweenness centrality based node influence metrics cannot. Our findings show that spatial wireless networks and regular grid networks, respectively, have lowest and highest LInE values. Finally, performance analysis of LInE is carried out on a real-world network as well as on a wireless mesh network testbed to study the influence of our metric as well as influence stability of nodes in dynamic networks.

  2. Secure Link Middleware

    Science.gov (United States)

    2008-08-01

    Secure Link middleware as specified by the circled ‘sld’, sld . Using a network traffic analyzer (e.g., tcpdump) at router bulldog and tiger, ARL...or nfs (remote accessing file systems) to be securely operated and used among networked computer systems without any bulldog (router3) bear (router2

  3. FTO genetic variants, dietary intake and body mass index: insights from 177 330 individuals

    Science.gov (United States)

    Qi, Qibin; Kilpeläinen, Tuomas O.; Downer, Mary K.; Tanaka, Toshiko; Smith, Caren E.; Sluijs, Ivonne; Sonestedt, Emily; Chu, Audrey Y.; Renström, Frida; Lin, Xiaochen; Ängquist, Lars H.; Huang, Jinyan; Liu, Zhonghua; Li, Yanping; Asif Ali, Muhammad; Xu, Min; Ahluwalia, Tarunveer Singh; Boer, Jolanda M.A.; Chen, Peng; Daimon, Makoto; Eriksson, Johan; Perola, Markus; Friedlander, Yechiel; Gao, Yu-Tang; Heppe, Denise H.M.; Holloway, John W.; Houston, Denise K.; Kanoni, Stavroula; Kim, Yu-Mi; Laaksonen, Maarit A.; Jääskeläinen, Tiina; Lee, Nanette R.; Lehtimäki, Terho; Lemaitre, Rozenn N.; Lu, Wei; Luben, Robert N.; Manichaikul, Ani; Männistö, Satu; Marques-Vidal, Pedro; Monda, Keri L.; Ngwa, Julius S.; Perusse, Louis; van Rooij, Frank J.A.; Xiang, Yong-Bing; Wen, Wanqing; Wojczynski, Mary K; Zhu, Jingwen; Borecki, Ingrid B.; Bouchard, Claude; Cai, Qiuyin; Cooper, Cyrus; Dedoussis, George V.; Deloukas, Panos; Ferrucci, Luigi; Forouhi, Nita G.; Hansen, Torben; Christiansen, Lene; Hofman, Albert; Johansson, Ingegerd; Jørgensen, Torben; Karasawa, Shigeru; Khaw, Kay-Tee; Kim, Mi-Kyung; Kristiansson, Kati; Li, Huaixing; Lin, Xu; Liu, Yongmei; Lohman, Kurt K.; Long, Jirong; Mikkilä, Vera; Mozaffarian, Dariush; North, Kari; Pedersen, Oluf; Raitakari, Olli; Rissanen, Harri; Tuomilehto, Jaakko; van der Schouw, Yvonne T.; Uitterlinden, André G.; Zillikens, M. Carola; Franco, Oscar H.; Shyong Tai, E.; Ou Shu, Xiao; Siscovick, David S.; Toft, Ulla; Verschuren, W.M. Monique; Vollenweider, Peter; Wareham, Nicholas J.; Witteman, Jacqueline C.M.; Zheng, Wei; Ridker, Paul M.; Kang, Jae H.; Liang, Liming; Jensen, Majken K.; Curhan, Gary C.; Pasquale, Louis R.; Hunter, David J.; Mohlke, Karen L.; Uusitupa, Matti; Cupples, L. Adrienne; Rankinen, Tuomo; Orho-Melander, Marju; Wang, Tao; Chasman, Daniel I.; Franks, Paul W.; Sørensen, Thorkild I.A.; Hu, Frank B.; Loos, Ruth J. F.; Nettleton, Jennifer A.; Qi, Lu

    2014-01-01

    FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177 330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m2, P = 1.9 × 10−105), and all participants (0.30 [0.30, 0.35] kg/m2, P = 3.6 × 10−107). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10−16), and relative weak associations with lower total energy intake (−6.4 [−10.1, −2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (−0.07 [−0.11, −0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10−9) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity. PMID:25104851

  4. Prions in the urine of patients with variant Creutzfeldt-Jakob disease.

    Science.gov (United States)

    Moda, Fabio; Gambetti, Pierluigi; Notari, Silvio; Concha-Marambio, Luis; Catania, Marcella; Park, Kyung-Won; Maderna, Emanuela; Suardi, Silvia; Haïk, Stéphane; Brandel, Jean-Philippe; Ironside, James; Knight, Richard; Tagliavini, Fabrizio; Soto, Claudio

    2014-08-07

    Prions, the infectious agents responsible for transmissible spongiform encephalopathies, consist mainly of the misfolded prion protein (PrP(Sc)). The unique mechanism of transmission and the appearance of a variant form of Creutzfeldt-Jakob disease, which has been linked to consumption of prion-contaminated cattle meat, have raised concerns about public health. Evidence suggests that variant Creutzfeldt-Jakob disease prions circulate in body fluids from people in whom the disease is silently incubating. To investigate whether PrP(Sc) can be detected in the urine of patients with variant Creutzfeldt-Jakob disease, we used the protein misfolding cyclic amplification (PMCA) technique to amplify minute quantities of PrP(Sc), enabling highly sensitive detection of the protein. We analyzed urine samples from several patients with various transmissible spongiform encephalopathies (variant and sporadic Creutzfeldt-Jakob disease and genetic forms of prion disease), patients with other degenerative or nondegenerative neurologic disorders, and healthy persons. PrP(Sc) was detectable only in the urine of patients with variant Creutzfeldt-Jakob disease and had the typical electrophoretic profile associated with this disease. PrP(Sc) was detected in 13 of 14 urine samples obtained from patients with variant Creutzfeldt-Jakob disease and in none of the 224 urine samples obtained from patients with other neurologic diseases and from healthy controls, resulting in an estimated sensitivity of 92.9% (95% confidence interval [CI], 66.1 to 99.8) and a specificity of 100.0% (95% CI, 98.4 to 100.0). The PrP(Sc) concentration in urine calculated by means of quantitative PMCA was estimated at 1×10(-16) g per milliliter, or 3×10(-21) mol per milliliter, which extrapolates to approximately 40 to 100 oligomeric particles of PrP(Sc) per milliliter of urine. Urine samples obtained from patients with variant Creutzfeldt-Jakob disease contained minute quantities of PrP(Sc). (Funded by the

  5. Prions in the Urine of Patients with Variant Creutzfeldt–Jakob Disease

    Science.gov (United States)

    Moda, Fabio; Gambetti, Pierluigi; Notari, Silvio; Concha-Marambio, Luis; Catania, Marcella; Park, Kyung-Won; Maderna, Emanuela; Suardi, Silvia; Haïk, Stéphane; Brandel, Jean-Philippe; Ironside, James; Knight, Richard; Tagliavini, Fabrizio; Soto, Claudio

    2014-01-01

    BACKGROUND Prions, the infectious agents responsible for transmissible spongiform encephalopathies, consist mainly of the misfolded prion protein (PrPSc). The unique mechanism of transmission and the appearance of a variant form of Creutzfeldt–Jakob disease, which has been linked to consumption of prion-contaminated cattle meat, have raised concerns about public health. Evidence suggests that variant Creutzfeldt–Jakob disease prions circulate in body fluids from people in whom the disease is silently incubating. METHODS To investigate whether PrPSc can be detected in the urine of patients with variant Creutzfeldt–Jakob disease, we used the protein misfolding cyclic amplification (PMCA) technique to amplify minute quantities of PrPSc, enabling highly sensitive detection of the protein. We analyzed urine samples from several patients with various transmissible spongiform encephalopathies (variant and sporadic Creutzfeldt–Jakob disease and genetic forms of prion disease), patients with other degenerative or nondegenerative neurologic disorders, and healthy persons. RESULTS PrPSc was detectable only in the urine of patients with variant Creutzfeldt–Jakob disease and had the typical electrophoretic profile associated with this disease. PrPSc was detected in 13 of 14 urine samples obtained from patients with variant Creutzfeldt–Jakob disease and in none of the 224 urine samples obtained from patients with other neurologic diseases and from healthy controls, resulting in an estimated sensitivity of 92.9% (95% confidence interval [CI], 66.1 to 99.8) and a specificity of 100.0% (95% CI, 98.4 to 100.0). The PrPSc concentration in urine calculated by means of quantitative PMCA was estimated at 1×10−16 g per milliliter, or 3×10−21 mol per milliliter, which extrapolates to approximately 40 to 100 oligomeric particles of PrPSc per milliliter of urine. CONCLUSIONS Urine samples obtained from patients with variant Creutzfeldt–Jakob disease contained minute

  6. Obesity-linked diabetes in the Arab world: a review.

    Science.gov (United States)

    Abuyassin, B; Laher, I

    2015-09-08

    The Arab world is experiencing an epidemic of obesity and type 2 diabetes mellitus. This review summarizes the major pathological factors linking obesity to diabetes, focussing on current epidemiological data related to obese diabetic patients in the Arab world, the etiology of the disease and the genetic determinants of diabetes and obesity. There are alarming data related to the rising prevalence of obesity and type 2 diabetes mellitus in children of Arab ethnicity. Replication studies identify several genetic variants in Arabs with obesitylinked diabetes. For example, variants of the ADIPOQ gene (the rs266729 single-nucleotide polymorphism) are associated with obesity and diabetes in various Arab countries. Gaps exist in our information about diabetes and obesity in Arab populations in relation to ethnic-specific cut-off points for diagnosis and treatment of diabetes. Further genome-wide association studies in obese and diabetic Arab populations could add to our understanding of the pathophysiology, prevention and reversal of this disease.

  7. A new variant selection criterion for twin variants in titanium alloys. Pt. 2

    Energy Technology Data Exchange (ETDEWEB)

    Schuman, Christophe [Laboratoire d' Etude des Microstructures et de Mecanique des Materiaux, LEM3, CNRS 7239, Universite Paul Verlaine - Metz, Ile du Saulcy, Metz (France); Bao, Lei; Lecomte, Jean Sebastien; Zhang, Yudong; Raulot, Jean Marc; Philippe, Marie Jeanne; Esling, Claude [LEM3, CNRS 7239, Universite Paul Verlaine - Metz, Ile du Saulcy, Metz (France)

    2012-05-15

    A new selection criterion to explain the activation of the twinning variant is proposed. This criterion is based on the calculation of the deformation energy to create a primary twin. The calculation takes into account the effect of the grain size using a Hall-Petch type relation. This criterion allows to obtain a very good prediction for the twin family selection and twin variant selection. The calculations are compared with the experimental results obtained on T40 (ASTM grade 2) deformed by Channel Die compression. (Copyright copyright 2012 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

  8. The rs3857059 variant of the SNCA gene is associated with Parkinson’s disease in Mexican Mestizos

    Directory of Open Access Journals (Sweden)

    S. García

    2016-06-01

    Full Text Available ABSTRACT Among the candidate genes for Parkinson’s disease (PD, SNCA has replicated association in different populations. Besides other known mutations in the SNCA gene, the rs3857059 variant has also been linked to various neurodegenerative disorders. Therefore, the aim of the present study was to search for association of this variant and sporadic PD in Mexican Mestizo patients. A case-control study was performed including 241 individuals, 106 patients, and 135 healthy controls. Genotyping was performed using real-time PCR. The rs3857059 variant demonstrated an association with PD in Mexican Mestizos (OR = 2.40, CI, 1.1 to 5.1, p = 0.02 under the recessive model. In addition, a gender effect was found for the GG genotype in females (OR = 1.31, CI, 1.01 to 1.7, p = 0.037. This is the first study to confirm an association of the rs3857059 variant with PD and also to show a gender effect. Our data contribute to the elucidation of the link between rs3857059 and susceptibility to PD observed in the Mexican Mestizo population.

  9. Identification of a variant antigenic neutralizing epitope in hypervariable region 1 of avian leukosis virus subgroup J.

    Science.gov (United States)

    Hou, Minbo; Zhou, Defang; Li, Gen; Guo, Huijun; Liu, Jianzhu; Wang, Guihua; Zheng, Qiankun; Cheng, Ziqiang

    2016-03-08

    Avian leukosis virus subgroup J (ALV-J) is a hypervariable oncogenic retrovirus that causes great economic loss in poultry. Antigenic variations in the variable regions make the development of an effective vaccine a challenging task. In the present study, we identified a variant antigenic neutralizing epitope using reverse vaccinology methods. First, we predicted the B-cell epitopes in gp85 gene of ALV-J strains by DNAman and bioinformatics. Fourteen candidate epitopes were selected and linked in tandem with glycines or serines as a multi-epitope gene. The expressed protein of multi-epitope gene can induce high-titer antibody that can recognize nature ALV-J and neutralize the infectivity of ALV-J strains. Next, we identified a high effective epitope using eight overlapping fragments of gp85 gene reacting with mAb 2D5 and anti-multi-epitope sera. The identified epitope contained one of the predicted epitopes and localized in hyervariable region 1 (hr1), indicating a variant epitope. To better understand if the variants of the epitope have a good antigenicity, we synthesized four variants to react with mAb 2D5 and anti-ALV-J sera. The result showed that all variants could react with the two kinds of antibodies though they showed different antigenicity, while could not react with ALV-J negative sera. Thus, the variant antigenic neutralizing epitope was determined as 137-LRDFIA/E/TKWKS/GDDL/HLIRPYVNQS-158. The result shows a potential use of this variant epitopes as a novel multi-epitope vaccine against ALV-J in poultry.

  10. Oligomeric α-synuclein and β-amyloid variants as potential biomarkers for Parkinson's and Alzheimer's diseases.

    Science.gov (United States)

    Williams, Stephanie M; Schulz, Philip; Sierks, Michael R

    2016-01-01

    Oligomeric forms of α-synuclein and β-amyloid are toxic protein variants that are thought to contribute to the onset and progression of Parkinson's disease (PD) and Alzheimer's disease (AD), respectively. The detection of toxic variants in human cerebrospinal fluid (CSF) and blood has great promise for facilitating early and accurate diagnoses of these devastating diseases. Two hurdles that have impeded the use of these protein variants as biomarkers are the availability of reagents that can bind the different variants and a sensitive assay to detect their very low concentrations. We previously isolated antibody-based reagents that selectively bind two different oligomeric variants of α-synuclein and two of β-amyloid, and developed a phage-based capture enzyme-linked immunosorbent assay (ELISA) with subfemtomolar sensitivity to quantify their presence. Here, we used these reagents to show that these oligomeric α-synuclein variants are preferentially present in PD brain tissue, CSF and serum, and that the oligomeric β-amyloid variants are preferentially present in AD brain tissue, CSF, and serum. Some AD samples also had α-synuclein pathology and some PD samples also had β-amyloid pathology, and, very intriguingly, these PD cases also had a history of dementia. Detection of different oligomeric α-synuclein and β-amyloid species is an effective method for identifying tissue, CSF and sera from PD and AD samples, respectively, and samples that also contained early stages of other protein pathologies, indicating their potential value as blood-based biomarkers for neurodegenerative diseases.

  11. Expression screening of bacterial libraries of recombinant alpha-1 proteinase inhibitor variants for candidates with thrombin inhibitory capacity.

    Science.gov (United States)

    Bhakta, Varsha; Gierczak, Richard F; Sheffield, William P

    2013-12-01

    Exhaustive mutagenesis studies of the reactive centre loop (RCL), a key structural component of proteins belonging to the serpin superfamily of protease inhibitors, are complicated by the size of the RCL, serpin conformational complexity, and, for most serpins, the lack of a serpin-dependent phenotype of expressing cells. Here, we describe a thrombin capture assay that distinguished thrombin-inhibitory recombinant human alpha-1 proteinase inhibitor (API M358R) from non-inhibitory API variants in Escherichia coli lysates prepared from either single clones or pools. Binding of API proteins in the lysates to thrombin immobilized on microtiter plate wells was quantified via colour generated by a peroxidase-coupled anti-API antibody. Bacterial expression plasmids encoding inhibitory API M358R were mixed 1:99 with plasmids encoding non-inhibitory API T345R/M358R and the resulting library screened in pools of 10. All above-background signals arising from pools or subsequently re-probed single clones were linked to the presence of plasmids encoding API M358R. Screening of a portion of another expression library encoding hypervariable API with all possibilities at codons 352-358 also yielded only novel, thrombin-inhibitory variants. Probing a smaller library expressing all possible codons at Ala347 yielded the wild type, 6 different functional variants, one partially active variant, and two variants with no thrombin-inhibitory activity. API antigen levels varied considerably less among Ala347 variants than activity levels, and comparison of rate constants of inhibition of purified API variants to their corresponding thrombin capture assay lysate values was used to establish the sensitivity and specificity of the assay. The results indicate that the approach is sufficiently robust to correctly identify functional versus non-functional candidates in API expression libraries, and could be of value in systematically probing structure/function relationships not only in the API

  12. Characterization of 2 genetic variants of Na(v) 1.5-arginine 689 found in patients with cardiac arrhythmias.

    Science.gov (United States)

    Sottas, Valentin; Rougier, Jean-Sébastien; Jousset, Florian; Kucera, Jan P; Shestak, Anna; Makarov, Leonid M; Zaklyazminskaya, Elena V; Abriel, Hugues

    2013-09-01

    Hundreds of genetic variants in SCN5A, the gene coding for the pore-forming subunit of the cardiac sodium channel, Na(v) 1.5, have been described in patients with cardiac channelopathies as well as in individuals from control cohorts. The aim of this study was to characterize the biophysical properties of 2 naturally occurring Na(v) 1.5 variants, p.R689H and p.R689C, found in patients with cardiac arrhythmias and in control individuals. In addition, this study was motivated by the finding of the variant p.R689H in a family with sudden cardiac death (SCD) in children. When expressed in HEK293 cells, most of the sodium current (I(Na)) biophysical properties of both variants were indistinguishable from the wild-type (WT) channels. In both cases, however, an ∼2-fold increase of the tetrodotoxin-sensitive late I(Na) was observed. Action potential simulations and reconstruction of pseudo-ECGs demonstrated that such a subtle increase in the late I(Na) may prolong the QT interval in a nonlinear fashion. In conclusion, despite the fact that the causality link between p.R689H and the phenotype of the studied family cannot be demonstrated, this study supports the notion that subtle alterations of Na(v) 1.5 variants may increase the risk for cardiac arrhythmias.

  13. PGC1α -1 Nucleosome Position and Splice Variant Expression and Cardiovascular Disease Risk in Overweight and Obese Individuals.

    Science.gov (United States)

    Henagan, Tara M; Stewart, Laura K; Forney, Laura A; Sparks, Lauren M; Johannsen, Neil; Church, Timothy S

    2014-01-01

    PGC1α, a transcriptional coactivator, interacts with PPARs and others to regulate skeletal muscle metabolism. PGC1α undergoes splicing to produce several mRNA variants, with the NTPGC1α variant having a similar biological function to the full length PGC1α (FLPGC1α). CVD is associated with obesity and T2D and a lower percentage of type 1 oxidative fibers and impaired mitochondrial function in skeletal muscle, characteristics determined by PGC1α expression. PGC1α expression is epigenetically regulated in skeletal muscle to determine mitochondrial adaptations, and epigenetic modifications may regulate mRNA splicing. We report in this paper that skeletal muscle PGC1α  -1 nucleosome (-1N) position is associated with splice variant NTPGC1α but not FLPGC1α expression. Division of participants based on the -1N position revealed that those individuals with a -1N phased further upstream from the transcriptional start site (UP) expressed lower levels of NTPGC1α than those with the -1N more proximal to TSS (DN). UP showed an increase in body fat percentage and serum total and LDL cholesterol. These findings suggest that the -1N may be a potential epigenetic regulator of NTPGC1α splice variant expression, and -1N position and NTPGC1α variant expression in skeletal muscle are linked to CVD risk. This trial is registered with clinicaltrials.gov, identifier NCT00458133.

  14. PGC1α −1 Nucleosome Position and Splice Variant Expression and Cardiovascular Disease Risk in Overweight and Obese Individuals

    Directory of Open Access Journals (Sweden)

    Tara M. Henagan

    2014-01-01

    Full Text Available PGC1α, a transcriptional coactivator, interacts with PPARs and others to regulate skeletal muscle metabolism. PGC1α undergoes splicing to produce several mRNA variants, with the NTPGC1α variant having a similar biological function to the full length PGC1α (FLPGC1α. CVD is associated with obesity and T2D and a lower percentage of type 1 oxidative fibers and impaired mitochondrial function in skeletal muscle, characteristics determined by PGC1α expression. PGC1α expression is epigenetically regulated in skeletal muscle to determine mitochondrial adaptations, and epigenetic modifications may regulate mRNA splicing. We report in this paper that skeletal muscle PGC1α  −1 nucleosome (−1N position is associated with splice variant NTPGC1α but not FLPGC1α expression. Division of participants based on the −1N position revealed that those individuals with a −1N phased further upstream from the transcriptional start site (UP expressed lower levels of NTPGC1α than those with the −1N more proximal to TSS (DN. UP showed an increase in body fat percentage and serum total and LDL cholesterol. These findings suggest that the −1N may be a potential epigenetic regulator of NTPGC1α splice variant expression, and −1N position and NTPGC1α variant expression in skeletal muscle are linked to CVD risk. This trial is registered with clinicaltrials.gov, identifier NCT00458133.

  15. Lactase persistence variants in Arabia and in the African Arabs.

    Science.gov (United States)

    Priehodová, Edita; Abdelsawy, Abdelhay; Heyer, Evelyne; Cerný, Viktor

    2014-01-01

    Lactase persistence (LP), the state enabling the digestion of milk sugar in adulthood, occurs only in some human populations. The convergent and independent origin of this physiological ability in Europe and Africa is linked with animal domestication that either had started in both places independently or had spread from the Near East by acculturation. However, it has recently been shown that at least in its southern parts, the population of Arabia not only has a different LP-associated mutation profile than the rest of Africa and Europe but also had experienced an independent demographic expansion occurring before the Neolithic around the Pleistocene-Holocene boundary. In Arabia, LP is associated with mutation -13,915*G and not, as in Europe, with -13,910*T or, as in Africa, with -13,907*G and -14,010*C. We show here that, in Arabia, -13,915*G frequency conforms to a partial clinal pattern and that this specific mutation has likely been spread from Arabia to Africa only recently from the sixth century AD onward by nomadic Arabs (Bedouins) looking for new pastures. Arabic populations in Africa that still maintain a nomadic way of life also have more -13,915*G variants and fewer sub-Saharan L-type mitochondrial DNA haplogroups; this observation matches archaeological and historical records suggesting that the migration of Arabic pastoralists was accompanied by gradual sedentarization that allowed for admixture with the local African population.

  16. Loss aversion and 5HTT gene variants in adolescent anxiety

    Directory of Open Access Journals (Sweden)

    Monique Ernst

    2014-04-01

    Full Text Available Loss aversion, a well-documented behavioral phenomenon, characterizes decisions under risk in adult populations. As such, loss aversion may provide a reliable measure of risky behavior. Surprisingly, little is known about loss aversion in adolescents, a group who manifests risk-taking behavior, or in anxiety disorders, which are associated with risk-avoidance. Finally, loss aversion is expected to be modulated by genotype, particularly the serotonin transporter (SERT gene variant, based on its role in anxiety and impulsivity. This genetic modulation may also differ between anxious and healthy adolescents, given their distinct propensities for risk taking. The present work examines the modulation of loss aversion, an index of risk-taking, and reaction-time to decision, an index of impulsivity, by the serotonin-transporter-gene-linked polymorphisms (5HTTLPR in healthy and clinically anxious adolescents. Findings show that loss aversion (1 does manifest in adolescents, (2 does not differ between healthy and clinically anxious participants, and (3, when stratified by SERT genotype, identifies a subset of anxious adolescents who are high SERT-expressers, and show excessively low loss-aversion and high impulsivity. This last finding may serve as preliminary evidence for 5HTTLPR as a risk factor for the development of comorbid disorders associated with risk-taking and impulsivity in clinically anxious adolescents.

  17. Beyond words: Pragmatic inference in behavioral variant of frontotemporal degeneration.

    Science.gov (United States)

    Spotorno, Nicola; McMillan, Corey T; Rascovsky, Katya; Irwin, David J; Clark, Robin; Grossman, Murray

    2015-08-01

    When the message of a speaker goes beyond the literal or logical meaning of the sentences used, a pragmatic inference is required to understand the complete meaning of an utterance. Here we study one example of pragmatic inference, called scalar implicature. Such an inference is required when a weaker term "some" is used in a sentence like "Some of the students passed the exam" because the speaker presumably had a reason not to use a stronger term like "all". We investigated the comprehension of scalar implicatures in a group of 17 non-aphasic patients with behavioral variant frontotemporal degeneration (bvFTD) in order to test the contribution of non-linguistic decision-making ability and the role of prefrontal cortex in supporting the computation of pragmatic inferences. The results of two experiments point to a deficit in producing alternative interpretations beyond a logical reading. bvFTD patients thus prefer the narrowly literal or logical interpretation of a scalar term when they must generate a possible alternative interpretation by themselves, but patients prefer a pragmatic reading when offered a choice between the logical and the pragmatic interpretation of the same sentence. An imaging analysis links bvFTD patients' spontaneous tendency toward a narrowly logical interpretation with atrophy in ventromedial prefrontal cortex. Our findings are consistent with the pragmatic tolerance hypothesis, which proposes that difficulty generating alternative interpretations of an utterance, rather than a frank inability to compute an inference, affects the comprehension of a scalar term.

  18. Mutation Update: The Spectra of Nebulin Variants and Associated Myopathies

    Science.gov (United States)

    Lehtokari, Vilma-Lotta; Kiiski, Kirsi; Sandaradura, Sarah A.; Laporte, Jocelyn; Repo, Pauliina; Frey, Jennifer A.; Donner, Kati; Marttila, Minttu; Saunders, Carol; Barth, Peter G.; den Dunnen, Johan T.; Beggs, Alan H.; Clarke, Nigel F.; North, Kathryn N.; Laing, Nigel G.; Romero, Norma B.; Winder, Thomas L.; Pelin, Katarina; Wallgren-Pettersson, Carina

    2015-01-01

    A mutation update on the nebulin gene (NEB) is necessary because of recent developments in analysis methodology, the identification of increasing numbers and novel types of variants, and a widening in the spectrum of clinical and histological phenotypes associated with this gigantic, 183 exons containing gene. Recessive pathogenic variants in NEB are the major cause of nemaline myopathy (NM), one of the most common congenital myopathies. Moreover, pathogenic NEB variants have been identified in core-rod myopathy and in distal myopathies. In this update, we present the disease-causing variants in NEB in 159 families, 143 families with NM, and 16 families with NM-related myopathies. Eighty-eight families are presented here for the first time. We summarize 86 previously published and 126 unpublished variants identified in NEB. Furthermore, we have analyzed the NEB variants deposited in the Exome Variant Server (http://evs.gs.washington.edu/EVS/), identifying that pathogenic variants are a minor fraction of all coding variants (~7%). This indicates that nebulin tolerates substantial changes in its amino acid sequence, providing an explanation as to why variants in such a large gene result in relatively rare disorders. Lastly, we discuss the difficulties of drawing reliable genotype–phenotype correlations in NEB-associated disease. PMID:25205138

  19. XVCL: XML-based Variant Configuration Language

    DEFF Research Database (Denmark)

    Jarzabek, Stan; Basset, Paul; Zhang, Hongyu;

    2003-01-01

    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...... achieved substantial gains in industry, the underlying principles of the XVCL have been thoroughly tested in practice. We envision many other applications in software and non-software domains, as we can apply XVCL to any domain that can be represented as a collection of textual documents....

  20. Clinical variants of idiopathic torsion dystonia.

    Science.gov (United States)

    Fahn, S

    1989-06-01

    Some patients with dystonic movements and postures not known to be caused by environmental or degenerative disorders can be segregated from classical-appearing idiopathic torsion dystonia on the basis of distinctive clinical and pharmacologic features. Many of them should be considered within the family of dystonia, as clinical variants of idiopathic torsion dystonia, while others are better classified as being part of other families of dyskinesias. In the former group are paradoxical dystonia, myoclonic dystonia, diurnal dystonia, and dopa-responsive dystonia. The latter group consists of dystonic tics and the various entities comprising paroxysmal dystonia, namely kinesigenic, nonkinesigenic and hypnogenic dystonia.

  1. 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.

  2. Pitfalls and variants in pediatric chest imaging.

    Science.gov (United States)

    García Asensio, D; Fernández Martín, M

    2016-05-01

    Most pitfalls in the interpretation of pediatric chest imaging are closely related with the technique used and the characteristics of pediatric patients. To obtain a quality image that will enable the correct diagnosis, it is very important to use an appropriate technique. It is important to know how technical factors influence the image and to be aware of the possible artifacts that can result from poor patient cooperation. Moreover, radiologists need to be familiar with the normal anatomy in children, with the classic radiologic findings, and with the anatomic and developmental variants to avoid misinterpreting normal findings as pathological.

  3. 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.

  4. 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)

  5. [Necrobiosis lipoidica. Variants on a theme].

    Science.gov (United States)

    Geissler, E; Laaff, H; Technau, K; Bruckner-Tuderman, L; Nashan, D

    2011-08-01

    A 69-year-old patient presented with different skin lesions all of which belonged to group of necrobiosis lipoidica. The initial histologic diagnosis was actinic granuloma O'Brien. A subsequent biopsy was interpreted as granulomatous necrobiosis lipoidica. The history of these necrobiotic variants is reviewed and exemplarily depicted with this case. Necrobiosis lipoidica is part of the spectrum of granulomatous skin disorders. Although its etiology is unclear, an association with diabetes mellitus is often discussed. Multiple therapeutic options exist, but standardized guidelines for treatment are missing.

  6. 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.

  7. 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

  8. XIAP Deficiency and MEFV Variants Resulting in Severe Manifestations – A Case Report

    DEFF Research Database (Denmark)

    Christiansen, Mette

    2016-01-01

    Genetic testing identified variants in the MEFV gene (c.1223G>A; p.R408Q) indicating Familial Mediterranean Fever. Importantly, a hemizygous mutation in the X-linked inhibitor of apoptosis (XIAP)-gene (c.1026delT; I342fs) resulting in a frameshift was identified by whole exome sequencing in the patient......Background Heterozygous dominant or homozygous recessive MEFV mutations result in recurrent fever and abdominal pain, while XIAP deficiency is characterized by a high susceptibility to develop haemophagocytic lymphohistiocytosis triggered by EBV infection, recurrent splenomegaly and inflammatory...

  9. Volumes of chain links

    CERN Document Server

    Kaiser, James; Rollins, Clint

    2011-01-01

    Agol has conjectured that minimally twisted n-chain links are the smallest volume hyperbolic manifolds with n cusps, for n at most 10. In his thesis, Venzke mentions that these cannot be smallest volume for n at least 11, but does not provide a proof. In this paper, we give a proof of Venzke's statement. The proof for n at least 60 is completely rigorous. The proof for n between 11 and 59 uses a computer calculation, and can be made rigorous for manifolds of small enough complexity, using methods of Moser and Milley. Finally, we prove that the n-chain link with 2m or 2m+1 half-twists cannot be the minimal volume hyperbolic manifold with n cusps, provided n is at least 60 or |m| is at least 8, and we give computational data indicating this remains true for smaller n and |m|.

  10. Immunogenic variants obtained by mutagenesis of mouse mastocytoma P815. V. H-2 associativity of variant-specific antigens.

    Science.gov (United States)

    Van Snick, J; Maryanski, J; Van Pel, A; Parmiani, G; Boon, T

    1982-11-01

    By in vitro mutagenesis of mastocytoma P815, it is possible to obtain tumor cell variants that are rejected by syngeneic mice (tum-). Most of these variants carry new individual antigens and stimulate a specific cytolytic T cell (CTL) response in mixed leukocyte tumor cell culture (MLTC). The H-2 associativity of this response was examined for six different variants by measuring the inhibition of cell-mediated cytolysis by antibodies directed against products of the K or the D end of the H-2d complex. The lysis was either not inhibited (variants P91 and P116) or inhibited selectively by anti-Kd (variants P21, P32 and P198) or anti-Dd antibodies (variant P35). All these tum- variants expressed Kd and Dd antigens as measured by absorption of H-2 alloantisera. Long-term CTL clones can be obtained that are specific for individual tum- antigens. The pattern of H-2 associativity obtained with MLTC-derived CTL against four tum- variants was verified with CTL clones directed against the specific antigens of these variants. Concordant results were observed in all cases. In addition to CTL clones specific for tum- antigens, it is possible to isolate clones against a P815 tumor-associated antigen found on all P815 tum- variants. For these clones no clear associativity with either Kd or Dd products was found.

  11. Linking assumptions in amblyopia

    Science.gov (United States)

    LEVI, DENNIS M.

    2017-01-01

    Over the last 35 years or so, there has been substantial progress in revealing and characterizing the many interesting and sometimes mysterious sensory abnormalities that accompany amblyopia. A goal of many of the studies has been to try to make the link between the sensory losses and the underlying neural losses, resulting in several hypotheses about the site, nature, and cause of amblyopia. This article reviews some of these hypotheses, and the assumptions that link the sensory losses to specific physiological alterations in the brain. Despite intensive study, it turns out to be quite difficult to make a simple linking hypothesis, at least at the level of single neurons, and the locus of the sensory loss remains elusive. It is now clear that the simplest notion—that reduced contrast sensitivity of neurons in cortical area V1 explains the reduction in contrast sensitivity—is too simplistic. Considerations of noise, noise correlations, pooling, and the weighting of information also play a critically important role in making perceptual decisions, and our current models of amblyopia do not adequately take these into account. Indeed, although the reduction of contrast sensitivity is generally considered to reflect “early” neural changes, it seems plausible that it reflects changes at many stages of visual processing. PMID:23879956

  12. Collaboratively Patching Linked Data

    CERN Document Server

    Knuth, Magnus; Sack, Harald

    2012-01-01

    Today's Web of Data is noisy. Linked Data often needs extensive preprocessing to enable efficient use of heterogeneous resources. While consistent and valid data provides the key to efficient data processing and aggregation we are facing two main challenges: (1st) Identification of erroneous facts and tracking their origins in dynamically connected datasets is a difficult task, and (2nd) efforts in the curation of deficient facts in Linked Data are exchanged rather rarely. Since erroneous data often is duplicated and (re-)distributed by mashup applications it is not only the responsibility of a few original publishers to keep their data tidy, but progresses to be a mission for all distributers and consumers of Linked Data too. We present a new approach to expose and to reuse patches on erroneous data to enhance and to add quality information to the Web of Data. The feasibility of our approach is demonstrated by example of a collaborative game that patches statements in DBpedia data and provides notifications ...

  13. X linked mental retardation.

    Science.gov (United States)

    Rejeb, Imen; Ben Jemaa, Lamia; Chaabouni, Habiba

    2009-05-01

    Mental retardation (MR) is a group of heterogeneous clinical conditions. There are more than 900 genetic disorders associated with MR and it affects around 3% of the general population. Many MR conditions described are syndromic, fragile X syndrome being the most common clinical entity among them. X linked mental retardation (XLMR) is subdivided in two categories: syndromic XLMR (MRXS) when MR is associated with clinical features and non-syndromic XLMR (MRX) when MR is isolated. The aim of this systematic review of the literature was to join together the results of several studies related to X linked mental retardation and to present various genes implicated in this disease. In this review, focus has been given on genes implicated in mental retardation, the clinical data and on phenotype-genotype correlations. An exhaustive electronic and library research of the recent literature was carried out on the Web sites "Science Direct" and "Interscience Wiley". The key words used were "mental retardation", "X chromosome", "gene", "syndromic mental retardation", "non-syndromic mental retardation". In this review a number of X linked genes, the clinical features associated with the gene abnormality, and the prevalence of the disease gene are discussed. We classified these genes by order of their first implication in MR. A table presented on the XLMR Update Web site who list the 82 known XLMR genes is available as XLMR Genes and corresponding proteins.

  14. Schizophrenia copy number variants and associative learning

    Science.gov (United States)

    Clifton, N E; Pocklington, A J; Scholz, B; Rees, E; Walters, J T R; Kirov, G; O'Donovan, M C; Owen, M J; Wilkinson, L S; Thomas, K L; Hall, J

    2017-01-01

    Large-scale genomic studies have made major progress in identifying genetic risk variants for schizophrenia. A key finding from these studies is that there is an increased burden of genomic copy number variants (CNVs) in schizophrenia cases compared with controls. The mechanism through which these CNVs confer risk for the symptoms of schizophrenia, however, remains unclear. One possibility is that schizophrenia risk CNVs impact basic associative learning processes, abnormalities of which have long been associated with the disorder. To investigate whether genes in schizophrenia CNVs impact on specific phases of associative learning we combined human genetics with experimental gene expression studies in animals. In a sample of 11 917 schizophrenia cases and 16 416 controls, we investigated whether CNVs from patients with schizophrenia are enriched for genes expressed during the consolidation, retrieval or extinction of associative memories. We show that CNVs from cases are enriched for genes expressed during fear extinction in the hippocampus, but not genes expressed following consolidation or retrieval. These results suggest that CNVs act to impair inhibitory learning in schizophrenia, potentially contributing to the development of core symptoms of the disorder. PMID:27956746

  15. [Variant phenotype of Lesch-Nyhan syndrome].

    Science.gov (United States)

    Torres Jiménez, Rosa; García García, Marta; García Puig, Juan

    2011-01-29

    Lesch-Nyhan syndrome (LNS) and LNS variants are due to mutations in the HPRT1 gene causing HPRT enzymatic activity deficiency. We report a patient presenting a variant phenotype and a major genetic defect. The mutation has been previously reported as always associated with complete Lesch-Nyhan phenotype. We analyzed the presence of complete HPRT mRNA in this patient, in two patients with the complete Lesch Nyhan syndrome phenotype, and in control subjects. We found a minor amount of normal HPRT mRNA in the present patient but also in the two patients with splice mutation and the complete Lesch Nyhan syndrome phenotype. To our knowledge, this patient is the first report of a major genetic defect, with no detectable enzymatic activity, and a partial HPRT deficiency phenotype. Our results question the hypothesis of a normally spliced HPRT cDNA as the sole cause of the patient partial phenotype. Copyright © 2010 Elsevier España, S.L. All rights reserved.

  16. 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.

  17. Canonical and variant histones of protozoan parasites.

    Science.gov (United States)

    Dalmasso, Maria Carolina; Sullivan, William Joseph; Angel, Sergio Oscar

    2011-06-01

    Protozoan parasites have tremendously diverse lifestyles that require adaptation to a remarkable assortment of different environmental conditions. In order to complete their life cycles, protozoan parasites rely on fine-tuning gene expression. In general, protozoa use novel regulatory elements, transcription factors, and epigenetic mechanisms to regulate their transcriptomes. One of the most surprising findings includes the nature of their histones--these primitive eukaryotes lack some histones yet harbor novel histone variants of unknown function. In this review, we describe the histone components of different protozoan parasites based on literature and database searching. We summarize the key discoveries regarding histones and histone variants and their impact on chromatin regulation in protozoan parasites. In addition, we list histone genes IDs, sequences, and genomic localization of several protozoan parasites and Microsporidia histones, obtained from a thorough search of genome databases. We then compare these findings with those observed in higher eukaryotes, allowing us to highlight some novel aspects of epigenetic regulation in protists and to propose questions to be addressed in the upcoming years.

  18. Flavonoids as Inhibitors of Human Butyrylcholinesterase Variants

    Directory of Open Access Journals (Sweden)

    Maja Katalinić

    2014-01-01

    Full Text Available The inhibition of butyrylcholinesterase (BChE, EC 3.1.1.8 appears to be of interest in treating diseases with symptoms of reduced neurotransmitter levels, such as Alzheimer’s disease. However, BCHE gene polymorphism should not be neglected in research since it could have an effect on the expected outcome. Several well-known cholinergic drugs (e.g. galantamine, huperzine and rivastigmine originating from plants, or synthesised as derivatives of plant compounds, have shown that herbs could serve as a source of novel target-directed compounds. We focused our research on flavonoids, biologically active polyphenolic compounds found in many plants and plant-derived products, as BChE inhibitors. All of the tested flavonoids: galangin, quercetin, fisetin and luteolin reversibly inhibited usual, atypical, and fluoride-resistant variants of human BChE. The inhibition potency increased in the following order, identically for all three BChE variants: luteolin

  19. Kenny-Caffey syndrome: an Arab variant?

    Science.gov (United States)

    Sabry, M A; Farag, T I; Shaltout, A A; Zaki, M; Al-Mazidi, Z; Abulhassan, S J; Al-Torki, N; Quishawi, A; Al Awadi, S A

    1999-01-01

    We describe 2 unrelated Bedouin girls who met the criteria for the diagnosis of Kenny-Caffey syndrome. The girls had some unusual features--microcephaly and psychomotor retardation--that distinguish the Kenny-Caffey syndrome profile in Arab children from the classical Kenny-Caffey syndrome phenotype characterized by macrocephaly and normal intelligence. The 2 girls did not harbor the 22q11 microdeletion (the hallmark of the DiGeorge cluster of diseases) that we previously reported in another Bedouin family with the Kenny-Caffey syndrome (Sabry et al. J Med Genet 1998: 35(1): 31-36). This indicates considerable genetic heterogeneity for this syndrome. We also review previously reported 44 Arab/Bedouin patients with the same profile of hypoparathyroidism, short stature, seizures, mental retardation and microcephaly. Our results suggest that these patients represent an Arab variant of Kenny-Caffey syndrome with characteristic microcephaly and psychomotor retardation. We suggest that all patients with Kenny-Caffey syndrome should be investigated for the 22q11 microdeletion. Other possible genetic causes for the Kenny-Caffey syndrome or its Arab variant include chromosome 10p abnormalities.

  20. RcsB contributes to the distinct stress fitness between Escherichia coli O157:H7 curli variants of 1993 hamburger-associated outbreak strains

    Science.gov (United States)

    Curli are adhesive fimbriae of Enterobactericaeae and are involved in surface attachment, cell aggregation and biofilm formation. We previously reported that natural curli variants of E. coli O157:H7 (EcO157) displayed distinct acid resistance; however, this difference was not linked to the curli fi...

  1. 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...

  2. Rare variant detection using family-based sequencing analysis.

    Science.gov (United States)

    Peng, Gang; Fan, Yu; Palculict, Timothy B; Shen, Peidong; Ruteshouser, E Cristy; Chi, Aung-Kyaw; Davis, Ronald W; Huff, Vicki; Scharfe, Curt; Wang, Wenyi

    2013-03-05

    Next-generation sequencing is revolutionizing genomic analysis, but this analysis can be compromised by high rates of missing true variants. To develop a robust statistical method capable of identifying variants that would otherwise not be called, we conducted sequence data simulations and both whole-genome and targeted sequencing data analysis of 28 families. Our method (Family-Based Sequencing Program, FamSeq) integrates Mendelian transmission information and raw sequencing reads. Sequence analysis using FamSeq reduced the number of false negative variants by 14-33% as assessed by HapMap sample genotype confirmation. In a large family affected with Wilms tumor, 84% of variants uniquely identified by FamSeq were confirmed by Sanger sequencing. In children with early-onset neurodevelopmental disorders from 26 families, de novo variant calls in disease candidate genes were corrected by FamSeq as mendelian variants, and the number of uniquely identified variants in affected individuals increased proportionally as additional family members were included in the analysis. To gain insight into maximizing variant detection, we studied factors impacting actual improvements of family-based calling, including pedigree structure, allele frequency (common vs. rare variants), prior settings of minor allele frequency, sequence signal-to-noise ratio, and coverage depth (∼20× to >200×). These data will help guide the design, analysis, and interpretation of family-based sequencing studies to improve the ability to identify new disease-associated genes.

  3. 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.

  4. 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.

  5. Common Variants in Mendelian Kidney Disease Genes and Their Association with Renal Function

    Science.gov (United States)

    Fuchsberger, Christian; Köttgen, Anna; O’Seaghdha, Conall M.; Pattaro, Cristian; de Andrade, Mariza; Chasman, Daniel I.; Teumer, Alexander; Endlich, Karlhans; Olden, Matthias; Chen, Ming-Huei; Tin, Adrienne; Kim, Young J.; Taliun, Daniel; Li, Man; Feitosa, Mary; Gorski, Mathias; Yang, Qiong; Hundertmark, Claudia; Foster, Meredith C.; Glazer, Nicole; Isaacs, Aaron; Rao, Madhumathi; Smith, Albert V.; O’Connell, Jeffrey R.; Struchalin, Maksim; Tanaka, Toshiko; Li, Guo; Hwang, Shih-Jen; Atkinson, Elizabeth J.; Lohman, Kurt; Cornelis, Marilyn C.; Johansson, Åsa; Tönjes, Anke; Dehghan, Abbas; Couraki, Vincent; Holliday, Elizabeth G.; Sorice, Rossella; Kutalik, Zoltan; Lehtimäki, Terho; Esko, Tõnu; Deshmukh, Harshal; Ulivi, Sheila; Chu, Audrey Y.; Murgia, Federico; Trompet, Stella; Imboden, Medea; Kollerits, Barbara; Pistis, Giorgio; Harris, Tamara B.; Launer, Lenore J.; Aspelund, Thor; Eiriksdottir, Gudny; Mitchell, Braxton D.; Boerwinkle, Eric; Schmidt, Helena; Hofer, Edith; Hu, Frank; Demirkan, Ayse; Oostra, Ben A.; Turner, Stephen T.; Ding, Jingzhong; Andrews, Jeanette S.; Freedman, Barry I.; Giulianini, Franco; Koenig, Wolfgang; Illig, Thomas; Döring, Angela; Wichmann, H.-Erich; Zgaga, Lina; Zemunik, Tatijana; Boban, Mladen; Minelli, Cosetta; Wheeler, Heather E.; Igl, Wilmar; Zaboli, Ghazal; Wild, Sarah H.; Wright, Alan F.; Campbell, Harry; Ellinghaus, David; Nöthlings, Ute; Jacobs, Gunnar; Biffar, Reiner; Ernst, Florian; Homuth, Georg; Kroemer, Heyo K.; Nauck, Matthias; Stracke, Sylvia; Völker, Uwe; Völzke, Henry; Kovacs, Peter; Stumvoll, Michael; Mägi, Reedik; Hofman, Albert; Uitterlinden, Andre G.; Rivadeneira, Fernando; Aulchenko, Yurii S.; Polasek, Ozren; Hastie, Nick; Vitart, Veronique; Helmer, Catherine; Wang, Jie Jin; Stengel, Bénédicte; Ruggiero, Daniela; Bergmann, Sven; Kähönen, Mika; Viikari, Jorma; Nikopensius, Tiit; Province, Michael; Colhoun, Helen; Doney, Alex; Robino, Antonietta; Krämer, Bernhard K.; Portas, Laura; Ford, Ian; Buckley, Brendan M.; Adam, Martin; Thun, Gian-Andri; Paulweber, Bernhard; Haun, Margot; Sala, Cinzia; Mitchell, Paul; Ciullo, Marina; Vollenweider, Peter; Raitakari, Olli; Metspalu, Andres; Palmer, Colin; Gasparini, Paolo; Pirastu, Mario; Jukema, J. Wouter; Probst-Hensch, Nicole M.; Kronenberg, Florian; Toniolo, Daniela; Gudnason, Vilmundur; Shuldiner, Alan R.; Coresh, Josef; Schmidt, Reinhold; Ferrucci, Luigi; van Duijn, Cornelia M.; Borecki, Ingrid; Kardia, Sharon L.R.; Liu, Yongmei; Curhan, Gary C.; Rudan, Igor; Gyllensten, Ulf; Wilson, James F.; Franke, Andre; Pramstaller, Peter P.; Rettig, Rainer; Prokopenko, Inga; Witteman, Jacqueline; Hayward, Caroline; Ridker, Paul M.; Bochud, Murielle; Heid, Iris M.; Siscovick, David S.; Fox, Caroline S.; Kao, W. Linda; Böger, Carsten A.

    2013-01-01

    Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research. PMID:24029420

  6. Common Variant of FTO Gene, rs9939609, and Obesity in Pakistani Females

    Directory of Open Access Journals (Sweden)

    Adeela Shahid

    2013-01-01

    Full Text Available Numerous studies confirmed the association of FTO (fat mass and obesity associated gene common variant, rs9939609, with obesity in European populations. However, studies in Asian populations revealed conflicting results. We examined the association of rs9939609 variant of FTO gene with obesity and obesity-related anthropometric and metabolic parameters in Pakistani population. Body weight, height, waist circumference, hip circumference, and blood pressure (BP were measured. BMI and waist-to-hip ratio (WHR were calculated. Levels of fasting blood glucose (FBG, insulin, leptin, and leptin receptors were measured by enzyme linked immunosorbent assay (ELISA, and homeostasis model assessment of insulin resistance (HOMA-IR was calculated. The results showed association of FTO gene, rs9939609, with obesity in females (>18 years of age. FTO minor allele increased the risk of obesity by 2.8 times (95% CI = 1.3–6.0 in females. This allele showed association with body weight, BMI, waist circumference, hip circumference, WHR, BP, plasma FBG levels, HOMA-IR, plasma insulin levels, and plasma leptin levels. In conclusion, FTO gene, rs9939609, is associated with BMI and risk of obesity in adult Pakistani females. Association of rs9939609 variant with higher FBG, plasma insulin, and leptin levels indicates that this polymorphism may disturb the metabolism in adult females and predispose them to obesity and type 2 diabetes. However, the above-mentioned findings were not seen in children or males.

  7. Cancer-associated splicing variant of tumor suppressor AIMP2/p38: pathological implication in tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Jin Woo Choi

    2011-03-01

    Full Text Available Although ARS-interacting multifunctional protein 2 (AIMP2, also named as MSC p38 was first found as a component for a macromolecular tRNA synthetase complex, it was recently discovered to dissociate from the complex and work as a potent tumor suppressor. Upon DNA damage, AIMP2 promotes apoptosis through the protective interaction with p53. However, it was not demonstrated whether AIMP2 was indeed pathologically linked to human cancer. In this work, we found that a splicing variant of AIMP2 lacking exon 2 (AIMP2-DX2 is highly expressed by alternative splicing in human lung cancer cells and patient's tissues. AIMP2-DX2 compromised pro-apoptotic activity of normal AIMP2 through the competitive binding to p53. The cells with higher level of AIMP2-DX2 showed higher propensity to form anchorage-independent colonies and increased resistance to cell death. Mice constitutively expressing this variant showed increased susceptibility to carcinogen-induced lung tumorigenesis. The expression ratio of AIMP2-DX2 to normal AIMP2 was increased according to lung cancer stage and showed a positive correlation with the survival of patients. Thus, this work identified an oncogenic splicing variant of a tumor suppressor, AIMP2/p38, and suggests its potential for anti-cancer target.

  8. In1-ghrelin splicing variant is overexpressed in pituitary adenomas and increases their aggressive features.

    Science.gov (United States)

    Ibáñez-Costa, Alejandro; Gahete, Manuel D; Rivero-Cortés, Esther; Rincón-Fernández, David; Nelson, Richard; Beltrán, Manuel; de la Riva, Andrés; Japón, Miguel A; Venegas-Moreno, Eva; Gálvez, Ma Ángeles; García-Arnés, Juan A; Soto-Moreno, Alfonso; Morgan, Jennifer; Tsomaia, Natia; Culler, Michael D; Dieguez, Carlos; Castaño, Justo P; Luque, Raúl M

    2015-03-04

    Pituitary adenomas comprise a heterogeneous subset of pathologies causing serious comorbidities, which would benefit from identification of novel, common molecular/cellular biomarkers and therapeutic targets. The ghrelin system has been linked to development of certain endocrine-related cancers. Systematic analysis of the presence and functional implications of some components of the ghrelin system, including native ghrelin, receptors and the recently discovered splicing variant In1-ghrelin, in human normal pituitaries (n = 11) and pituitary adenomas (n = 169) revealed that expression pattern of ghrelin system suffers a clear alteration in pituitary adenomasas compared with normal pituitary, where In1-ghrelin is markedly overexpressed. Interestingly, in cultured pituitary adenoma cells In1-ghrelin treatment (acylated peptides at 100 nM; 24-72 h) increased GH and ACTH secretion, Ca(2+) and ERK1/2 signaling and cell viability, whereas In1-ghrelin silencing (using a specific siRNA; 100 nM) reduced cell viability. These results indicate that an alteration of the ghrelin system, specially its In1-ghrelin variant, could contribute to pathogenesis of different pituitary adenomas types, and suggest that this variant and its related ghrelin system could provide new tools to identify novel, more general diagnostic, prognostic and potential therapeutic targets in pituitary tumors.

  9. Multigenerational pedigree with STAR syndrome: A novel FAM58A variant and expansion of the phenotype.

    Science.gov (United States)

    Boczek, Nicole J; Kruisselbrink, Teresa; Cousin, Margot A; Blackburn, Patrick R; Klee, Eric W; Gavrilova, Ralitza H; Lanpher, Brendan C

    2017-05-01

    STAR syndrome is a rare X-linked dominant disorder characterized by toe Syndactyly, Telecanthus, Anogenital malformations, and Renal malformations, and is caused by loss-of-function variants in FAM58A. Our proband presented with the hallmark features of STAR syndrome, as well as some additional less typical features including tethered cord and hearing loss. The proband's mother and maternal half-sister had similar clinical histories, but had variability in phenotypic severity. Clinical whole exome sequencing revealed a novel pathogenic nonsense variant, c.651G>A (p.Trp217X; NM_152274), in FAM58A in the proband, mother, and maternal half-sister. This pedigree represents the 11-13th patients described with STAR syndrome and the third instance of familial inheritance. To our knowledge, this is the first occurrence of a nonsense variant in FAM58A described in individuals with STAR syndrome and the phenotype in this pedigree suggests that tethered cord and hearing loss are features of STAR syndrome. © 2017 Wiley Periodicals, Inc.

  10. Distribution of Gifsy-3 and of variants of ST64B and Gifsy-1 prophages amongst Salmonella enterica Serovar Typhimurium isolates: evidence that combinations of prophages promote clonality.

    Directory of Open Access Journals (Sweden)

    Lester Hiley

    Full Text Available Salmonella isolates harbour a range of resident prophages which can influence their virulence and ability to compete and survive in their environment. Phage gene profiling of a range of phage types of Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium indicates a significant level of correlation of phage gene profile with phage type as well as correlation with genotypes determined by a combination of multi-locus variable-number tandem repeat (VNTR typing and clustered regularly interspaced short palindromic repeats (CRISPR typing. Variation in phage gene profiles appears to be partly linked to differences in composition of variants of known prophages. We therefore conducted a study of the distribution of variants of ST64B and Gifsy-1 prophages and coincidently the presence of Gifsy-3 prophage in a range of S. Typhimurium phage types and genotypes. We have discovered two variants of the DT104 variant of ST64B and at least two new variants of Gifsy-1 as well as variants of related phage genes. While there is definite correlation between phage type and the prophage profile based on ST64B and Gifsy-1 variants we find stronger correlation between the VNTR/CRISPR genotype and prophage profile. Further differentiation of some genotypes is obtained by addition of the distribution of Gifsy-3 and a sequence variant of the substituted SB26 gene from the DT104 variant of ST64B. To explain the correlation between genotype and prophage profile we propose that suites of resident prophages promote clonality possibly through superinfection exclusion systems.

  11. Habenular expression of rare missense variants of the β4 nicotinic receptor subunit alters nicotine consumption

    Science.gov (United States)

    Ślimak, Marta A.; Ables, Jessica L.; Frahm, Silke; Antolin-Fontes, Beatriz; Santos-Torres, Julio; Moretti, Milena; Gotti, Cecilia; Ibañez-Tallon, Inés

    2013-01-01

    The CHRNA5-CHRNA3-CHRNB4 gene cluster, encoding the α5, α3, and β4 nicotinic acetylcholine receptor (nAChR) subunits, has been linked to nicotine dependence. The habenulo-interpeduncular (Hb-IPN) tract is particularly enriched in α3β4 nAChRs. We recently showed that modulation of these receptors in the medial habenula (MHb) in mice altered nicotine consumption. Given that β4 is rate-limiting for receptor activity and that single nucleotide polymorphisms (SNPs) in CHRNB4 have been linked to altered risk of nicotine dependence in humans, we were interested in determining the contribution of allelic variants of β4 to nicotine receptor activity in the MHb. We screened for missense SNPs that had allele frequencies >0.0005 and introduced the corresponding substitutions in Chrnb4. Fourteen variants were analyzed by co-expression with α3. We found that β4A90I and β4T374I variants, previously shown to associate with reduced risk of smoking, and an additional variant β4D447Y, significantly increased nicotine-evoked current amplitudes, while β4R348C, the mutation most frequently encountered in sporadic amyotrophic lateral sclerosis (sALS), showed reduced nicotine currents. We employed lentiviruses to express β4 or β4 variants in the MHb. Immunoprecipitation studies confirmed that β4 lentiviral-mediated expression leads to specific upregulation of α3β4 but not β2 nAChRs in the Mhb. Mice injected with the β4-containing virus showed pronounced aversion to nicotine as previously observed in transgenic Tabac mice overexpressing Chrnb4 at endogenous sites including the MHb. Habenular expression of the β4 gain-of-function allele T374I also resulted in strong aversion, while transduction with the β4 loss-of function allele R348C failed to induce nicotine aversion. Altogether, these data confirm the critical role of habenular β4 in nicotine consumption, and identify specific SNPs in CHRNB4 that modify nicotine-elicited currents and alter nicotine consumption in

  12. Phenotypic and Enzymatic Comparative Analysis of the KPC Variants, KPC-2 and Its Recently Discovered Variant KPC-15

    OpenAIRE

    Dongguo Wang; Jiayu Chen; Linjun Yang; Yonghua Mou; Yijun Yang

    2014-01-01

    Sixteen different variants (KPC-2 to KPC-17) in the KPC family have been reported, and most current studies are focusing on KPC-2 and KPC-3. The KPC-15 variant, which isolated from Klebsiella pneumoniae in a Chinese hospital, was a recently discovered KPC enzyme. To compare the characteristics of KPC-15 and KPC-2, the variants were determined by susceptibility testing, PCR amplification and sequencing, and study of kinetic parameters. The strain harboring the KPC-15 showed resistance to 18 co...

  13. Knots and links

    CERN Document Server

    Rolfsen, Dale

    2003-01-01

    Rolfsen's beautiful book on knots and links can be read by anyone, from beginner to expert, who wants to learn about knot theory. Beginners with a basic background find an inviting introduction to the elements of topology, emphasizing the tools needed for understanding knots, the fundamental group and van Kampen's theorem, for example, which are then applied to concrete problems, such as computing knot groups. For experts, Rolfsen explains advanced topics, such as the connections between knot theory and surgery and how they are useful to understanding three-manifolds. Besides providing a guide

  14. The weakest link

    Energy Technology Data Exchange (ETDEWEB)

    Lumley, G. [GBI Consulting, Qld. (Australia)

    2005-08-01

    In part seven of his series on dragline productivity, the author tackles the subject of the dump rope, the weakest link in the operation of the dragline, is traded. Five factors have been identified as critical to dump life: ratio of dump block to dump rope diameter; excessive loads in dumps rope; rope abrasion against dump block; rope abrasion against bucket; dump rope construction. These factors are considered in the article. The author comments that in the drive to increase dragline productivity, rope life has been sacrificed. 4 figs., 1 tab.

  15. Linking consumer experiences

    DEFF Research Database (Denmark)

    Smed, Karina Madsen

    Consumers consume products in various ways serving a number of purposes. Much attention has been paid to experiences attached to consumption, sometimes very explicitly, e.g. in tourism, the essence of which is experiences of various sorts, but often also implicitly as internalised experiences...... become part of the individual self, worldview, and behaviour. This paper seeks to explore links between consumer experiences through the exploration of narrative sequences in travel blogs. Findings indicate that non-consumption is a central element to the bloggers and also indicative of a community...

  16. EEE Links. Volume 5

    Science.gov (United States)

    Humphrey, Robert (Editor)

    1999-01-01

    The EEE Links Newsletter is a quarterly publication produced by Code 562 in support of the NASA HQ funded NASA Electronic Parts and Packaging (NEPP) Program. The newsletter is produced as an electronic format deliverable made available via the referenced www site administered by Code 562, The newsletter publishes brief articles on topics of interest to NASA programs and projects in the area of electronic parts and packaging. The newsletter does not provide information pertaining to patented or proprietary information. The information provided is at the level of that produced by industry and university researchers and is published at national and international conferences.

  17. Functional variants of human papillomavirus type 16 demonstrate host genome integration and transcriptional alterations corresponding to their unique cancer epidemiology.

    Science.gov (United States)

    Jackson, Robert; Rosa, Bruce A; Lameiras, Sonia; Cuninghame, Sean; Bernard, Josee; Floriano, Wely B; Lambert, Paul F; Nicolas, Alain; Zehbe, Ingeborg

    2016-11-02

    Human papillomaviruses (HPVs) are a worldwide burden as they are a widespread group of tumour viruses in humans. Having a tropism for mucosal tissues, high-risk HPVs are detected in nearly all cervical cancers. HPV16 is the most common high-risk type but not all women infected with high-risk HPV develop a malignant tumour. Likely relevant, HPV genomes are polymorphic and some HPV16 single nucleotide polymorphisms (SNPs) are under evolutionary constraint instigating variable oncogenicity and immunogenicity in the infected host. To investigate the tumourigenicity of two common HPV16 variants, we used our recently developed, three-dimensional organotypic model reminiscent of the natural HPV infectious cycle and conducted various "omics" and bioinformatics approaches. Based on epidemiological studies we chose to examine the HPV16 Asian-American (AA) and HPV16 European Prototype (EP) variants. They differ by three non-synonymous SNPs in the transforming and virus-encoded E6 oncogene where AAE6 is classified as a high- and EPE6 as a low-risk variant. Remarkably, the high-risk AAE6 variant genome integrated into the host DNA, while the low-risk EPE6 variant genome remained episomal as evidenced by highly sensitive Capt-HPV sequencing. RNA-seq experiments showed that the truncated form of AAE6, integrated in chromosome 5q32, produced a local gene over-expression and a large variety of viral-human fusion transcripts, including long distance spliced transcripts. In addition, differential enrichment of host cell pathways was observed between both HPV16 E6 variant-containing epithelia. Finally, in the high-risk variant, we detected a molecular signature of host chromosomal instability, a common property of cancer cells. We show how naturally occurring SNPs in the HPV16 E6 oncogene cause significant changes in the outcome of HPV infections and subsequent viral and host transcriptome alterations prone to drive carcinogenesis. Host genome instability is closely linked to viral

  18. Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families.

    Directory of Open Access Journals (Sweden)

    Carlos Cruchaga

    Full Text Available Pathogenic mutations in APP, PSEN1, PSEN2, MAPT and GRN have previously been linked to familial early onset forms of dementia. Mutation screening in these genes has been performed in either very small series or in single families with late onset AD (LOAD. Similarly, studies in single families have reported mutations in MAPT and GRN associated with clinical AD but no systematic screen of a large dataset has been performed to determine how frequently this occurs. We report sequence data for 439 probands from late-onset AD families with a history of four or more affected individuals. Sixty sequenced individuals (13.7% carried a novel or pathogenic mutation. Eight pathogenic variants, (one each in APP and MAPT, two in PSEN1 and four in GRN three of which are novel, were found in 14 samples. Thirteen additional variants, present in 23 families, did not segregate with disease, but the frequency of these variants is higher in AD cases than controls, indicating that these variants may also modify risk for disease. The frequency of rare variants in these genes in this series is significantly higher than in the 1,000 genome project (p = 5.09 × 10⁻⁵; OR = 2.21; 95%CI = 1.49-3.28 or an unselected population of 12,481 samples (p = 6.82 × 10⁻⁵; OR = 2.19; 95%CI = 1.347-3.26. Rare coding variants in APP, PSEN1 and PSEN2, increase risk for or cause late onset AD. The presence of variants in these genes in LOAD and early-onset AD demonstrates that factors other than the mutation can impact the age at onset and penetrance of at least some variants associated with AD. MAPT and GRN mutations can be found in clinical series of AD most likely due to misdiagnosis. This study clearly demonstrates that rare variants in these genes could explain an important proportion of genetic heritability of AD, which is not detected by GWAS.

  19. 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.

  20. Rare Variants in Neurodegeneration Associated Genes Revealed by Targeted Panel Sequencing in a German ALS Cohort

    Directory of Open Access Journals (Sweden)

    Stefanie Krüger

    2016-10-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a progressive fatal multisystemic neurodegenerative disorder caused by preferential degeneration of upper and lower motor neurons. To further delineate the genetic architecture of the disease, we used comprehensive panel sequencing in a cohort of 80 German ALS patients. The panel covered 39 confirmed ALS genes and candidate genes, as well as 238 genes associated with other entities of the neurodegenerative disease spectrum. In addition, we performed repeat length analysis for C9orf72. Our aim was to (1 identify potentially disease-causing variants, to (2 assess a proposed model of polygenic inheritance in ALS and to (3 connect ALS with other neurodegenerative entities.We identified 79 rare potentially pathogenic variants in 27 ALS associated genes in familial and sporadic cases. Five patients had pathogenic C9orf72 repeat expansions, a further four patients harbored intermediate length repeat expansions. Our findings demonstrate that a genetic background of the disease can actually be found in a large proportion of seemingly sporadic cases and that it is not limited to putative most frequently affected genes such as C9orf72 or SOD1. Assessing the polygenic nature of ALS, we identified 15 patients carrying at least two rare potentially pathogenic variants in ALS associated genes including pathogenic or intermediate C9orf72 repeat expansions. Multiple variants might influence severity or duration of disease or could account for intrafamilial phenotypic variability or reduced penetrance. However, we could not observe a correlation with age of onset in this study. We further detected potentially pathogenic variants in other neurodegeneration associated genes in 12 patients, supporting the hypothesis of common pathways in neurodegenerative diseases and linking ALS to other entities of the neurodegenerative spectrum. Most interestingly we found variants in GBE1 and SPG7 which might represent differential diagnoses

  1. Rare Variants in Neurodegeneration Associated Genes Revealed by Targeted Panel Sequencing in a German ALS Cohort.

    Science.gov (United States)

    Krüger, Stefanie; Battke, Florian; Sprecher, Andrea; Munz, Marita; Synofzik, Matthis; Schöls, Ludger; Gasser, Thomas; Grehl, Torsten; Prudlo, Johannes; Biskup, Saskia

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is a progressive fatal multisystemic neurodegenerative disorder caused by preferential degeneration of upper and lower motor neurons. To further delineate the genetic architecture of the disease, we used comprehensive panel sequencing in a cohort of 80 German ALS patients. The panel covered 39 confirmed ALS genes and candidate genes, as well as 238 genes associated with other entities of the neurodegenerative disease spectrum. In addition, we performed repeat length analysis for C9orf72. Our aim was to (1) identify potentially disease-causing variants, to (2) assess a proposed model of polygenic inheritance in ALS and to (3) connect ALS with other neurodegenerative entities. We identified 79 rare potentially pathogenic variants in 27 ALS associated genes in familial and sporadic cases. Five patients had pathogenic C9orf72 repeat expansions, a further four patients harbored intermediate length repeat expansions. Our findings demonstrate that a genetic background of the disease can actually be found in a large proportion of seemingly sporadic cases and that it is not limited to putative most frequently affected genes such as C9orf72 or SOD1. Assessing the polygenic nature of ALS, we identified 15 patients carrying at least two rare potentially pathogenic variants in ALS associated genes including pathogenic or intermediate C9orf72 repeat expansions. Multiple variants might influence severity or duration of disease or could account for intrafamilial phenotypic variability or reduced penetrance. However, we could not observe a correlation with age of onset in this study. We further detected potentially pathogenic variants in other neurodegeneration associated genes in 12 patients, supporting the hypothesis of common pathways in neurodegenerative diseases and linking ALS to other entities of the neurodegenerative spectrum. Most interestingly we found variants in GBE1 and SPG7 which might represent differential diagnoses. Based on our

  2. Rare Variants in Neurodegeneration Associated Genes Revealed by Targeted Panel Sequencing in a German ALS Cohort

    Science.gov (United States)

    Krüger, Stefanie; Battke, Florian; Sprecher, Andrea; Munz, Marita; Synofzik, Matthis; Schöls, Ludger; Gasser, Thomas; Grehl, Torsten; Prudlo, Johannes; Biskup, Saskia

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is a progressive fatal multisystemic neurodegenerative disorder caused by preferential degeneration of upper and lower motor neurons. To further delineate the genetic architecture of the disease, we used comprehensive panel sequencing in a cohort of 80 German ALS patients. The panel covered 39 confirmed ALS genes and candidate genes, as well as 238 genes associated with other entities of the neurodegenerative disease spectrum. In addition, we performed repeat length analysis for C9orf72. Our aim was to (1) identify potentially disease-causing variants, to (2) assess a proposed model of polygenic inheritance in ALS and to (3) connect ALS with other neurodegenerative entities. We identified 79 rare potentially pathogenic variants in 27 ALS associated genes in familial and sporadic cases. Five patients had pathogenic C9orf72 repeat expansions, a further four patients harbored intermediate length repeat expansions. Our findings demonstrate that a genetic background of the disease can actually be found in a large proportion of seemingly sporadic cases and that it is not limited to putative most frequently affected genes such as C9orf72 or SOD1. Assessing the polygenic nature of ALS, we identified 15 patients carrying at least two rare potentially pathogenic variants in ALS associated genes including pathogenic or intermediate C9orf72 repeat expansions. Multiple variants might influence severity or duration of disease or could account for intrafamilial phenotypic variability or reduced penetrance. However, we could not observe a correlation with age of onset in this study. We further detected potentially pathogenic variants in other neurodegeneration associated genes in 12 patients, supporting the hypothesis of common pathways in neurodegenerative diseases and linking ALS to other entities of the neurodegenerative spectrum. Most interestingly we found variants in GBE1 and SPG7 which might represent differential diagnoses. Based on our

  3. Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration.

    Science.gov (United States)

    Zareparsi, Sepideh; Buraczynska, Monika; Branham, Kari E H; Shah, Sapna; Eng, Donna; Li, Mingyao; Pawar, Hemant; Yashar, Beverly M; Moroi, Sayoko E; Lichter, Paul R; Petty, Howard R; Richards, Julia E; Abecasis, Gonçalo R; Elner, Victor M; Swaroop, Anand

    2005-06-01

    Age-related macular degeneration (AMD) is a genetically heterogeneous disease that leads to progressive and irreversible vision loss among the elderly. Inflammation, oxidative damage, cholesterol metabolism and/or impaired function of retinal pigment epithelium (RPE) have been implicated in AMD pathogenesis. We examined toll-like receptor 4 (TLR4) as a candidate gene for AMD susceptibility because: (i) the TLR4 gene is located on chromosome 9q32-33, a region exhibiting evidence of linkage to AMD in three independent reports; (ii) the TLR4-D299G variant is associated with reduced risk of atherosclerosis, a chronic inflammatory disease with subendothelial accumulation; (iii) the TLR4 is not only a key mediator of proinflammatory signaling pathways but also linked to regulation of cholesterol efflux and (iv) the TLR4 participates in phagocytosis of photoreceptor outer segments by the RPE. We examined D299G and T399I variants of TLR4 in a sample of 667 unrelated AMD patients and 439 unrelated controls, all of Caucasian ancestry. Multiple logistic regression demonstrated an increased risk of AMD in carriers of the G allele at TLR4 residue 299 (odds ratio=2.65, P=0.025), but lack of an independent effect by T399I variant. TLR4-D299G showed an additive effect on AMD risk (odds ratio=4.13, P=0.002) with allelic variants of apolipoprotein E (APOE) and ATP-binding cassette transporter-1 (ABCA1), two genes involved in cholesterol efflux. Interestingly, the effect of TLR4, APOE and ABCA1 variants on AMD susceptibility was opposite to that of association with atherosclerosis risk. Our data provide evidence of a link between multiple diverse mechanisms underlying AMD pathogenesis.

  4. Identification of a novel variant of LMP-1 of EBV in patients with endemic Burkitt lymphoma in western Kenya.

    Science.gov (United States)

    Wohlford, Eric M; Asito, Amolo S; Chelimo, Kiprotich; Sumba, Peter O; Baresel, Paul C; Oot, Rebecca A; Moormann, Ann M; Rochford, Rosemary

    2013-09-09

    Epstein Barr virus (EBV) is a gammaherpesvirus that is associated with nasopharyngeal carcinoma (NPC) and endemic Burkitt lymphoma (eBL). EBV carries several latent genes that contribute to oncogenesis including the latent membrane protein 1 (LMP-1), a known oncogene and constitutively active CD40 homolog. Variation in the C terminal region of LMP-1 has been linked to NPC pathogenesis, but little is known regarding LMP-1 variation and eBL. In the present study, peripheral blood samples were obtained from 38 eBL patients and 22 healthy controls in western Kenya, where the disease is endemic. The LMP-1 C-terminal region from these samples was sequenced and analyzed. The frequency of a 30 base pair deletion of LMP-1 previously linked to NPC was not associated with eBL compared to healthy controls. However a novel LMP-1 variant was identified, called K for Kenya and for the G318K mutation that characterizes it. The K variant LMP-1 was found in 40.5% of eBL sequences and 25.0% of healthy controls. All K variant sequences contained mutations in both of the previously described minimal T cell epitopes in the C terminal end of LMP-1. These mutations occurred in the anchor residue at the C-terminal binding groove of both epitopes, a pocket necessary for MHC loading. Overall, our results suggest that there is a novel K variant of LMP-1 in Kenya that may be associated with eBL. Further studies are necessary to determine the functional implications of the LMP-1 variant on early events in eBL genesis.

  5. 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...

  6. 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.)

  7. 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.

  8. Genetic variants associated with lung function

    DEFF Research Database (Denmark)

    Thyagarajan, Bharat; Wojczynski, Mary; Minster, Ryan L

    2014-01-01

    BACKGROUND: Reduced forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) are strong predictors of mortality and lung function is higher among individuals with exceptional longevity. However, genetic factors associated with lung function in individuals...... 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...... used the residuals of the FEV1 and FEV1/FVC, adjusted for age, sex, height, ancestry principal components (PCs), smoking status, pack-years, and field center. RESULTS: We identified nine SNPs in strong linkage disequilibrium in the CYP2U1 gene to be associated with FEV1 and a novel SNP (rs889574...

  9. 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.

  10. Sturge -Weber Syndrome - Three Classic variants

    Directory of Open Access Journals (Sweden)

    R S Sathawane

    2006-01-01

    Full Text Available Sturge-Weber syndrome (SWS, also known as encephalotrigeminal angiomatosis, a sporadic, non-familial, congenital disorder consists of congenital hamartomatous malformations that may affect the eye, skin and central nervous system at different times. Sturge-Weber syndrome is classified as 1 Complete trisymptomatic: - when all three organ systems i.e. eye, skin and CNS are involved 2 Incomplete bisymptomatic:- when the involvement is either oculocutaneous or neurocutaneous, and 3 Incomplete monosymptomatic: when there is only neural or cutaneous involvement. Failure of proper vascular development is believed to be the most likely cause of this condition. The malformed blood vessels or hemangiomas may lead to port-wine stain, epilepsy and glaucoma depending on its location. Three classic variants with typical findings are discussed.

  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...... acquisition and order fulfilment, i.e. the creation of drawings, bill-of-materials, routings, product descriptions, quote letters etc. The present thesis is rooted in the assumption that variant specification systems supporting the cross-functional processes of order acquisition and order fulfilment must...... be 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...

  12. 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.

  13. Probabilistic Transcriptome Assembly and Variant Graph Genotyping

    DEFF Research Database (Denmark)

    Sibbesen, Jonas Andreas

    the resulting sequencing data should be interpreted. This has over the years spurred the development of many probabilistic methods that are capable of modelling dierent aspects of the sequencing process. Here, I present two of such methods that were developed to each tackle a dierent problem in bioinformatics......, together with an application of the latter method to a large Danish sequencing project. The rst is a probabilistic method for transcriptome assembly that is based on a novel generative model of the RNA sequencing process and provides condence estimates on the assembled transcripts. We show...... that this approach outperforms existing state-of-the-art methods measured using sensitivity and precision on both simulated and real data. The second is a novel probabilistic method that uses exact alignment of k-mers to a set of variants graphs to provide unbiased estimates of genotypes in a population...

  14. WNT10A exonic variant increases the risk of keratoconus by decreasing corneal thickness.

    Science.gov (United States)

    Cuellar-Partida, Gabriel; Springelkamp, Henriët; Lucas, Sionne E M; Yazar, Seyhan; Hewitt, Alex W; Iglesias, Adriana I; Montgomery, Grant W; Martin, Nicholas G; Pennell, Craig E; van Leeuwen, Elisabeth M; Verhoeven, Virginie J M; Hofman, Albert; Uitterlinden, André G; Ramdas, Wishal D; Wolfs, Roger C W; Vingerling, Johannes R; Brown, Matthew A; Mills, Richard A; Craig, Jamie E; Klaver, Caroline C W; van Duijn, Cornelia M; Burdon, Kathryn P; MacGregor, Stuart; Mackey, David A

    2015-09-01

    Keratoconus is a degenerative eye condition which results from thinning of the cornea and causes vision distortion. Treatments such as ultraviolet (UV) cross-linking have proved effective for management of keratoconus when performed in early stages of the disease. The central corneal thickness (CCT) is a highly heritable endophenotype of keratoconus, and it is estimated that up to 95% of its phenotypic variance is due to genetics. Genome-wide association efforts of CCT have identified common variants (i.e. minor allele frequency (MAF) >5%). However, these studies typically ignore the large set of exonic variants whose MAF is usually low. In this study, we performed a CCT exome-wide association analysis in a sample of 1029 individuals from a population-based study in Western Australia. We identified a genome-wide significant exonic variant rs121908120 (P = 6.63 × 10(-10)) in WNT10A. This gene is 437 kb from a gene previously associated with CCT (USP37). We showed in a conditional analysis that the WNT10A variant completely accounts for the signal previously seen at USP37. We replicated our finding in independent samples from the Brisbane Adolescent Twin Study, Twin Eye Study in Tasmania and the Rotterdam Study. Further, we genotyped rs121908120 in 621 keratoconus cases and compared the frequency to a sample of 1680 unscreened controls from the Queensland Twin Registry. We found that rs121908120 increases the risk of keratoconus two times (odds ratio 2.03, P = 5.41 × 10(-5)). © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. HPRTYale proposed as a pathogenic variant for Lesch-Nyhan syndrome: a case report.

    Science.gov (United States)

    Stur, E; Reis, R S; Agostini, L P; Silva-Conforti, A M A; Louro, I D

    2016-06-24

    Lesch-Nyhan syndrome (LNS) is an X-linked recessive disorder caused by a deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT), an enzyme encoded by the HPRT1 gene. The classic disease phenotype described by Lesch and Nyhan in 1964 includes hyperuricemia, mental retardation, severe motor deficiency, and recurring self-mutilation. Here, we report the case of a family with 4 affected males and several female obligate carriers. In 1989, Fujimori et al. reported on a patient diagnosed with LNS who had an HPRT variant thereafter codenamed HPRTYale. The same patient was studied by Wilson et al. in 1986, who found no detectable HPRT enzymatic activity, even though normal HPRT mRNA and protein levels were observed. Disease severity is closely related to residual enzymatic activity, which fits the phenotype presented for this previously reported case, as well as for the patients we report on herein. As it has been reported in only one patient, this mutation is still considered a variant of unknown significance. The HPRTYale mutation is a G>C transversion that leads to a different amino acid with different biochemical properties at position 71, potentially causing the major lack of function. To evaluate the impact of this variant, we used the PolyPhen-2 software, which classified it as possibly damaging. Furthermore, the frequency of this mutant allele is likely extremely rare, since it has only been reported on twice, and a population frequency is not yet available. In conclusion, we propose that the HPRTYale variant is pathogenic, and should be included on lab reports hereafter.

  16. An obesity-associated FTO gene variant and increased energy intake in children.

    Science.gov (United States)

    Cecil, Joanne E; Tavendale, Roger; Watt, Peter; Hetherington, Marion M; Palmer, Colin N A

    2008-12-11

    Variation in the fat mass and obesity-associated (FTO) gene has provided the most robust associations with common obesity to date. However, the role of FTO variants in modulating specific components of energy balance is unknown. We studied 2726 Scottish children, 4 to 10 years of age, who underwent genotyping for FTO variant rs9939609 and were measured for height and weight. A subsample of 97 children was examined for possible association of the FTO variant with adiposity, energy expenditure, and food intake. In the total study group and the subsample, the A allele of rs9939609 was associated with increased weight (P=0.003 and P=0.049, respectively) and body-mass index (P=0.003 and P=0.03, respectively). In the intensively phenotyped subsample, the A allele was also associated with increased fat mass (P=0.01) but not with lean mass. Although total and resting energy expenditures were increased in children with the A allele (P=0.009 and P=0.03, respectively), resting energy expenditure was identical to that predicted for the age and weight of the child, indicating that there is no defect in metabolic adaptation to obesity in persons bearing the risk-associated allele. The A allele was associated with increased energy intake (P=0.006) independently of body weight. In contrast, the weight of food ingested by children who had the allele was similar to that in children who did not have the allele (P=0.82). The FTO variant that confers a predisposition to obesity does not appear to be involved in the regulation of energy expenditure but may have a role in the control of food intake and food choice, suggesting a link to a hyperphagic phenotype or a preference for energy-dense foods. 2008 Massachusetts Medical Society

  17. Substrate-Induced Dimerization of Engineered Monomeric Variants of Triosephosphate Isomerase from Trichomonas vaginalis.

    Directory of Open Access Journals (Sweden)

    Samuel Lara-Gonzalez

    Full Text Available The dimeric nature of triosephosphate isomerases (TIMs is maintained by an extensive surface area interface of more than 1600 Å2. TIMs from Trichomonas vaginalis (TvTIM are held in their dimeric state by two mechanisms: a ball and socket interaction of residue 45 of one subunit that fits into the hydrophobic pocket of the complementary subunit and by swapping of loop 3 between subunits. TvTIMs differ from other TIMs in their unfolding energetics. In TvTIMs the energy necessary to unfold a monomer is greater than the energy necessary to dissociate the dimer. Herein we found that the character of residue I45 controls the dimer-monomer equilibrium in TvTIMs. Unfolding experiments employing monomeric and dimeric mutants led us to conclude that dimeric TvTIMs unfold following a four state model denaturation process whereas monomeric TvTIMs follow a three state model. In contrast to other monomeric TIMs, monomeric variants of TvTIM1 are stable and unexpectedly one of them (I45A is only 29-fold less active than wild-type TvTIM1. The high enzymatic activity of monomeric TvTIMs contrast with the marginal catalytic activity of diverse monomeric TIMs variants. The stability of the monomeric variants of TvTIM1 and the use of cross-linking and analytical ultracentrifugation experiments permit us to understand the differences between the catalytic activities of TvTIMs and other marginally active monomeric TIMs. As TvTIMs do not unfold upon dimer dissociation, herein we found that the high enzymatic activity of monomeric TvTIM variants is explained by the formation of catalytic dimeric competent species assisted by substrate binding.

  18. Nuclear variants of bone morphogenetic proteins

    Directory of Open Access Journals (Sweden)

    Meinhart Christopher A

    2010-03-01

    Full Text Available Abstract Background Bone morphogenetic proteins (BMPs contribute to many different aspects of development including mesoderm formation, heart development, neurogenesis, skeletal development, and axis formation. They have previously been recognized only as secreted growth factors, but the present study detected Bmp2, Bmp4, and Gdf5/CDMP1 in the nuclei of cultured cells using immunocytochemistry and immunoblotting of nuclear extracts. Results In all three proteins, a bipartite nuclear localization signal (NLS was found to overlap the site at which the proproteins are cleaved to release the mature growth factors from the propeptides. Mutational analyses indicated that the nuclear variants of these three proteins are produced by initiating translation from downstream alternative start codons. The resulting proteins lack N-terminal signal peptides and are therefore translated in the cytoplasm rather than the endoplasmic reticulum, thus avoiding proteolytic processing in the secretory pathway. Instead, the uncleaved proteins (designated nBmp2, nBmp4, and nGdf5 containing the intact NLSs are translocated to the nucleus. Immunostaining of endogenous nBmp2 in cultured cells demonstrated that the amount of nBmp2 as well as its nuclear/cytoplasmic distribution differs between cells that are in M-phase versus other phases of the cell cycle. Conclusions The observation that nBmp2 localization varies throughout the cell cycle, as well as the conservation of a nuclear localization mechanism among three different BMP family members, suggests that these novel nuclear variants of BMP family proteins play an important functional role in the cell.

  19. Assessing pathogenicity of MLH1 variants by co-expression of human MLH1 and PMS2 genes in yeast

    Directory of Open Access Journals (Sweden)

    Hudler Petra

    2009-10-01

    Full Text Available Abstract Background Loss of DNA mismatch repair (MMR in humans, mainly due to mutations in the hMLH1 gene, is linked to hereditary nonpolyposis colorectal cancer (HNPCC. Because not all MLH1 alterations result in loss of MMR function, accurate characterization of variants and their classification in terms of their effect on MMR function is essential for reliable genetic testing and effective treatment. To date, in vivo assays for functional characterization of MLH1 mutations performed in various model systems have used episomal expression of the modified MMR genes. We describe here a novel approach to determine accurately the functional significance of hMLH1 mutations in vivo, based on co-expression of human MLH1 and PMS2 in yeast cells. Methods Yeast MLH1 and PMS1 genes, whose protein products form the MutLα complex, were replaced by human orthologs directly on yeast chromosomes by homologous recombination, and the resulting MMR activity was tested. Results The yeast strain co-expressing hMLH1 and hPMS2 exhibited the same mutation rate as the wild-type. Eight cancer-related MLH1 variants were introduced, using the same approach, into the prepared yeast model, and their effect on MMR function was determined. Five variants (A92P, S93G, I219V, K618R and K618T were classified as non-pathogenic, whereas variants T117M, Y646C and R659Q were characterized as pathogenic. Conclusion Results of our in vivo yeast-based approach correlate well with clinical data in five out of seven hMLH1 variants and the described model was thus shown to be useful for functional characterization of MLH1 variants in cancer patients found throughout the entire coding region of the gene.

  20. Plasma Levels of Risk-Variant APOL1 Do Not Associate with Renal Disease in a Population-Based Cohort.

    Science.gov (United States)

    Kozlitina, Julia; Zhou, Haihong; Brown, Patricia N; Rohm, Rory J; Pan, Yi; Ayanoglu, Gulesi; Du, Xiaoyan; Rimmer, Eric; Reilly, Dermot F; Roddy, Thomas P; Cully, Doris F; Vogt, Thomas F; Blom, Daniel; Hoek, Maarten

    2016-10-01

    Two common missense variants in APOL1 (G1 and G2) have been definitively linked to CKD in black Americans. However, not all individuals with the renal-risk genotype develop CKD, and little is known about how APOL1 variants drive disease. Given the association of APOL1 with HDL particles, which are cleared by the kidney, differences in the level or quality of mutant APOL1‑HDL particles could be causal for disease and might serve as a useful risk stratification marker. We measured plasma levels of G0 (low risk), G1, and G2 APOL1 in 3450 individuals in the Dallas Heart Study using a liquid chromatography-MS method that enabled quantitation of the different variants. Additionally, we characterized native APOL1‑HDL from donors with no or two APOL1 risk alleles by size-exclusion chromatography and analysis of immunopurified APOL1‑HDL particles. Finally, we identified genetic loci associated with plasma APOL1 levels and tested for APOL1-dependent association with renal function. Although we replicated the previous association between APOL1 variant status and renal function in nondiabetic individuals, levels of circulating APOL1 did not associate with microalbuminuria or GFR. Furthermore, the size or known components of APOL1‑HDL did not consistently differ in subjects with the renal-risk genotype. Genetic association studies implicated variants in loci harboring haptoglobin-related protein (HPR), APOL1, and ubiquitin D (UBD) in the regulation of plasma APOL1 levels, but these variants did not associate with renal function. Collectively, these data demonstrate that the risk of renal disease associated with APOL1 is probably not related to circulating levels of the mutant protein.

  1. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... Projects » Learn the Link - Drugs and HIV Learn the Link - Drugs and HIV Email Facebook Twitter 2005 – ... and to help us Send the Message . Get the Facts What are HIV and AIDS? HIV (human ...

  2. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... the link between drug abuse and HIV infection. It contains information for young people, parents and teachers, ... present time. The virus (HIV) and the disease it causes (AIDS) are often linked and referred to ...

  3. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... the Link - Drugs and HIV Learn the Link - Drugs and HIV Email Facebook Twitter 2005 –Ongoing Behaviors ... GA: CDC, DHHS. Retrieved June 2012 How are Drug Abuse and HIV Related? Drug abuse and addiction ...

  4. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... the Link - Drugs and HIV Learn the Link - Drugs and HIV Email Facebook Twitter 2005 –Ongoing Behaviors ... GA: CDC, DHHS. Retrieved June 2012 How are Drug Abuse and HIV Related? Drug abuse and addiction ...

  5. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... the link between drug abuse and HIV infection. It contains information for young people, parents and teachers, ... present time. The virus (HIV) and the disease it causes (AIDS) are often linked and referred to ...

  6. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... Projects » Learn the Link - Drugs and HIV Learn the Link - Drugs and HIV Email Facebook Twitter 2005 – ... and to help us Send the Message . Get the Facts What are HIV and AIDS? HIV (human ...

  7. Excess variants in AFF2 detected by massively parallel sequencing of males with autism spectrum disorder.

    Science.gov (United States)

    Mondal, Kajari; Ramachandran, Dhanya; Patel, Viren C; Hagen, Katie R; Bose, Promita; Cutler, David J; Zwick, Michael E

    2012-10-01

    Autism spectrum disorder (ASD) is a heterogeneous disorder with substantial heritability, most of which is unexplained. ASD has a population prevalence of one percent and affects four times as many males as females. Patients with fragile X E (FRAXE) intellectual disability, which is caused by a silencing of the X-linked gene AFF2, display a number of ASD-like phenotypes. Duplications and deletions at the AFF2 locus have also been reported in cases with moderate intellectual disability and ASD. We hypothesized that other rare X-linked sequence variants at the AFF2 locus might contribute to ASD. We sequenced the AFF2 genomic region in 202 male ASD probands and found that 2.5% of males sequenced had missense mutations at highly conserved evolutionary sites. When compared with the frequency of missense mutations in 5545 X chromosomes from unaffected controls, we saw a statistically significant enrichment in patients with ASD (OR: 4.9; P < 0.014). In addition, we identified rare AFF2 3' UTR variants at conserved sites which alter gene expression in a luciferase assay. These data suggest that rare variation in AFF2 may be a previously unrecognized ASD susceptibility locus and may help explain some of the male excess of ASD.

  8. Managing Process Variants in the Process Life Cycle

    NARCIS (Netherlands)

    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 supp

  9. 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.

  10. Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    van Es, M.A.; Schelhaas, H.J.; van Vught, P.W.; Ticozzi, N.; Andersen, P.M.; Groen, E.J.; Schulte, C.; Blauw, H.M.; Koppers, M.; Diekstra, F.P.; Fumoto, K.; Leclerc, A.L.; Keagle, P.; Bloem, B.R.; Scheffer, H.; van Nuenen, B.F.; van Blitterswijk, M.; van Rheenen, W.; Wills, A.M.; Lowe, P.P.; Hu, G.F.; Yu, W.; Kishikawa, H.; Wu, D.; Folkerth, R.D.; Mariani, C.; Goldwurm, S.; Pezzoli, G.; van Damme, P.A.; Lemmens, R.; Dahlberg, C.; Birve, A.; Fernandez-Santiago, R.; Waibel, S.; Klein, C.; Weber, M.; van der Kooi, A.J.; de Visser, M.; Verbaan, D.; van Hilten, J.J.; Heutink, P.; Hennekam, E.A.; Cuppen, E.; Berg, D.; Brown Jr., R.H.; Silani, V.; Gasser, T.; Ludolph, A.C.; Robberecht, W.; Ophoff, R.A.; Veldink, J.H.; Pasterkamp, R.J.; Bakker, P.A.H.M.; Landers, J.E.; van de Warrenburg, B.P.; van den Berg, L.

    2011-01-01

    OBJECTIVE: Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS

  11. Rare variants in PLXNA4 and Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Eva C Schulte

    Full Text Available Approximately 20% of individuals with Parkinson's disease (PD report a positive family history. Yet, a large portion of causal and disease-modifying variants is still unknown. We used exome sequencing in two affected individuals from a family with late-onset familial PD followed by frequency assessment in 975 PD cases and 1014 ethnically-matched controls and linkage analysis to identify potentially causal variants. Based on the predicted penetrance and the frequencies, a variant in PLXNA4 proved to be the best candidate and PLXNA4 was screened for additional variants in 862 PD cases and 940 controls, revealing an excess of rare non-synonymous coding variants in PLXNA4 in individuals with PD. Although we cannot conclude that the variant in PLXNA4 is indeed the causative variant, these findings are interesting in the light of a surfacing role of axonal guidance mechanisms in neurodegenerative disorders but, at the same time, highlight the difficulties encountered in the study of rare variants identified by next-generation sequencing in diseases with autosomal dominant or complex patterns of inheritance.

  12. 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.

  13. 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.

  14. Hepatitis E Virus Variant in Farmed Mink, Denmark

    DEFF Research Database (Denmark)

    Krog, Jesper Schak; Breum, Solvej Østergaard; Jensen, Trine Hammer

    2013-01-01

    Hepatitis E virus (HEV) is a zoonotic virus for which pigs are the primary animal reservoir. To investigate whether HEV occurs in mink in Denmark, we screened feces and tissues from domestic and wild mink. Our finding of a novel HEV variant supports previous findings of HEV variants in a variety...

  15. Two new variants of the manifold-mapping technique

    NARCIS (Netherlands)

    Echeverria, D.

    2006-01-01

    Manifold-mapping is an efficient surrogate-based optimization technique aimed at the acceleration of very time-consuming design problems. In this paper we present two new variants of the original algorithm that make it applicable to a broader range of optimization scenarios. The first variant is use

  16. denovo-db: a compendium of human de novo variants.

    Science.gov (United States)

    Turner, Tychele N; Yi, Qian; Krumm, Niklas; Huddleston, John; Hoekzema, Kendra; F Stessman, Holly A; Doebley, Anna-Lisa; Bernier, Raphael A; Nickerson, Deborah A; Eichler, Evan E

    2017-01-04

    Whole-exome and whole-genome sequencing have facilitated the large-scale discovery of de novo variants in human disease. To date, most de novo discovery through next-generation sequencing focused on congenital heart disease and neurodevelopmental disorders (NDDs). Currently, de novo variants are one of the most significant risk factors for NDDs with a substantial overlap of genes involved in more than one NDD. To facilitate better usage of published data, provide standardization of annotation, and improve accessibility, we created denovo-db (http://denovo-db.gs.washington.edu), a database for human de novo variants. As of July 2016, denovo-db contained 40 different studies and 32,991 de novo variants from 23,098 trios. Database features include basic variant information (chromosome location, change, type); detailed annotation at the transcript and protein levels; severity scores; frequency; validation status; and, most importantly, the phenotype of the individual with the variant. We included a feature on our browsable website to download any query result, including a downloadable file of the full database with additional variant details. denovo-db provides necessary information for researchers to compare their data to other individuals with the same phenotype and also to controls allowing for a better understanding of the biology of de novo variants and their contribution to disease. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  17. Rare variants in XRCC2 as breast cancer susceptibility alleles

    NARCIS (Netherlands)

    Hilbers, F.S.; Wijnen, J.T.; Hoogerbrugge-van der Linden, N.; Oosterwijk, J.C.; Collee, M.J.; Peterlongo, P.; Radice, P.; Manoukian, S.; Feroce, I.; Capra, F.; Couch, F.J.; Wang, X.; Guidugli, L.; Offit, K.; Shah, S.; Campbell, I.G.; Thompson, E.R.; James, P.A.; Trainer, A.H.; Gracia, J.; Benitez, J.; Asperen, C.J. van; Devilee, P.

    2012-01-01

    BACKGROUND: Recently, rare germline variants in XRCC2 were detected in non-BRCA1/2 familial breast cancer cases, and a significant association with breast cancer was reported. However, the breast cancer risk associated with these variants needs further evaluation. METHODS: The coding regions and exo

  18. Isolation and characterization of human rhinovirus antigenic variants

    Energy Technology Data Exchange (ETDEWEB)

    Watson, D.G.

    1985-01-01

    Isolation of antigenic variants of human rhinovirus types 2, 14, and 17 was attempted by plaquing untreated virus (P-isolates), selecting variants in the presence of homologous antiserum (C-isolates), and by selecting variants in the presence of antibody following 5-fluorouracil mutagenesis (M-isolates). All viruses were triple-plaque purified and purity neutralization tested prior to isolate selection. Based on a fourfold reduction in neutralizing antibody titer to homologous antiserum, no antigenic variation was found in P-isolates from the three serotypes examined. Antigenic variants of all three serotypes could be isolated by the antiserum selection method (C-isolates). However, antigenic variants of RV17 were isolated at a much higher frequency and showed a larger degree of variation than those of RV2 and RV14. At least two of the variants selected, RV17 (C301) and RV2 (M803), failed to be neutralized by the known 89 rhinovirus antiserum. SDS-polyacrylamide gel electrophoresis of (/sup 35/S) methionine-labelled virion polypeptides revealed that each serotype had a characteristic pattern and that selected RV2 and RV17 isolates had patterns identical to those of the prototype strains. By isoelectric focusing an antigenic variant of RV2 was shown to contain altered virion polypeptides VP1 and VP2 whereas two RV17 antigenic variants demonstrated alterations only in the VP1 polypeptide.

  19. ADULT VARIANT BARTTER’S SYNDROME- A CASE REPORT

    Directory of Open Access Journals (Sweden)

    Ishwar Sidappa Hasabi

    2017-02-01

    Full Text Available BACKGROUND Bartter syndrome is a group of channelopathies with different genetic origins and molecular pathophysiologies, but sharing common feature of decreased tubular transport of sodium chloride in thick ascending loop of Henle (TAL, 1 although more common in antenatal group. Classic adult variant of Bartter syndrome is a rare entity. We hereby present a rare adult variant of classic Bartter syndrome.

  20. 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 b...

  1. Pathological assessment of mismatch repair gene variants in Lynch syndrome

    DEFF Research Database (Denmark)

    Rasmussen, Lene Juel; Heinen, Christopher D; Royer-Pokora, Brigitte;

    2012-01-01

    . Also, identifying family members that do not carry the variant is important so they can be released from the intensive surveillance. Determining which genetic variants are pathogenic and which are neutral is a major challenge in clinical genetics. The profound mechanistic knowledge on the genetics...

  2. ITK optical links backup document

    CERN Document Server

    Huffman, B T; The ATLAS collaboration; Flick, T; Ye, J

    2013-01-01

    This document describes the proposed optical links to be used for the ITK in the phase II upgrade. The current R&D for optical links pursued in the Versatile Link group is reviewed. In particular the results demonstrating the radiation tolerance of all the on-detector components are documented. The bandwidth requirements and the resulting numerology are given.

  3. Hyperbolic semi-adequate links

    OpenAIRE

    Futer, David; Kalfagianni, Efstratia; Purcell, Jessica S.

    2013-01-01

    We provide a diagrammatic criterion for semi-adequate links to be hyperbolic. We also give a conjectural description of the satellite structures of semi-adequate links. One application of our result is that the closures of sufficiently complicated positive braids are hyperbolic links.

  4. Martel's links with USA

    Directory of Open Access Journals (Sweden)

    Trevor Shaw

    1997-01-01

    Full Text Available Of the 29% foreign members in the Société de Spéléologie, five lived in USA. They were Luella Owen (the only woman member of the Société, R. Ellsworth Cali, H.C. Hovey, E Van Epps and C. R. Blackall. E.S. Balch, though not a member, also knew Martel. These members, between them, published ten papers in Spelunca, which also reviewed their other work. The activities of these six, and their links with France, are discussed. Martel actively encouraged cave work in America, as elsewhere, and Hovey, who had been with him during the survey of Aven Armand, he knew quite well. In 1912 Martel at last visited USA himself and the barometer readings he took in Mamoth Cave to measure altitude enabled him to draw the first longitudinal section of the cave since 1835.

  5. Linking place and mind

    DEFF Research Database (Denmark)

    Jensen, Marie Møller

    2016-01-01

    This paper investigates the salience of vernacular Tyneside forms on the basis of theories of enregisterment and exemplar processing. On one level, exemplar theory provides a psycholinguistic account of how the link between social value and linguistic features is possible. Conversely, integrating...... the notion of social value into exemplar theory extends the value of this originally cognitive theory to social domains. It is suggested that the association of social value and particular local, linguistic forms may contribute to the salience of these forms among local speakers. The empirical work reported...... here takes the form of a questionnaire study, which aims to uncover Tyneside inhabitants' awareness of forms as well as their affiliation with the local community. Results showed differences in frequency perceptions between participants themselves and others which indicate that speakers can identify...

  6. Heterosexual Transmission of Subtype C HIV-1 Selects Consensus-Like Variants without Increased Replicative Capacity or Interferon-α Resistance.

    Directory of Open Access Journals (Sweden)

    Martin J Deymier

    2015-09-01

    Full Text Available Heterosexual transmission of HIV-1 is characterized by a genetic bottleneck that selects a single viral variant, the transmitted/founder (TF, during most transmission events. To assess viral characteristics influencing HIV-1 transmission, we sequenced 167 near full-length viral genomes and generated 40 infectious molecular clones (IMC including TF variants and multiple non-transmitted (NT HIV-1 subtype C variants from six linked heterosexual transmission pairs near the time of transmission. Consensus-like genomes sensitive to donor antibodies were selected for during transmission in these six transmission pairs. However, TF variants did not demonstrate increased viral fitness in terms of particle infectivity or viral replicative capacity in activated peripheral blood mononuclear cells (PBMC and monocyte-derived dendritic cells (MDDC. In addition, resistance of the TF variant to the antiviral effects of interferon-α (IFN-α was not significantly different from that of non-transmitted variants from the same transmission pair. Thus neither in vitro viral replicative capacity nor IFN-α resistance discriminated the transmission potential of viruses in the quasispecies of these chronically infected individuals. However, our findings support the hypothesis that within-host evolution of HIV-1 in response to adaptive immune responses reduces viral transmission potential.

  7. Expression of Caspase-1 Gene Transcript Variant mRNA in Peripheral Blood Mononuclear Cells of Patients with Primary Gout in Different TCM Syndromes

    Science.gov (United States)

    Dang, Wan-Tai; Xu, Dan; Xie, Wen-Guang; Zhou, Jing-Guo

    2015-01-01

    A large number of studies have shown that cysteinyl aspartate specific protease-1 (CASP1) played an important role in the inflammatory response of primary gout, but the decreased expression of different CASP1 transcript variant could inhibit the activation of IL-1β. Our study mainly analyzed the expression level and function of CASP1 gene transcript variant mRNA in peripheral blood mononuclear cells of patients with gout in different TCM syndromes. The expression of CASP1 gene transcript variant and IL-1β mRNA in PBMCs were detected in patients with PG [acute phase (AP: 44 cases); nonacute phase (NAP: 52 cases)] and healthy controls (HC: 30 cases) by reverse transcription-polymerase chain reaction and/or real-time quantitative polymerase chain reaction. The expressions of plasma IL-1β in patients with PG and HC were detected by enzyme-linked immunosorbent assay. Dysregulated expression of the CASP1 gene and its transcript variant, plasma proinflammatory cytokines in all patients with primary gout in different TCM syndromes, correlation analysis showed that there was negative correlation between the expression of CASP1-gamma gene transcript variant mRNA and IL-1β protein in APPG group. The study suggested that CASP1 gene and its transcript variant may play a critical role in the inflammatory response of patients with PG in different phases and TCM syndromes. PMID:26557856

  8. Expression of Caspase-1 Gene Transcript Variant mRNA in Peripheral Blood Mononuclear Cells of Patients with Primary Gout in Different TCM Syndromes

    Directory of Open Access Journals (Sweden)

    Wan-Tai Dang

    2015-01-01

    Full Text Available A large number of studies have shown that cysteinyl aspartate specific protease-1 (CASP1 played an important role in the inflammatory response of primary gout, but the decreased expression of different CASP1 transcript variant could inhibit the activation of IL-1β. Our study mainly analyzed the expression level and function of CASP1 gene transcript variant mRNA in peripheral blood mononuclear cells of patients with gout in different TCM syndromes. The expression of CASP1 gene transcript variant and IL-1β mRNA in PBMCs were detected in patients with PG [acute phase (AP: 44 cases; nonacute phase (NAP: 52 cases] and healthy controls (HC: 30 cases by reverse transcription-polymerase chain reaction and/or real-time quantitative polymerase chain reaction. The expressions of plasma IL-1β in patients with PG and HC were detected by enzyme-linked immunosorbent assay. Dysregulated expression of the CASP1 gene and its transcript variant, plasma proinflammatory cytokines in all patients with primary gout in different TCM syndromes, correlation analysis showed that there was negative correlation between the expression of CASP1-gamma gene transcript variant mRNA and IL-1β protein in APPG group. The study suggested that CASP1 gene and its transcript variant may play a critical role in the inflammatory response of patients with PG in different phases and TCM syndromes.

  9. Targeted sequencing identifies a novel SH2D1A pathogenic variant in a Chinese family: Carrier screening and prenatal genetic testing

    Science.gov (United States)

    Chen, Yi-Yao; Li, Shu-Yuan; Zhang, Lan-Lan; Shen, Ying-Hua; Chang, Chun-Xin; Xiang, Yu-Qian; Huang, He-Feng; Xu, Chen-Ming

    2017-01-01

    X-linked lymphoproliferative disease type 1 (XLP1) is a rare primary immunodeficiency characterized by a clinical triad consisting of severe EBV-induced hemophagocytic lymphohistiocytosis, B-cell lymphoma, and dysgammaglobulinemia. Mutations in SH2D1A gene have been revealed as the cause of XLP1. In this study, a pregnant woman with recurrence history of birthing immunodeficiency was screened for pathogenic variant because the proband sample was unavailable. We aimed to clarify the genetic diagnosis and provide prenatal testing for the family. Next-generation sequencing (NGS)-based multigene panel was used in carrier screening of the pregnant woman. Variants of immunodeficiency related genes were analyzed and prioritized. Candidate variant was verified by using Sanger sequencing. The possible influence of the identified variant was evaluated through RNA assay. Amniocentesis, karyotyping, and Sanger sequencing were performed for prenatal testing. We identified a novel de novo frameshift SH2D1A pathogenic variant (c.251_255delTTTCA) in the pregnant carrier. Peripheral blood RNA assay indicated that the mutant transcript could escape nonsense-mediated mRNA decay (NMD) and might encode a C-terminal truncated protein. Information of the variant led to success prenatal diagnosis of the fetus. In conclusion, our study clarified the genetic diagnosis and altered disease prevention for a pregnant carrier of XLP1. PMID:28231257

  10. Beyond words: Pragmatic inference in behavioral variant of frontotemporal degeneration

    Science.gov (United States)

    Spotorno, Nicola; McMillan, Corey T.; Rascovsky, Katya; Irwin, David J.; Clark, Robin; Grossman, Murray

    2015-01-01

    When the message of a speaker goes beyond the literal or logical meaning of the sentences used, a pragmatic inference is required to understand the complete meaning of an utterance. Here we study one example of pragmatic inference, called scalar implicature. Such an inference is required when a weaker term “some” is used in a sentence like “Some of the students passed the exam” because the speaker presumably had a reason not to use a stronger term like “all”. We investigated the comprehension of scalar implicatures in a group of 17 non-aphasic patients with behavioral variant frontotemporal degeneration (bvFTD) in order to test the contribution of non-linguistic decision-making ability and the role of prefrontal cortex in supporting the computation of pragmatic inferences. The results of two experiments point to a deficit in producing alternative interpretations beyond a logical reading. bvFTD patients thus prefer the narrowly literal or logical interpretation of a scalar term when they must generate a possible alternative interpretation by themselves, but patients prefer a pragmatic reading when offered a choice between the logical and the pragmatic interpretation of the same sentence. An imaging analysis links bvFTD patients’ spontaneous tendency toward a narrowly logical interpretation with atrophy in ventromedial prefrontal cortex. Our findings are consistent with the pragmatic tolerance hypothesis, which proposes that difficulty generating alternative interpretations of an utterance, rather than a frank inability to compute an inference, affects the comprehension of a scalar term. PMID:26150205

  11. 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.

  12. Variante oncocítica del carcinoma mucoepidermoide Oncocyte variant of mucoepidermoid carcinoma

    Directory of Open Access Journals (Sweden)

    Sirced Salazar Rodríguez

    2011-03-01

    Full Text Available El carcinoma mucoepidermoide es el más común de todos los tumores malignos de glándulas salivales, constituye el 30 % de ellos. Aproximadamente la mitad de los casos (53 % ocurre en las glándulas salivales mayores. El 45 % predomina en glándula parótida, el 7 % en la submandibular y el 1 % en la glándula sublingual. Este tumor se presenta con más frecuencia en el sexo femenino (3:2 y en la quinta década de la vida. Múltiples variantes, con diferentes rangos de diferenciación han sido descritas, se incluyen: la oncocítica, esclerosante, uniquística, sebácea, de células claras, células globosas de alto grado, células fusocelular y psamomatosa. El carcinoma mucoepidermoide variante oncocítica es un subtipo raro que puede mostrar prominentes cambios oncocíticos. Se reporta un caso de carcinoma mucoepidermoide variante oncocítica de alto grado histológico. El índice de Ki 67 fue del 5 %, el tumor fue negativo para C-erb2 y presentó inmunorreactividad para E-caderina y Syndecan-1.The mucoepidermoid carcinoma is the commonest of all malignant tumors of salivary glands, accounting for the 30 % of them. Approximately the half of cases (53 % occurs in the major salivary glands. The 45 % has predominance in parotid gland, the 7 % in the submandibular one, and the 1 % in the sublingual gland one. This type of tumor is more frequent in female sex (3-2 and at fifth decade of life. Multiple variants with different ranks have been described including the oncocyte, sclerosant, unicystic, sebaceous, of clear cells, high degree spherical cells, fusocellular and psammomatous. The mucoepidermoid carcinoma, oncocyte variant, is an unusual subtype that may to shows significant oncocyte changes. Authors report a case of histological high degree mucoepidermoid carcinoma. The rate of Ki 67 was of 5 %, the negative tumor for C-erb2 and had immunoreaction to E-caderine and Syndecan-1.

  13. Meta-analysis of Gene-Level Associations for Rare Variants Based on Single-Variant Statistics

    NARCIS (Netherlands)

    Hu, Y.J.; Berndt, S.I.; Gustafsson, S.; Ganna, A.; Hirschhorn, J.; North, K.E.; Ingelsson, E.; Lin, D.Y.; Kiemeney, L.A.L.M.; Vermeulen, S.

    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 rar

  14. Ecological estimation of the possible variants new Ukrainian shipping way between the Danube and the Black Sea

    Science.gov (United States)

    Berlinsky, N.

    2007-05-01

    The better way or optimal variant means economic advisability of organization and using the way and the same time minimization of anthropogenic press. The first problem's factor is - all kinds' variants cross the area of the Danube Biosphere Reserve. The next factor is - all kinds of variants need dredging works in the sea shallow water so called bar's zone for marine entrance channel. As for natural factors there are also two. The first one is a long term delta evolution and the second is the process of water discharge redistribution. If the human influence to the first factor is still limited the second factor's influence can be unlimited - it is easy to do by jetty or dams construction. At present there are nine possible variants of the DWW: Variant 1. It is an artificial canal built as an ameliorative at 80-s between the Danube and Sasik liman. It provokes the water discharge redistribution up on 16.6% from the Danube run off (from the total Q=3000 m3/c for 54 km), hydrological regime in Ukrainian delta and ecological conditions will be sharply worsened. This project supposed a giant dredging works. Variant 2. The Project of engineer P.S. Chekhovich (1904). The length of the canal is 10 km. (The problems are: it is an artificial canal, needs the bridge, cross the wetlands area, redistribute water discharge from the Danube). Variant 3. Solomonov branch - Zhebryany bay modern Project by engineer V.P. Zizak (2000), The problems are: it is an artificial canal also, but with locks, needs the bridge, to cross the wetlands area, the water discharge redistribution from the Danube up on 2.27% (from the total Q=3000 m3/c for 54 km). The length of the canal is 9 km. Two last variants have orientation from Solomonov arm to Zhebriany bay. The other variants of DWW linked with Ochakovsky and Starostambulsky arms systems. Ochakosky system is dying off system from geological point of view. There are two arms which can be examined for DWW - Prorva arm and Potapovo arm. Besides

  15. Plasminogen activator inhibitor 1 4G/5G and -844G/A variants in idiopathic recurrent pregnancy loss.

    Science.gov (United States)

    Magdoud, Kalthoum; Herbepin, Viviana G; Touraine, Renaud; Almawi, Wassim Y; Mahjoub, Touhami

    2013-09-01

    Plasminogen activator inhibitor type 1 (PAI-1) regulates fibrinolysis, and the common promoter region variants -675G/A (4G/5G) and -844G/A are associated with increased thrombotic risk. Despite evidence linking altered fibrinolysis with adverse pregnancy events, including idiopathic recurrent pregnancy loss (RPL), the contribution of PAI-1 variants to RPL risk remains controversial. We investigated the association between the PAI-1 -844G/A and 4G/5G (-675G/A) variants with altered risk of RPL. This was a case-control study involving 304 women with confirmed RPL and 371 age- and ethnically matched control women. PAI-1 genotyping was performed by PCR single-specific primer -675 (G/A) and real-time PCR (-844G/A) analysis. Minor allele frequency (MAF) of 4G/5G (P 5G single-nucleotide polymorphism (SNP) was significantly associated with RPL under additive, dominant, and recessive genetic models; no association of -844G/A with RPL was seen irrespective of the genetic model tested. Taking common -844G/5G haplotype as reference (OR = 1.00), multivariate analysis confirmed the association of 4G-containing -844A/4G (P 5G, but not -844G/A, PAI-1 variant is associated with an increased risk of RPL. © 2013 John Wiley & Sons Ltd.

  16. Genetic variants in FGFR2 and FGFR4 genes and skin cancer risk in the Nurses' Health Study

    Directory of Open Access Journals (Sweden)

    Qureshi Abrar A

    2009-06-01

    Full Text Available Abstract Background 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. Methods 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. Results We found no evidence for associations between these seven genetic variants and the risks of melanoma and nonmelanocytic skin cancer. Conclusion 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.

  17. Characterization of Genomic Variants Associated with Scout and Recruit Behavioral Castes in Honey Bees Using Whole-Genome Sequencing.

    Directory of Open Access Journals (Sweden)

    Bruce R Southey

    Full Text Available Among forager honey bees, scouts seek new resources and return to the colony, enlisting recruits to collect these resources. Differentially expressed genes between these behaviors and genetic variability in scouting phenotypes have been reported. Whole-genome sequencing of 44 Apis mellifera scouts and recruits was undertaken to detect variants and further understand the genetic architecture underlying the behavioral differences between scouts and recruits. The median coverage depth in recruits and scouts was 10.01 and 10.7 X, respectively. Representation of bacterial species among the unmapped reads reflected a more diverse microbiome in scouts than recruits. Overall, 1,412,705 polymorphic positions were analyzed for associations with scouting behavior, and 212 significant (p-value 1000 bp apart from each other. A number of these variants were mapped to ncRNA LOC100578102, solute carrier family 12 member 6-like gene, and LOC100576965 (meprin and TRAF-C homology domain containing gene. Functional categories represented among the genes corresponding to significant variants included: neuronal function, exoskeleton, immune response, salivary gland development, and enzymatic food processing. These categories offer a glimpse into the molecular support to the behaviors of scouts and recruits. The level of association between genomic variants and scouting behavior observed in this study may be linked to the honey bee's genomic plasticity and fluidity of transition between castes.

  18. A method of predicting changes in human gene splicing induced by genetic variants in context of cis-acting elements

    Directory of Open Access Journals (Sweden)

    Hicks Chindo

    2010-01-01

    Full Text Available Abstract Background Polymorphic variants and mutations disrupting canonical splicing isoforms are among the leading causes of human hereditary disorders. While there is a substantial evidence of aberrant splicing causing Mendelian diseases, the implication of such events in multi-genic disorders is yet to be well understood. We have developed a new tool (SpliceScan II for predicting the effects of genetic variants on splicing and cis-regulatory elements. The novel Bayesian non-canonical 5'GC splice site (SS sensor used in our tool allows inference on non-canonical exons. Results Our tool performed favorably when compared with the existing methods in the context of genes linked to the Autism Spectrum Disorder (ASD. SpliceScan II was able to predict more aberrant splicing isoforms triggered by the mutations, as documented in DBASS5 and DBASS3 aberrant splicing databases, than other existing methods. Detrimental effects behind some of the polymorphic variations previously associated with Alzheimer's and breast cancer could be explained by changes in predicted splicing patterns. Conclusions We have developed SpliceScan II, an effective and sensitive tool for predicting the detrimental effects of genomic variants on splicing leading to Mendelian and complex hereditary disorders. The method could potentially be used to screen resequenced patient DNA to identify de novo mutations and polymorphic variants that could contribute to a genetic disorder.

  19. Identification of rare variants of DSP gene in sudden unexplained nocturnal death syndrome in the southern Chinese Han population.

    Science.gov (United States)

    Zhao, Qianhao; Chen, Yili; Peng, Longlun; Gao, Rui; Liu, Nian; Jiang, Pingping; Liu, Chao; Tang, Shuangbo; Quan, Li; Makielski, Jonathan C; Cheng, Jianding

    2016-03-01

    Sudden unexplained nocturnal death syndrome (SUNDS) is a perplexing disorder to both forensic pathologists and clinic physicians. Desmoplakin (DSP) gene was the first desmosomal gene linked to arrhythmogenic right ventricular cardiomyopathy (ARVC) which was associated with sudden death. To identify the genetic variants of the DSP gene in SUNDS in the southern Chinese Han population, we genetically screened the DSP gene in 40 sporadic SUNDS victims, 16 Brugada syndrome (BrS) patients, and 2 early repolarization syndrome (ERS) patients using next generation sequencing (NSG) and direct Sanger sequencing. A total of 10 genetic variants of the DSP gene were detected in 11 cases, comprised of two novel missense mutations (p.I125F and p.D521A) and eight previously reported rare variants. Of eight reported variants, two were previously considered pathogenic (p.Q90R and p.R2639Q), three were predicted in silico to be pathogenic (p.R315C, p.E1357D and p.D2579H), and the rest three were predicted to be benign (p.N1234S, p.R1308Q, and p.T2267S). This is the first report of DSP genetic screening in Chinese SUNDS and Brugada syndrome. Our results imply that DSP mutations contribute to the genetic cause of some SUNDS victims and maybe a new susceptible gene for Brugada syndrome.

  20. Common variants in the regulative regions of GRIA1 and GRIA3 receptor genes are associated with migraine susceptibility

    Directory of Open Access Journals (Sweden)

    Gianfrancesco Fernando

    2010-06-01

    Full Text Available Abstract Background Glutamate is the principal excitatory neurotransmitter in the central nervous system which acts by the activation of either ionotropic (AMPA, NMDA and kainate receptors or G-protein coupled metabotropic receptors. Glutamate is widely accepted to play a major role in the path physiology of migraine as implicated by data from animal and human studies. Genes involved in synthesis, metabolism and regulation of both glutamate and its receptors could be, therefore, considered as potential candidates for causing/predisposing to migraine when mutated. Methods The association of polymorphic variants of GRIA1-GRIA4 genes which encode for the four subunits (GluR1-GluR4 of the alpha-amino-3- hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA receptor for glutamate was tested in migraineurs with and without aura (MA and MO and healthy controls. Results Two variants in the regulative regions of GRIA1 (rs2195450 and GRIA3 (rs3761555 genes resulted strongly associated with MA (P = 0.00002 and P = 0.0001, respectively, but not associated with MO, suggesting their role in cortical spreading depression. Whereas the rs548294 variant in GRIA1 gene showed association primarily with MO phenotype, supporting the hypothesis that MA and MO phenotypes could be genetically related. These variants modify binding sites for transcription factors altering the expression of GRIA1 and GRIA3 genes in different conditions. Conclusions This study represents the first genetic evidence of a link between glutamate receptors and migraine.

  1. αIIbβ3 variants defined by next-generation sequencing: Predicting variants likely to cause Glanzmann thrombasthenia

    Science.gov (United States)

    Buitrago, Lorena; Rendon, Augusto; Liang, Yupu; Simeoni, Ilenia; Negri, Ana; Filizola, Marta; Ouwehand, Willem H.; Coller, Barry S.; Alessi, Marie-Christine; Ballmaier, Matthias; Bariana, Tadbir; Bellissimo, Daniel; Bertoli, Marta; Bray, Paul; Bury, Loredana; Carrell, Robin; Cattaneo, Marco; Collins, Peter; French, Deborah; Favier, Remi; Freson, Kathleen; Furie, Bruce; Germeshausen, Manuela; Ghevaert, Cedric; Gomez, Keith; Goodeve, Anne; Gresele, Paolo; Guerrero, Jose; Hampshire, Dan J.; Hadinnapola, Charaka; Heemskerk, Johan; Henskens, Yvonne; Hill, Marian; Hogg, Nancy; Johnsen, Jill; Kahr, Walter; Kerr, Ron; Kunishima, Shinji; Laffan, Michael; Natwani, Amit; Neerman-Arbez, Marguerite; Nurden, Paquita; Nurden, Alan; Ormiston, Mark; Othman, Maha; Ouwehand, Willem; Perry, David; Vilk, Shoshana Ravel; Reitsma, Pieter; Rondina, Matthew; Simeoni, Ilenia; Smethurst, Peter; Stephens, Jonathan; Stevenson, William; Szkotak, Artur; Turro, Ernest; Van Geet, Christel; Vries, Minka; Ward, June; Waye, John; Westbury, Sarah; Whiteheart, Sidney; Wilcox, David; Zhang, Bi

    2015-01-01

    Next-generation sequencing is transforming our understanding of human genetic variation but assessing the functional impact of novel variants presents challenges. We analyzed missense variants in the integrin αIIbβ3 receptor subunit genes ITGA2B and ITGB3 identified by whole-exome or -genome sequencing in the ThromboGenomics project, comprising ∼32,000 alleles from 16,108 individuals. We analyzed the results in comparison with 111 missense variants in these genes previously reported as being associated with Glanzmann thrombasthenia (GT), 20 associated with alloimmune thrombocytopenia, and 5 associated with aniso/macrothrombocytopenia. We identified 114 novel missense variants in ITGA2B (affecting ∼11% of the amino acids) and 68 novel missense variants in ITGB3 (affecting ∼9% of the amino acids). Of the variants, 96% had minor allele frequencies (MAF) < 0.1%, indicating their rarity. Based on sequence conservation, MAF, and location on a complete model of αIIbβ3, we selected three novel variants that affect amino acids previously associated with GT for expression in HEK293 cells. αIIb P176H and β3 C547G severely reduced αIIbβ3 expression, whereas αIIb P943A partially reduced αIIbβ3 expression and had no effect on fibrinogen binding. We used receiver operating characteristic curves of combined annotation-dependent depletion, Polyphen 2-HDIV, and sorting intolerant from tolerant to estimate the percentage of novel variants likely to be deleterious. At optimal cut-off values, which had 69–98% sensitivity in detecting GT mutations, between 27% and 71% of the novel αIIb or β3 missense variants were predicted to be deleterious. Our data have implications for understanding the evolutionary pressure on αIIbβ3 and highlight the challenges in predicting the clinical significance of novel missense variants. PMID:25827233

  2. Clinical importance of risk variants in the dihydropyrimidine dehydrogenase gene for the prediction of early-onset fluoropyrimidine toxicity.

    Science.gov (United States)

    Froehlich, Tanja K; Amstutz, Ursula; Aebi, Stefan; Joerger, Markus; Largiadèr, Carlo R

    2015-02-01

    We investigated the clinical relevance of dihydropyrimidine dehydrogenase gene (DPYD) variants to predict severe early-onset fluoropyrimidine (FP) toxicity, in particular of a recently discovered haplotype hapB3 and a linked deep intronic splice site mutation c.1129-5923C>G. Selected regions of DPYD were sequenced in prospectively collected germline DNA of 500 patients receiving FP-based chemotherapy. Associations of DPYD variants and haplotypes with hematologic, gastrointestinal, infectious, and dermatologic toxicity in therapy cycles 1-2 and resulting FP-dose interventions (dose reduction, therapy delay or cessation) were analyzed accounting for clinical and demographic covariates. Fifteen additional cases with toxicity-related therapy delay or cessation were retrospectively examined for risk variants. The association of c.1129-5923C>G/hapB3 (4.6% carrier frequency) with severe toxicity was replicated in an independent prospective cohort. Overall, c.1129-5923G/hapB3 carriers showed a relative risk of 3.74 (RR, 95% CI = 2.30-6.09, p = 2 × 10(-5)) for severe toxicity (grades 3-5). Of 31 risk variant carriers (c.1129-5923C>G/hapB3, c.1679T>G, c.1905+1G>A or c.2846A>T), 11 (all with c.1129-5923C>G/hapB3) experienced severe toxicity (15% of 72 cases, RR = 2.73, 95% CI = 1.61-4.63, p = 5 × 10(-6)), and 16 carriers (55%) required FP-dose interventions. Seven of the 15 (47%) retrospective cases carried a risk variant. The c.1129-5923C>G/hapB3 variant is a major contributor to severe early-onset FP toxicity in Caucasian patients. This variant may substantially improve the identification of patients at risk of FP toxicity compared to established DPYD risk variants (c.1905+1G>A, c.1679T>G and c.2846A>T). Pre-therapeutic DPYD testing may prevent 20-30% of life-threatening or lethal episodes of FP toxicity in Caucasian patients. © 2014 UICC.

  3. Rare variant analysis for family-based design.

    Directory of Open Access Journals (Sweden)

    Gourab De

    Full Text Available Genome-wide association studies have been able to identify disease associations with many common variants; however most of the estimated genetic contribution explained by these variants appears to be very modest. Rare variants are thought to have larger effect sizes compared to common SNPs but effects of rare variants cannot be tested in the GWAS setting. Here we propose a novel method to test for association of rare variants obtained by sequencing in family-based samples by collapsing the standard family-based association test (FBAT statistic over a region of interest. We also propose a suitable weighting scheme so that low frequency SNPs that may be enriched in functional variants can be upweighted compared to common variants. Using simulations we show that the family-based methods perform at par with the population-based methods under no population stratification. By construction, family-based tests are completely robust to population stratification; we show that our proposed methods remain valid even when population stratification is present.

  4. 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.

  5. Sialyloligosaccharide receptors of binding variants of polyoma virus.

    Science.gov (United States)

    Cahan, L D; Singh, R; Paulson, J C

    1983-10-30

    Hemagglutination and lytic infection of host cells by polyoma virus has been shown to require specific sialyloligosaccharide structures. The nature of the sialyloligosaccharide sequence recognized by three binding variants of polyoma virus, the large plaque (LP), small plaque (SP), and Py235 variants, was examined. Hemagglutination of native erythrocytes and erythrocytes derivatized with highly specific sialyltransferases to contain cell surface sialyloligosaccharides of defined sequence was compared for the three variants. In addition, soluble glycoprotein inhibitors of known sialyloligosaccharide structure were used to further elucidate the specificities of the three variants. There are important differences in the receptors for these variants. While all three appear to bind the structure NeuAc alpha 2,3Gal beta 1,3GalNAc the LP and Py235 variant bind the disialyl structure NeuAc alpha 2,3Gal beta 1,3(NeuAc alpha 2,6)GalNAc with much lower affinity than does the SP virus. It is suggested that polyoma virus adsorption to cells may depend on the cell surface content of at least three different sialyloligosaccharide sequences and the relative abilities of the virus variant to utilize them as receptor determinants.

  6. How important are rare variants in common disease?

    Science.gov (United States)

    Saint Pierre, Aude; Génin, Emmanuelle

    2014-09-01

    Genome-wide association studies have uncovered hundreds of common genetic variants involved in complex diseases. However, for most complex diseases, these common genetic variants only marginally contribute to disease susceptibility. It is now argued that rare variants located in different genes could in fact play a more important role in disease susceptibility than common variants. These rare genetic variants were not captured by genome-wide association studies using single nucleotide polymorphism-chips but with the advent of next-generation sequencing technologies, they have become detectable. It is now possible to study their contribution to common disease by resequencing samples of cases and controls or by using new genotyping exome arrays that cover rare alleles. In this review, we address the question of the contribution of rare variants in common disease by taking the examples of different diseases for which some resequencing studies have already been performed, and by summarizing the results of simulation studies conducted so far to investigate the genetic architecture of complex traits in human. So far, empirical data have not allowed the exclusion of many models except the most extreme ones involving only a small number of rare variants with large effects contributing to complex disease. To unravel the genetic architecture of complex disease, case-control data will not be sufficient, and alternative study designs need to be proposed together with methodological developments.

  7. 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.

  8. 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.

  9. Probabilistic Transcriptome Assembly and Variant Graph Genotyping

    DEFF Research Database (Denmark)

    Sibbesen, Jonas Andreas

    The introduction of second-generation sequencing, has in recent years allowed the biological community to determine the genomes and transcriptomes of organisms and individuals at an unprecedented rate. However, almost every step in the sequencing protocol introduces uncertainties in how the resul......The introduction of second-generation sequencing, has in recent years allowed the biological community to determine the genomes and transcriptomes of organisms and individuals at an unprecedented rate. However, almost every step in the sequencing protocol introduces uncertainties in how...... the resulting sequencing data should be interpreted. This has over the years spurred the development of many probabilistic methods that are capable of modelling dierent aspects of the sequencing process. Here, I present two of such methods that were developed to each tackle a dierent problem in bioinformatics...... that this approach outperforms existing state-of-the-art methods measured using sensitivity and precision on both simulated and real data. The second is a novel probabilistic method that uses exact alignment of k-mers to a set of variants graphs to provide unbiased estimates of genotypes in a population...

  10. Linking to the Future

    Science.gov (United States)

    Moore, John W.

    1999-09-01

    of JCE in the mail each month, and I expect you do too. I can glance at the cover to get an overview of an issue's content, and I usually am enticed inside by intriguing cover art. I can scan the table of contents to find articles I want to read, or I can just browse through the issue to see what looks interesting. Usually the editors have juxtaposed related articles so that I often find a small treasure trove. The printed Journal is quite portable and can be read in a car or airplane. It will last a long time, and until the paper deteriorates, I will never have a problem reading back issues. I have almost every issue from the first day I subscribed and have even added some older ones from collections of retired colleagues who no longer had shelf space for them. I certainly would not want to give up my printed copies, and I want to keep getting them. I find that JCE Online provides a different kind of resource that is equally valuable. It contains more information, and information that is more appropriate in electronic form. It links related ideas into a much more complex web of information than is possible in print. And it opens pathways to lots of information that is not part of JCE but resides elsewhere. Using this issue as an example, let's take a tour of what JCE Online can do. Point your Web browser to http://jchemed.chem.wisc.edu Click on Journal and then on Current Issue (unless September 1999 is no longer the current issue, in which case you will find it in Past Issues). In the table of contents, find the article "UV Catalysis, Cyanotype Photography, and Sunscreens". Click on the title. When the abstract appears, click on Full Text (PDF) to see the article, just as it appears on page 1199 in this issue. When you are prompted, enter the name and subscriber number from your address label. At the end of the article you will find that supplementary materials are available (including a procedure for testing sunscreens) and you can click on the link to view them

  11. [Hospitals as vital links].

    Science.gov (United States)

    Klink, A

    2013-01-01

    The reform of the system in 2006 aimed at reducing waiting lists in an efficient manner. Performance-linked funding and regulated competition did indeed lead to improved efficiency. The other side of the coin is overtreatment, and expensive and not infrequently damaging growth in volume. In order to control costs, three strategies have been determined: agreements with an annual cap on volume; (b) collaboration of regional health-care providers with the mission of improving results in health care (with profit-sharing if costs fall); and (c) fusions reducing the number of hospitals which reduces the burden of injuries (supply no longer creates its own demand). This article comments on these strategies. The author argues for a fourth approach: if the quality of health care improves, the number of complications will fall, overtreatment will decline and the outcome will be a decrease in burden of injuries. This requires the health care insurers to modify the way they manage their contracts and methods of payment, and stimulates competition based on quality.

  12. Human papillomavirus type-16 variants in Quechua aboriginals from Argentina.

    Science.gov (United States)

    Picconi, María Alejandra; Alonio, Lidia Virginia; Sichero, Laura; Mbayed, Viviana; Villa, Luisa Lina; Gronda, Jorge; Campos, Rodolfo; Teyssié, Angélica

    2003-04-01

    Cervical carcinoma is the leading cause of cancer death in Quechua indians from Jujuy (northwestern Argentina). To determine the prevalence of HPV-16 variants, 106 HPV-16 positive cervical samples were studied, including 33 low-grade squamous intraepithelial lesions (LSIL), 28 high-grade squamous intraepithelial lesions (HSIL), 9 invasive cervical cancer (ICC), and 36 samples from women with normal colposcopy and cytology. HPV genome variability was examined in the L1 and E6 genes by PCR-hybridization. In a subset of 20 samples, a LCR fragment was also analyzed by PCR-sequencing. Most variants belonged to the European branch with subtle differences that depended on the viral gene fragment studied. Only about 10% of the specimens had non-European variants, including eight Asian-American, two Asian, and one North-American-1. E6 gene analysis revealed that 43% of the samples were identical to HPV-16 prototype, while 57% corresponded to variants. Interestingly, the majority (87%) of normal smears had HPV-16 prototype, whereas variants were detected mainly in SIL and ICC. LCR sequencing yielded 80% of variants, including 69% of European, 19% Asian-American, and 12% Asian. We identified a new variant, the Argentine Quechua-51 (AQ-51), similar to B-14 plus two additional changes: G7842-->A and A7837-->C; phylogenetic inference allocated it in the Asian-American branch. The high proportion of European variants may reflect Spanish colonial influence on these native Inca descendants. The predominance of HPV-16 variants in pathologic samples when compared to normal controls could have implications for the natural history of cervical lesions.

  13. Migraine variants--occurrence in pediatric neurology practice.

    Science.gov (United States)

    Pacheva, Iliyana H; Ivanov, Ivan S

    2013-09-01

    Migraine is common in pediatric neurology practice, while migraine variants are rare and pose diagnostic problems. The aim was to establish the occurrence of migraine variants in pediatric neurology practice and among migraine, and to discuss their presentation. The files of 2509 newly diagnosed patients, aged 0-18 years, treated as in- and out-patients in the Neuropediatric Ward at the Plovdiv Medical University Hospital between 2002 and 2006 were examined retrospectively. Migraine forms were diagnosed according to ICHD-II. Benign paroxysmal torticolis and alternating hemiplegia of childhood were also accepted as migraine variants according to proposed diagnostic criteria in the appendix of ICHD-II. Some specific forms like acute confusional migraine (ACM), Alice in wonderland syndrome (AWS), ophthalmoplegic migraine were also diagnosed although not included as migraine variants in the ICHD-II classification. 111 patients met diagnostic criteria for migraine. Patients with migraine variants comprised 24.3% of migrainous cases. Basilar type migraine was the most common (6.3% of all migrainous patients), followed by benign paroxysmal vertigo (5.4%), hemiplegic migraine (3.6%), ACM (2.7%), benign paroxysmal torticolis (2.7%), typical aura without headache (1.8%), abdominal migraine (1.8%), AWS (0.9%), ophthalmoplegic migraine (0.9%) and cyclical vomiting (0.9%). Alternating hemiplegia of childhood and retinal migraine was not found. Some patients either presented or were classified as different migraine variants. Basilar type migraine was the most common migraine variant. ACM and AWS should be regarded as distinct entities in the ICHD as migraine with complex aura. Benign paroxysmal torticollis also deserves its place as a migraine variant. Cases of ophthalmoplegic migraine with spontaneous remission and no cranial nerve enhancement on MRI should be considered as migraine form. Analyzing migraine variants will contribute to better awareness and adequate diagnosis

  14. ARNTL (BMAL1 and NPAS2 gene variants contribute to fertility and seasonality.

    Directory of Open Access Journals (Sweden)

    Leena Kovanen

    Full Text Available BACKGROUND: Circadian clocks guide the metabolic, cell-division, sleep-wake, circadian and seasonal cycles. Abnormalities in these clocks may be a health hazard. Circadian clock gene polymorphisms have been linked to sleep, mood and metabolic disorders. Our study aimed to examine polymorphisms in four key circadian clock genes in relation to seasonal variation, reproduction and well-being in a sample that was representative of the general population, aged 30 and over, living in Finland. METHODOLOGY/PRINCIPAL FINDINGS: Single-nucleotide polymorphisms in the ARNTL, ARNTL2, CLOCK and NPAS2 genes were genotyped in 511 individuals. 19 variants were analyzed in relation to 31 phenotypes that were assessed in a health interview and examination study. With respect to reproduction, women with ARNTL rs2278749 TT genotype had more miscarriages and pregnancies, while NPAS2 rs11673746 T carriers had fewer miscarriages. NPAS2 rs2305160 A allele carriers had lower Global Seasonality Scores, a sum score of six items i.e. seasonal variation of sleep length, social activity, mood, weight, appetite and energy level. Furthermore, carriers of A allele at NPAS2 rs6725296 had greater loadings on the metabolic factor (weight and appetite of the global seasonality score, whereas individuals with ARNTL rs6290035 TT genotype experienced less seasonal variation of energy level. CONCLUSIONS/SIGNIFICANCE: ARNTL and NPAS2 gene variants were associated with reproduction and with seasonal variation. Earlier findings have linked ARNTL to infertility in mice, but this is the first time when any polymorphism of these genes is linked to fertility in humans.

  15. 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.

  16. De Novo Coding Variants Are Strongly Associated with Tourette Disorder

    DEFF Research Database (Denmark)

    Willsey, A Jeremy; Fernandez, Thomas V; Yu, Dongmei

    2017-01-01

    Whole-exome sequencing (WES) and de novo variant detection have proven a powerful approach to gene discovery in complex neurodevelopmental disorders. We have completed WES of 325 Tourette disorder trios from the Tourette International Collaborative Genetics cohort and a replication sample of 186...... trios from the Tourette Syndrome Association International Consortium on Genetics (511 total). We observe strong and consistent evidence for the contribution of de novo likely gene-disrupting (LGD) variants (rate ratio [RR] 2.32, p = 0.002). Additionally, de novo damaging variants (LGD and probably...

  17. The role of common genetic variants in atrial fibrillation

    DEFF Research Database (Denmark)

    Paludan-Muller, Christian; Svendsen, Jesper H.; Olesen, Morten S.

    2016-01-01

    this approach. Highly penetrant variants in lone AF have also been described in a number of cases. Furthermore, familial AF, although rare, have been recognized for many years. Variants associated with AF have been identified in more than 40 genes, including cardiac gap junction proteins, ion channels and beta......This review focuses on the genetic basis of atrial fibrillation (AF) and the role of variants in the susceptibility of developing the disease. AF is the most common cardiac arrhythmia affecting 1-2% of the general population. Studies in the last decade have demonstrated that AF, and in particular...... and non-cardiac diseases....

  18. 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.

  19. Variant Boussinesq方程组的精确解%Exact Solutions for Variant Boussinesq Equations

    Institute of Scientific and Technical Information of China (English)

    吴世旭

    2009-01-01

    F-展开法是近年提出的求非线性偏微分方程的精确解的一种简单而有效的方法.本文运用改进的F-展开法寻求Variant Boussinesq方程组的行波解,得到了该方程组多种类型的精确解,包括Jacobi椭圆函数解、孤立波解、三角函数解和有理函数解.

  20. Hierarchical generalized linear models for multiple groups of rare and common variants: jointly estimating group and individual-variant effects.

    Directory of Open Access Journals (Sweden)

    Nengjun Yi

    2011-12-01

    Full Text Available Complex diseases and traits are likely influenced by many common and rare genetic variants and environmental factors. Detecting disease susceptibility variants is a challenging task, especially when their frequencies are low and/or their effects are small or moderate. We propose here a comprehensive hierarchical generalized linear model framework for simultaneously analyzing multiple groups of rare and common variants and relevant covariates. The proposed hierarchical generalized linear models introduce a group effect and a genetic score (i.e., a linear combination of main-effect predictors for genetic variants for each group of variants, and jointly they estimate the group effects and the weights of the genetic scores. This framework includes various previous methods as special cases, and it can effectively deal with both risk and protective variants in a group and can simultaneously estimate the cumulative contribution of multiple variants and their relative importance. Our computational strategy is based on extending the standard procedure for fitting generalized linear models in the statistical software R to the proposed hierarchical models, leading to the development of stable and flexible tools. The methods are illustrated with sequence data in gene ANGPTL4 from the Dallas Heart Study. The performance of the proposed procedures is further assessed via simulation studies. The methods are implemented in a freely available R package BhGLM (http://www.ssg.uab.edu/bhglm/.

  1. Hierarchical Generalized Linear Models for Multiple Groups of Rare and Common Variants: Jointly Estimating Group and Individual-Variant Effects

    Science.gov (United States)

    Yi, Nengjun; Liu, Nianjun; Zhi, Degui; Li, Jun

    2011-01-01

    Complex diseases and traits are likely influenced by many common and rare genetic variants and environmental factors. Detecting disease susceptibility variants is a challenging task, especially when their frequencies are low and/or their effects are small or moderate. We propose here a comprehensive hierarchical generalized linear model framework for simultaneously analyzing multiple groups of rare and common variants and relevant covariates. The proposed hierarchical generalized linear models introduce a group effect and a genetic score (i.e., a linear combination of main-effect predictors for genetic variants) for each group of variants, and jointly they estimate the group effects and the weights of the genetic scores. This framework includes various previous methods as special cases, and it can effectively deal with both risk and protective variants in a group and can simultaneously estimate the cumulative contribution of multiple variants and their relative importance. Our computational strategy is based on extending the standard procedure for fitting generalized linear models in the statistical software R to the proposed hierarchical models, leading to the development of stable and flexible tools. The methods are illustrated with sequence data in gene ANGPTL4 from the Dallas Heart Study. The performance of the proposed procedures is further assessed via simulation studies. The methods are implemented in a freely available R package BhGLM (http://www.ssg.uab.edu/bhglm/). PMID:22144906

  2. Protective link for superconducting coil

    Science.gov (United States)

    Umans, Stephen D.

    2009-12-08

    A superconducting coil system includes a superconducting coil and a protective link of superconducting material coupled to the superconducting coil. A rotating machine includes first and second coils and a protective link of superconducting material. The second coil is operable to rotate with respect to the first coil. One of the first and second coils is a superconducting coil. The protective link is coupled to the superconducting coil.

  3. Using ATM over SATCOM links

    Science.gov (United States)

    Comparetto, Gary M.

    1995-01-01

    The Asynchronous Transfer Mode (ATM) protocol is studied from the standpoint of determining what limitations, if any, exist in using it over satellite links. It is concluded that, while there is nothing intrinsic about ATM that would generally preclude its use over satellite links, there are, however, several intrinsic characteristics of satellite links, as well as some satellite system configuration-specific issues, that must be taken into account.

  4. 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; Hirschhorn, Joel; North, Kari E; Ingelsson, Erik; Lin, Dan-Yu

    2013-08-08

    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.

  5. Channel Characterization and Robust Tracking for Diversity Reception over Time-Variant Off-Body Wireless Communication Channels

    Science.gov (United States)

    Van Torre, Patrick; Vallozzi, Luigi; Rogier, Hendrik; Moeneclaey, Marc; Verhaevert, Jo

    2010-12-01

    In the 2.45 GHz band, indoor wireless off-body data communication by a moving person can be problematic due to time-variant signal fading and the consequent variation in channel parameters. Off-body communication specifically suffers from the combined effects of fading, shadowing, and path loss due to time-variant multipath propagation in combination with shadowing by the human body. Measurements are performed to analyze the autocorrelation, coherence time, and power spectral density for a person equipped with a wearable receive system moving at different speeds for different configurations and antenna positions. Diversity reception with multiple textile antennas integrated in the clothing provides a means of improving the reliability of the link. For the dynamic channel estimation, a scheme using hard decision feedback after MRC with adaptive low-pass filtering is demonstrated to be successful in providing robust data detection for long data bursts, in the presence of dramatic channel variation.

  6. Antibodies to variant antigens on the surfaces of infected erythrocytes are associated with protection from malaria in Ghanaian children

    DEFF Research Database (Denmark)

    Dodoo, D; Staalsoe, T; Giha, H;

    2001-01-01

    Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a variant antigen expressed on the surface of infected erythrocytes. Each parasite genome contains about 40 PfEMP1 genes, but only 1 PfEMP1 gene is expressed at a given time. PfEMP1 serves as a parasite-sequestering ligand...... to endothelial cells and enables the parasites to avoid splenic passage. PfEMP1 antibodies may protect from disease by inhibiting sequestration, thus facilitating the destruction of infected erythrocytes in the spleen. In this study, we have measured antibodies in Ghanaian children to a conserved region of Pf......EMP1 by enzyme-linked immunosorbent assay and antibodies to variant molecules on erythrocytes infected with field isolates of P. falciparum by flow cytometry. Based on close clinical monitoring, the children were grouped into those who did (susceptible) and those who did not (protected) have malaria...

  7. "Conjectural" links in complex networks

    Science.gov (United States)

    Snarskii, A. A.; Zorinets, D. I.; Lande, D. V.

    2016-11-01

    This paper introduces the concept of Conjectural Link for Complex Networks, in particular, social networks. Conjectural Link we understand as an implicit link, not available in the network, but supposed to be present, based on the characteristics of its topology. It is possible, for example, when in the formal description of the network some connections are skipped due to errors, deliberately hidden or withdrawn (e.g. in the case of partial destruction of the network). Introduced a parameter that allows ranking the Conjectural Link. The more this parameter - the more likely that this connection should be present in the network. This paper presents a method of recovery of partially destroyed Complex Networks using Conjectural Links finding. Presented two methods of finding the node pairs that are not linked directly to one another, but have a great possibility of Conjectural Link communication among themselves: a method based on the determination of the resistance between two nodes, and method based on the computation of the lengths of routes between two nodes. Several examples of real networks are reviewed and performed a comparison to know network links prediction methods, not intended to find the missing links in already formed networks.

  8. 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

  9. Vitiligo: Pathogenesis, clinical variants and treatment approaches.

    Science.gov (United States)

    Iannella, Giannicola; Greco, Antonio; Didona, Dario; Didona, Biagio; Granata, Guido; Manno, Alessandra; Pasquariello, Benedetta; Magliulo, Giuseppe

    2016-04-01

    Vitiligo is a common chronic acquired disease of pigmentation whose etiology is unknown, which usually occurs with asymptomatic whitish patch or macule. Although several hypotheses have been proposed in the literature, the leading theory is still the auto-immune etiology linked to specific genetic mutations. Vitiligo can also be associated with several autoimmune diseases, including autoimmune thyroid diseases, alopecia areata, and halo nevi. Sensorineural hearing loss was reported in several vitiligo patients due to a reduction in the number of melanocytes contained in the membranous labyrinth of the inner ear. Because of its complexity, several therapeutic options are available to treat this systemic disease.

  10. Study on Variant Anatomy of Sciatic Nerve

    Science.gov (United States)

    V, Sangeetha

    2014-01-01

    Introduction: Sciatic Nerve (SN) is the nerve of the posterior compartment of thigh formed in the pelvis from the ventral rami of the L4 to S3 spinal nerves. It leaves the pelvis via the greater sciatic foramen below piriformis and divides into Common Peroneal Nerve (CPN) and Tibial Nerve (TN) at the level of the upper angle of the popliteal fossa. Higher division of the sciatic nerve is the most common variation where the TN and CPN may leave the pelvis through different routes. Such variation may lead to compression of the nerve and lead to Non-discogenic sciatica. Materials and Methods: Fifty lower limbs were used for the study from Department of Anatomy, J.J.M.M.C Davangere, Karnataka, India. Observation and Results: In our study on 25 cadavers (50 lower limbs), we have observed 4 (8 %) lower limbs high division of sciatic nerve was noted. High division of sciatic nerve in the back of thigh was noted in one specimen (2%), while high division within the pelvis was noted in 3 specimens (6%), while in 46 (92%) it occurred outside the pelvis. Conclusion: Knowledge regarding such variation and differences in the course of SN is important for the surgeons to plan for various surgical interventions pertaining to the gluteal region. The variant anatomy of SN may cause piriformis syndrome and failure of SN block. Hence present study is undertaken to know the level of division, exit, course, relationship to piriformis and variations in the branching pattern of SN. PMID:25302181

  11. Prolactin variants in ram adenohypophyses vary with season

    Science.gov (United States)

    Stroud, C. M.; Deaver, D. R.; Peters, J. L.; Loeper, D. C.; Toth, B. E.; Derr, J. A.; Hymer, W. C.

    1992-01-01

    Secretion of PRL in sheep is affected by photoperiod being highest during the spring and summer, lowest in fall and winter. The objectives of this study were to determine if 1) the production of variant forms of PRL, and 2) immuno- and bioactivities of PRL (iPRL and bPRL) differ during times of the year selected to represent periods of low, transitional and high PRL secretion. Twelve mature rams were maintained on pasture and killed in October, December, and April (n = 4/month). Individual pituitary glands were dispersed, cells obtained, and fixed for immunocytochemical flow cytometry, extracted with 0.01 N NaHCO3 or cultured in serum-free, defined media. The Mr of PRL extracted from cells immediately following dispersion ranged from 14-140K, with significantly more bands greater than 40K being detected from rams sacrificed in December than from those killed in October and April (P less than 0.01). No bands of PRL greater than 25K were observed when samples were reduced with beta-mercaptoethanol prior to electrophoresis, indicating that the high Mr forms were disulfide-linked aggregates. Culture media from October and April contained variants of PRL that ranged from 22-40K but those greater than 25K were generally not observed from cells harvested during December. Extracts of cells after 24 h in culture contained fewer high Mr species during December than had been present in initial extracts from that month. In contrast, during April more high Mr intracellular forms were present after culture than had been detected prior to culture during that month. The percentage of lactotrophs averaged 50.0 +/- 2.5, 47.4 +/- 5.7, and 59.4 +/- 5.5 for October, December, and April, respectively. Initial lactotroph content (pg/lactotroph) of iPRL was higher (P = 0.06) in April (46.0 +/- 17.0) when compared to October and December (8.0 +/- 2.0 and 20.0 +/- 10.0, respectively). In contrast, the bPRL content of initial extracts was higher (P = 0.05) in December (267.0 +/- 68.0) than

  12. Common Gene Variants Account for Most Genetic Risk for Autism

    Science.gov (United States)

    ... July 20, 2014 Common gene variants account for most genetic risk for autism Roles of heritability, mutations, ... factors. Population-Based Autism Genetics and Environment Study Most of the genetic risk for autism comes from ...

  13. Variant Plasmodium ovale isolated from a patient infected in Ghana

    Directory of Open Access Journals (Sweden)

    Petersen Eskild

    2011-01-01

    Full Text Available Abstract Recent data have found that Plasmodium ovale can be separated in two distinct species: classic and variant P. ovale based on multilocus typing of different genes. This study presents a P. ovale isolate from a patient infected in Ghana together with an analysis of the small subunit RNA, cytochrome b, cytochrome c oxidase I, cysteine protease and lactate dehydrogenase genes, which show that the sample is a variant P. ovale and identical or highly similar to variant P. ovale isolated from humans in South-East Asia and Africa, and from a chimpanzee in Cameroon. The split between the variant and classic P. ovale is estimated to have occurred 1.7 million years ago.

  14. Differential protein expression in phenotypic variants of Streptococcus pneumoniae

    NARCIS (Netherlands)

    K. Overweg (Karin); C.D. Pericone; G.G. Verhoef; J.N. Weiser; H.D. Meiring; A.P. de Jong; R. de Groot (Ronald); P.W.M. Hermans (Peter)

    2000-01-01

    textabstractStreptococcus pneumoniae undergoes spontaneous phase variation resulting in opaque and transparent colony forms. Differences in colony opacity correlate with differences in virulence: the transparent variants are more capable of colonizing the nasopharynx, w

  15. Neuropathology in classical and variant ataxia-telangiectasia.

    NARCIS (Netherlands)

    Verhagen, M.M.M.; Martin, J.J.; Deuren, M. van; Ceuterick-de Groote, C.; Weemaes, C.M.R.; Kremer, B.; Taylor, M.A.; Willemsen, M.A.A.P.; Lammens, M.M.Y.

    2012-01-01

    Ataxia-telangiectasia (A-T) is classically characterized by progressive neurodegeneration, oculocutaneous telangiectasia, immunodeficiency and elevated alpha-fetoprotein levels. Some patients, classified as variant A-T, exhibit a milder clinical course. In the latter patients extrapyramidal symptoms

  16. Method of generating ploynucleotides encoding enhanced folding variants

    Energy Technology Data Exchange (ETDEWEB)

    Bradbury, Andrew M.; Kiss, Csaba; Waldo, Geoffrey S.

    2017-05-02

    The invention provides directed evolution methods for improving the folding, solubility and stability (including thermostability) characteristics of polypeptides. In one aspect, the invention provides a method for generating folding and stability-enhanced variants of proteins, including but not limited to fluorescent proteins, chromophoric proteins and enzymes. In another aspect, the invention provides methods for generating thermostable variants of a target protein or polypeptide via an internal destabilization baiting strategy. Internally destabilization a protein of interest is achieved by inserting a heterologous, folding-destabilizing sequence (folding interference domain) within DNA encoding the protein of interest, evolving the protein sequences adjacent to the heterologous insertion to overcome the destabilization (using any number of mutagenesis methods), thereby creating a library of variants. The variants in the library are expressed, and those with enhanced folding characteristics selected.

  17. 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 m...

  18. Lipoprotein lipase gene variants: Association with acute myocardial ...

    African Journals Online (AJOL)

    Lipoprotein lipase gene variants: Association with acute myocardial infarction and lipid profiles. ... Therefore, genes involved in lipid and lipoprotein metabolism pathways such as lipoprotein lipase (LPL), are proper candidates ... Article Metrics.

  19. Genetic variant as a marker for bladder cancer therapy

    Science.gov (United States)

    Patients who have inherited a specific common genetic variant develop bladder cancer tumors that strongly express a protein known as prostate stem cell antigen (PSCA), which is also expressed in many pancreatic and prostate tumors, according to research a

  20. Influenza A (H3N2) Variant Virus

    Science.gov (United States)

    ... Error processing SSI file Influenza A (H3N2) Variant Virus Language: English Español Recommend on Facebook Tweet Share Compartir Influenza viruses that normally circulate in pigs are called “ ...

  1. Variant Timekeeping Patterns and Their Effects in Jazz Drumming

    National Research Council Canada - National Science Library

    Butterfield, Matthew W

    2010-01-01

    ...." This essay shows how one modern jazz drummer employs variants of common timekeeping patterns in a more "liquid" way to generate motional energy through the strategic production of metric dissonance...

  2. 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.

  3. Anorectal agenesis with rectovaginal fistula: A rare/regional variant

    Directory of Open Access Journals (Sweden)

    Subhasis Roy Choudhury

    2017-01-01

    Conclusion: RVF with anorectal agenesis is a rare/regional variant of female ARMs. Clinical examination along with distal colostogram, EUA, and endoscopy clinches the diagnosis. Anorectal reconstruction by posterior sagittal anorectoplasty results in a satisfactory outcome.

  4. Vitiligo, con énfasis en su variante inflamatoria Vitiligo, with emphasis in its inflammatory variant

    Directory of Open Access Journals (Sweden)

    C I Vera

    2009-03-01

    Full Text Available El vitiligo inflamatorio es un trastorno melanocitopénico adquirido, de baja frecuencia con características clínicas e histológicas propias. Ocurre en ambos sexos, a cualquier edad. Su fisiopatogenia parece involucrar mecanismos autoinmunes. En su evolución es frecuente la desaparición del componente inflamatorio que resulta en una mácula hipopigmentada clásica; a ello debe anticiparse también nuestra elección terapéutica. Se describe un paciente con vitiligo inflamatorio de resolución espontánea, junto a una revisión crítica de la bibliografía. Se discute si representa una variante de vitiligo vulgar o una entidad independiente.Inflammatory vitiligo is a low frequency melanocytopenic acquired entity with clinical and histological features of it 's own. It occurs in both sexes at any age. Fisiopathogenesis may involve autoimmune mechanisms. It's evolution most commonly ends up in a classic hypopigmented maculae, therefore our therapeutic choice has to be oriented to this outcome. A patient with inflammatory vitiligo is described along a critical review of the literature. It is discussed if it represents a variant of common vitiligo or an independent entity.

  5. Link Clustering with Extended Link Similarity and EQ Evaluation Division.

    Directory of Open Access Journals (Sweden)

    Lan Huang

    Full Text Available Link Clustering (LC is a relatively new method for detecting overlapping communities in networks. The basic principle of LC is to derive a transform matrix whose elements are composed of the link similarity of neighbor links based on the Jaccard distance calculation; then it applies hierarchical clustering to the transform matrix and uses a measure of partition density on the resulting dendrogram to determine the cut level for best community detection. However, the original link clustering method does not consider the link similarity of non-neighbor links, and the partition density tends to divide the communities into many small communities. In this paper, an Extended Link Clustering method (ELC for overlapping community detection is proposed. The improved method employs a new link similarity, Extended Link Similarity (ELS, to produce a denser transform matrix, and uses the maximum value of EQ (an extended measure of quality of modularity as a means to optimally cut the dendrogram for better partitioning of the original network space. Since ELS uses more link information, the resulting transform matrix provides a superior basis for clustering and analysis. Further, using the EQ value to find the best level for the hierarchical clustering dendrogram division, we obtain communities that are more sensible and reasonable than the ones obtained by the partition density evaluation. Experimentation on five real-world networks and artificially-generated networks shows that the ELC method achieves higher EQ and In-group Proportion (IGP values. Additionally, communities are more realistic than those generated by either of the original LC method or the classical CPM method.

  6. Circle of Willis Variants: Fetal PCA

    Directory of Open Access Journals (Sweden)

    Amir Shaban

    2013-01-01

    Full Text Available We sought to determine the prevalence of fetal posterior cerebral artery (fPCA and if fPCA was associated with specific stroke etiology and vessel territory affected. This paper is a retrospective review of prospectively identified patients with acute ischemic stroke from July 2008 to December 2010. We defined complete fPCA as absence of a P1 segment linking the basilar with the PCA and partial fPCA as small segment linking the basilar with the PCA. Patients without intracranial vascular imaging were excluded. We compared patients with complete fPCA, partial fPCA, and without fPCA in terms of demographics, stroke severity, distribution, and etiology and factored in whether the stroke was ipsilateral to the fPCA. Of the 536 included patients, 9.5% ( had complete fPCA and 15.1% ( had partial fPCA. Patients with complete fPCA were older and more often female than partial fPCA and no fPCA patients, and significant variation in TOAST classification was detected across groups (. Patients with complete fPCA had less small vessel and more large vessel strokes than patients with no fPCA and partial fPCA. Fetal PCA may predispose to stroke mechanism, but is not associated with vascular distribution, stroke severity, or early outcome.

  7. Histone variant innovation in a rapidly evolving chordate lineage

    Directory of Open Access Journals (Sweden)

    Jansen Pascal WTC

    2011-07-01

    Full Text Available Abstract Background Histone variants alter the composition of nucleosomes and play crucial roles in transcription, chromosome segregation, DNA repair, and sperm compaction. Modification of metazoan histone variant lineages occurs on a background of genome architecture that shows global similarities from sponges to vertebrates, but the urochordate, Oikopleura dioica, a member of the sister group to vertebrates, exhibits profound modification of this ancestral architecture. Results We show that a histone complement of 47 gene loci encodes 31 histone variants, grouped in distinct sets of developmental expression profiles throughout the life cycle. A particularly diverse array of 15 male-specific histone variants was uncovered, including a testes-specific H4t, the first metazoan H4 sequence variant reported. Universal histone variants H3.3, CenH3, and H2A.Z are present but O. dioica lacks homologs of macroH2A and H2AX. The genome encodes many H2A and H2B variants and the repertoire of H2A.Z isoforms is expanded through alternative splicing, incrementally regulating the number of acetylatable lysine residues in the functionally important N-terminal "charge patch". Mass spectrometry identified 40 acetylation, methylation and ubiquitylation posttranslational modifications (PTMs and showed that hallmark PTMs of "active" and "repressive" chromatin were present in O. dioica. No obvious reduction in silent heterochromatic marks was observed despite high gene density in this extraordinarily compacted chordate genome. Conclusions These results show that histone gene complements and their organization differ considerably even over modest phylogenetic distances. Substantial innovation among all core and linker histone variants has evolved in concert with adaptation of specific life history traits in this rapidly evolving chordate lineage.

  8. BIFURCATIONS OF TRAVELLING WAVE SOLUTIONS IN VARIANT BOUSSINESQ EQUATIONS

    Institute of Scientific and Technical Information of China (English)

    YUAN Yu-bo; PU Dong-mei; LI Shu-min

    2006-01-01

    The bifurcations of solitary waves and kink waves for variant Boussinesq equations are studied by using the bifurcation theory of planar dynamical systems. The bifurcation sets and the numbers of solitary waves and kink waves for the variant Boussinesq equations are presented. Several types explicit formulas of solitary waves solutions and kink waves solutions are obtained. In the end, several formulas of periodic wave solutions are presented.

  9. Whole genome sequencing of an African American family highlights toll like receptor 6 variants in Kawasaki disease susceptibility

    Science.gov (United States)

    Veeraraghavan, Narayanan; Levy, Eric; Ribeiro dos Santos, Andre M.; Yang, Hai; Hibberd, Martin L.; Tremoulet, Adriana H.; Harismendy, Olivier; Ohno-Machado, Lucila; Burns, Jane C.

    2017-01-01

    Kawasaki disease (KD) is the most common acquired pediatric heart disease. We analyzed Whole Genome Sequences (WGS) from a 6-member African American family in which KD affected two of four children. We sought rare, potentially causative genotypes by sequentially applying the following WGS filters: sequence quality scores, inheritance model (recessive homozygous and compound heterozygous), predicted deleteriousness, allele frequency, genes in KD-associated pathways or with significant associations in published KD genome-wide association studies (GWAS), and with differential expression in KD blood transcriptomes. Biologically plausible genotypes were identified in twelve variants in six genes in the two affected children. The affected siblings were compound heterozygous for the rare variants p.Leu194Pro and p.Arg247Lys in Toll-like receptor 6 (TLR6), which affect TLR6 signaling. The affected children were also homozygous for three common, linked (r2 = 1) intronic single nucleotide variants (SNVs) in TLR6 (rs56245262, rs56083757 and rs7669329), that have previously shown association with KD in cohorts of European descent. Using transcriptome data from pre-treatment whole blood of KD subjects (n = 146), expression quantitative trait loci (eQTL) analyses were performed. Subjects homozygous for the intronic risk allele (A allele of TLR6 rs56245262) had differential expression of Interleukin-6 (IL-6) as a function of genotype (p = 0.0007) and a higher erythrocyte sedimentation rate at diagnosis. TLR6 plays an important role in pathogen-associated molecular pattern recognition, and sequence variations may affect binding affinities that in turn influence KD susceptibility. This integrative genomic approach illustrates how the analysis of WGS in multiplex families with a complex genetic disease allows examination of both the common disease–common variant and common disease–rare variant hypotheses. PMID:28151979

  10. Essential role of PSM/SH2-B variants in insulin receptor catalytic activation and the resulting cellular responses.

    Science.gov (United States)

    Zhang, Manchao; Deng, Youping; Tandon, Ruchi; Bai, Cheng; Riedel, Heimo

    2008-01-01

    The positive regulatory role of PSM/SH2-B downstream of various mitogenic receptor tyrosine kinases or gene disruption experiments in mice support a role of PSM in the regulation of insulin action. Here, four alternative PSM splice variants and individual functional domains were compared for their role in the regulation of specific metabolic insulin responses. We found that individual PSM variants in 3T3-L1 adipocytes potentiated insulin-mediated glucose and amino acid transport, glycogenesis, lipogenesis, and key components in the metabolic insulin response including p70 S6 kinase, glycogen synthase, glycogen synthase kinase 3 (GSK3), Akt, Cbl, and IRS-1. Highest activity was consistently observed for PSM alpha, followed by beta, delta, and gamma with decreasing activity. In contrast, dominant-negative peptide mimetics of the PSM Pro-rich, pleckstrin homology (PH), or src homology 2 (SH2) domains inhibited any tested insulin response. Potentiation of the insulin response originated at the insulin receptor (IR) kinase level by PSM variant-specific regulation of the Km (ATP) whereas the Vmax remained unaffected. IR catalytic activation was inhibited by peptide mimetics of the PSM SH2 or dimerization domain (DD). Either peptide should disrupt the complex of a PSM dimer linked to IR via SH2 domains as proposed for PSM activation of tyrosine kinase JAK2. Either peptide abolished downstream insulin responses indistinguishable from PSM siRNA knockdown. Our results implicate an essential role of the PSM variants in the activation of the IR kinase and the resulting metabolic insulin response. PSM variants act as internal IR ligands that in addition to potentiating the insulin response stimulate IR catalytic activation even in the absence of insulin.

  11. Generalization of Rare Variant Association Tests for Longitudinal Family Studies.

    Science.gov (United States)

    Chien, Li-Chu; Hsu, Fang-Chi; Bowden, Donald W; Chiu, Yen-Feng

    2016-02-01

    Given the functional relevance of many rare variants, their identification is frequently critical for dissecting disease etiology. Functional variants are likely to be aggregated in family studies enriched with affected members, and this aggregation increases the statistical power to detect rare variants associated with a trait of interest. Longitudinal family studies provide additional information for identifying genetic and environmental factors associated with disease over time. However, methods to analyze rare variants in longitudinal family data remain fairly limited. These methods should be capable of accounting for different sources of correlations and handling large amounts of sequencing data efficiently. To identify rare variants associated with a phenotype in longitudinal family studies, we extended pedigree-based burden (BT) and kernel (KS) association tests to genetic longitudinal studies. Generalized estimating equation (GEE) approaches were used to generalize the pedigree-based BT and KS to multiple correlated phenotypes under the generalized linear model framework, adjusting for fixed effects of confounding factors. These tests accounted for complex correlations between repeated measures of the same phenotype (serial correlations) and between individuals in the same family (familial correlations). We conducted comprehensive simulation studies to compare the proposed tests with mixed-effects models and marginal models, using GEEs under various configurations. When the proposed tests were applied to data from the Diabetes Heart Study, we found exome variants of POMGNT1 and JAK1 genes were associated with type 2 diabetes.

  12. Five Rare β Globin Chain Hemoglobin Variants in India.

    Science.gov (United States)

    Colah, Roshan B; Nadkarni, Anita; Gorakshakar, Ajit; Sawant, Pratibha; Gorivale, Manju; Mehta, Pallavi; Sawant, Madhavi; Ghosh, Kanjaksha

    2016-06-01

    Thalassemias as well as structural hemoglobin (Hb) variants are common monogenic inherited disorders of Hb in India. In this paper we describe 5 rare β-chain Hb variants identified in the Indian population on the basis of high performance liquid chromatography (HPLC). Of these 3 were identified during antenatal screening of β-thalassemia while the other 2 cases were referred to us for a diagnostic work up. These 5 Hb variants were Hb British Columbia (β CD 101 GAG → AAG), Hb Saint Louis (β CD28 CTG → CAG), Hb G Coushatta (β CD 22 GAA → GCA), Hb Pyrgos (β CD 83 GGC → GAC) and Hb Agenogi (β CD 90 GAG → AAG). Hb Saint Louis and Hb G Coushatta eluted in the HbA2 window, Hb British Columbia and Hb Agenogi eluted in the Hb C window while Hb Pyrgos eluted in an unknown window on HPLC. They were all identified by DNA sequencing. The child having Hb St. Louis had hepatosplenomegaly and anemia while the individuals with the other 4 variants were asymptomatic. Rare Hb variants are diagnostic curiosities that may be encountered by laboratories. Correct identification requires the application of more than one technique to avoid misdiagnosing them as more common variants (e.g. St. Louis and G Coushatta as E or D Iran on HPLC. Some, like G Coushatta may interfere with HPLC-based HbA1c estimation).

  13. Common susceptibility variants examined for association with dilated cardiomyopathy.

    Science.gov (United States)

    Rampersaud, Evadnie; Kinnamon, Daniel D; Hamilton, Kara; Khuri, Sawsan; Hershberger, Ray E; Martin, Eden R

    2010-03-01

    Rare mutations in more than 20 genes have been suggested to cause dilated cardiomyopathy (DCM), but explain only a small percentage of cases, mainly in familial forms. We hypothesised that more common variants may also play a role in increasing genetic susceptibility to DCM, similar to that observed in other common complex disorders. To test this hypothesis, we performed case-control analyses on all DNA polymorphic variation identified in a resequencing study of six candidate DCM genes (CSRP3, LDB3, MYH7, SCN5A, TCAP, and TNNT2) conducted in 289 unrelated white probands with DCM of unknown cause and 188 unrelated white controls. In univariate analyses, we identified associated common variants at LDB3 site 10779, LDB3 site 57877, MYH7 sites 16384 and 17404, and TCAP sites 140 and 1735. Multivariate analyses to examine the joint effects of multiple gene variants confirmed univariate results for MYH7 and TCAP and identified a block of nine variants in MYH7 that was strongly associated with DCM. Common variants in genes known to be causative of DCM may play a role in genetic susceptibility to DCM. Our results suggest that examination of common genetic variants may be warranted in future studies of DCM and other Mendelian-like disorders.

  14. Update on lichen planus and its clinical variants

    Directory of Open Access Journals (Sweden)

    Gillian Weston, MSIII

    2015-08-01

    Full Text Available Lichen planus (LP is an inflammatory skin condition with characteristic clinical and histopathological findings. Classic LP typically presents as pruritic, polygonal, violaceous flat-topped papules and plaques; many variants in morphology and location also exist, including oral, nail, linear, annular, atrophic, hypertrophic, inverse, eruptive, bullous, ulcerative, lichen planus pigmentosus, lichen planopilaris, vulvovaginal, actinic, lichen planus-lupus erythematosus overlap syndrome, and lichen planus pemphigoides. Clinical presentation of the rarer variant lesions may be largely dissimilar to classic LP and therefore difficult to diagnose based solely on clinical examination. However, histopathological examination of LP and LP-variant lesions reveal similar features, aiding in the proper diagnosis of the disease. Management of LP and LP variants aims to control symptoms and to decrease time from onset to resolution; it often involves topical corticosteroids, but varies depending on the severity and location of the lesion. The literature contains an array of reports on the variations in presentation and successful management of LP and its variants. A familiarity with LP and its variants is important in achieving timely recognition and management of the disease.

  15. Sonographic and cytopathologic correlation of papillary thyroid carcinoma variants.

    Science.gov (United States)

    Lee, Ji Hyun; Shin, Jung Hee; Lee, Hyun-Woo; Oh, Young Lyun; Hahn, Soo Yeon; Ko, Eun Young

    2015-01-01

    Papillary thyroid carcinoma (PTC) is the most common thyroid cancer and constitutes more than 70% of thyroid malignancies. Although TNM staging is the most widely used parameter for determination of therapeutic plans, recent studies have suggested that different histopathologic variants of PTC can also have different clinical courses and patient prognoses. Sonographic criteria for PTC are well established and include a taller-than-wide shape, an irregular margin, microcalcifications, and marked hypoechogenicity. The role of sonography has expanded to enable the characterization of PTC variants based on their sonographic features. Tall cell and diffuse sclerosing variants appear to have more aggressive clinical courses with unfavorable prognoses, whereas the more recently described cribriform-morular and Warthin-like variants have relatively indolent clinical courses. The prognoses of patients with follicular, solid, columnar cell, and oncocytic variants are still controversial and may be similar to the prognosis of conventional PTC. Understanding the sonographic characteristics of PTC variants with clinicopathologic correlation may be helpful for suggesting an appropriate treatment plan.

  16. Variants affecting exon skipping contribute to complex traits.

    Directory of Open Access Journals (Sweden)

    Younghee Lee

    Full Text Available DNA variants that affect alternative splicing and the relative quantities of different gene transcripts have been shown to be risk alleles for some Mendelian diseases. However, for complex traits characterized by a low odds ratio for any single contributing variant, very few studies have investigated the contribution of splicing variants. The overarching goal of this study is to discover and characterize the role that variants affecting alternative splicing may play in the genetic etiology of complex traits, which include a significant number of the common human diseases. Specifically, we hypothesize that single nucleotide polymorphisms (SNPs in splicing regulatory elements can be characterized in silico to identify variants affecting splicing, and that these variants may contribute to the etiology of complex diseases as well as the inter-individual variability in the ratios of alternative transcripts. We leverage high-throughput expression profiling to 1 experimentally validate our in silico predictions of skipped exons and 2 characterize the molecular role of intronic genetic variations in alternative splicing events in the context of complex human traits and diseases. We propose that intronic SNPs play a role as genetic regulators within splicing regulatory elements and show that their associated exon skipping events can affect protein domains and structure. We find that SNPs we would predict to affect exon skipping are enriched among the set of SNPs reported to be associated with complex human traits.

  17. BRCA Share: A Collection of Clinical BRCA Gene Variants.

    Science.gov (United States)

    Béroud, Christophe; Letovsky, Stanley I; Braastad, Corey D; Caputo, Sandrine M; Beaudoux, Olivia; Bignon, Yves Jean; Bressac-De Paillerets, Brigitte; Bronner, Myriam; Buell, Crystal M; Collod-Béroud, Gwenaëlle; Coulet, Florence; Derive, Nicolas; Divincenzo, Christina; Elzinga, Christopher D; Garrec, Céline; Houdayer, Claude; Karbassi, Izabela; Lizard, Sarab; Love, Angela; Muller, Danièle; Nagan, Narasimhan; Nery, Camille R; Rai, Ghadi; Revillion, Françoise; Salgado, David; Sévenet, Nicolas; Sinilnikova, Olga; Sobol, Hagay; Stoppa-Lyonnet, Dominique; Toulas, Christine; Trautman, Edwin; Vaur, Dominique; Vilquin, Paul; Weymouth, Katelyn S; Willis, Alecia; Eisenberg, Marcia; Strom, Charles M

    2016-12-01

    As next-generation sequencing increases access to human genetic variation, the challenge of determining clinical significance of variants becomes ever more acute. Germline variants in the BRCA1 and BRCA2 genes can confer substantial lifetime risk of breast and ovarian cancer. Assessment of variant pathogenicity is a vital part of clinical genetic testing for these genes. A database of clinical observations of BRCA variants is a critical resource in that process. This article describes BRCA Share™, a database created by a unique international alliance of academic centers and commercial testing laboratories. By integrating the content of the Universal Mutation Database generated by the French Unicancer Genetic Group with the testing results of two large commercial laboratories, Quest Diagnostics and Laboratory Corporation of America (LabCorp), BRCA Share™ has assembled one of the largest publicly accessible collections of BRCA variants currently available. Although access is available to academic researchers without charge, commercial participants in the project are required to pay a support fee and contribute their data. The fees fund the ongoing curation effort, as well as planned experiments to functionally characterize variants of uncertain significance. BRCA Share™ databases can therefore be considered as models of successful data sharing between private companies and the academic world.

  18. Prebiotic Competition between Information Variants, With Low Error Catastrophe Risks

    Directory of Open Access Journals (Sweden)

    Radu Popa

    2015-07-01

    Full Text Available During competition for resources in primitive networks increased fitness of an information variant does not necessarily equate with successful elimination of its competitors. If variability is added fast to a system, speedy replacement of pre-existing and less-efficient forms of order is required as novel information variants arrive. Otherwise, the information capacity of the system fills up with information variants (an effect referred as “error catastrophe”. As the cost for managing the system’s exceeding complexity increases, the correlation between performance capabilities of information variants and their competitive success decreases, and evolution of such systems toward increased efficiency slows down. This impasse impedes the understanding of evolution in prebiotic networks. We used the simulation platform Biotic Abstract Dual Automata (BiADA to analyze how information variants compete in a resource-limited space. We analyzed the effect of energy-related features (differences in autocatalytic efficiency, energy cost of order, energy availability, transformation rates and stability of order on this competition. We discuss circumstances and controllers allowing primitive networks acquire novel information with minimal “error catastrophe” risks. We present a primitive mechanism for maximization of energy flux in dynamic networks. This work helps evaluate controllers of evolution in prebiotic networks and other systems where information variants compete.

  19. Homolog-specific PCR primer design for profiling splice variants.

    Science.gov (United States)

    Srivastava, Gyan Prakash; Hanumappa, Mamatha; Kushwaha, Garima; Nguyen, Henry T; Xu, Dong

    2011-05-01

    To study functional diversity of proteins encoded from a single gene, it is important to distinguish the expression levels among the alternatively spliced variants. A variant-specific primer pair is required to amplify each alternatively spliced variant individually. For this purpose, we developed a new feature, homolog-specific primer design (HSPD), in our high-throughput primer and probe design software tool, PRIMEGENS-v2. The algorithm uses a de novo approach to design primers without any prior information of splice variants or close homologs for an input query sequence. It not only designs primer pairs but also finds potential isoforms and homologs of the input sequence. Efficiency of this algorithm was tested for several gene families in soybean. A total of 187 primer pairs were tested under five different abiotic stress conditions with three replications at three time points. Results indicate a high success rate of primer design. Some primer pairs designed were able to amplify all splice variants of a gene. Furthermore, by utilizing combinations within the same multiplex pool, we were able to uniquely amplify a specific variant or duplicate gene. Our method can also be used to design PCR primers to specifically amplify homologs in the same gene family. PRIMEGENS-v2 is available at: http://primegens.org.

  20. Game Changer: Linked Learning Detroit

    Science.gov (United States)

    ConnectEd: The California Center for College and Career, 2016

    2016-01-01

    JP Morgan Chase joins the Skillman Foundation, the Ford Foundation, and the Ford Motor Company Fund, whose grants total $7 million and will connect 10,000 Detroit high school students to career education and work experiences over the next three years through Linked Learning Detroit. Learn about Linked Learning Detroit through interviews with…

  1. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... NIDA : Facebook LinkedIn Twitter YouTube Flickr RSS Menu Home Drugs of Abuse Commonly Abused Drugs Charts Emerging ... Badges Other Resources Strategic Plan Search Share Print Home » News & Events » Public Education Projects » Learn the Link - ...

  2. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... Plan Search Share Print Home » News & Events » Public Education Projects » Learn the Link - Drugs and HIV Learn the Link - Drugs and HIV Email Facebook Twitter 2005 –Ongoing Behaviors associated with drug abuse are among the main factors in the spread of HIV infection in the ...

  3. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... Plus Facebook LinkedIn Twitter YouTube Flickr RSS Menu Home Drugs of Abuse Commonly Abused Drugs Charts Emerging ... Badges Other Resources Strategic Plan Search Share Print Home » News & Events » Public Education Projects » Learn the Link - ...

  4. Optimizing pointer linked data structures

    NARCIS (Netherlands)

    Holm, Carl Wilhelm Mattias

    2013-01-01

    The thesis explores different ways of optimizing pointer linked data structures, and especially restructuring them. The mechanisms are based on compiler technology, theory, computer languages and hardware architecture that are capable of optimizing the memory layout of complex pointer linked data st

  5. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... link between drug abuse and HIV. http://1.usa.gov/1z20ww6 How many of us think about ... can’t ignore. Learn the Link: http://1.usa.gov/1uSUAI3 Think you’re not at risk? ...

  6. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... Parents & Educators Children & Teens Search Connect with NIDA : Facebook LinkedIn Twitter YouTube Flickr RSS Menu Home Drugs ... HIV Learn the Link - Drugs and HIV Email Facebook Twitter 2005 –Ongoing Behaviors associated with drug abuse ...

  7. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... the Link campaign. This campaign shows teens and young adults that non-injection drug use and alcohol use can lead to poor decision making, which ... message to America's youth that using drugs and alcohol even once can have ... in the lives of young people-with the Learn the Link message. Campaign ...

  8. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... in your posts! Learn the link between drug abuse and HIV. http://1.usa.gov/1z20ww6 How many of us ... not at risk? Learn the link between drug abuse and HIV. http://1.usa.gov/VF4sGf [Tag friends, colleagues, partners] ...

  9. [Sex-linked juvenile retinoschisis].

    Science.gov (United States)

    François, P; Turut, P; Soltysik, C; Hache, J C

    1976-02-01

    About 13 observations of sexe linked juvenile retinoschisis, the authors describe the ophthalmoscopic, fluorographic and functional aspects of the disease whose caracteristics are:--its sexe linked recessive heredity; --its clinical characterestics associating: a microcystic macular degeneration, peripheral retinal lesions, vitreous body alterations, --an electroretinogram of the negative type.

  10. Linking Information for Mobile Use

    Science.gov (United States)

    2007-09-01

    interface after reading the XML. .. 30 Figure 8. Display of an item’s content with linked items one click away. ........... 31 Figure 9. Movement...related, but the user has not viewed recently. Figure 8. Display of an item’s content with linked items one click away. Figure 9 shows the

  11. Amsterdam Museum Linked Open Data

    NARCIS (Netherlands)

    Boer, V. de; Wielemaker, J.; Gent, J. van; O'Connell, J.; Oosterbroek, M; Hildebrand, M.; Isaac, A.; Ossenbruggen, J.R. van; Schreiber, G.

    2013-01-01

    In this document we describe the Amsterdam Museum Linked Open Data set. The dataset is a five-star Linked Data representation and comprises the entire collection of the Amsterdam Museum consisting of more than 70,000 object descriptions. Furthermore, the institution's thesaurus and person authority

  12. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... Children & Teens Search Connect with NIDA : Google Plus Facebook LinkedIn Twitter YouTube Flickr RSS Menu Home Drugs ... HIV Learn the Link - Drugs and HIV Email Facebook Twitter 2005 –Ongoing Behaviors associated with drug abuse ...

  13. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... site. Please link these banners back to this site at: http://www.drugabuse.gov/news-events/public-education-projects/learn-link-drugs-hiv . 120x90 460x80 486x60 Social Media Send the message to young people and ...

  14. Cis and trans effects of human genomic variants on gene expression.

    Directory of Open Access Journals (Sweden)

    Julien Bryois

    2014-07-01

    Full Text Available Gene expression is a heritable cellular phenotype that defines the function of a cell and can lead to diseases in case of misregulation. In order to detect genetic variations affecting gene expression, we performed association analysis of single nucleotide polymorphisms (SNPs and copy number variants (CNVs with gene expression measured in 869 lymphoblastoid cell lines of the Avon Longitudinal Study of Parents and Children (ALSPAC cohort in cis and in trans. We discovered that 3,534 genes (false discovery rate (FDR = 5% are affected by an expression quantitative trait locus (eQTL in cis and 48 genes are affected in trans. We observed that CNVs are more likely to be eQTLs than SNPs. In addition, we found that variants associated to complex traits and diseases are enriched for trans-eQTLs and that trans-eQTLs are enriched for cis-eQTLs. As a variant affecting both a gene in cis and in trans suggests that the cis gene is functionally linked to the trans gene expression, we looked specifically for trans effects of cis-eQTLs. We discovered that 26 cis-eQTLs are associated to 92 genes in trans with the cis-eQTLs of the transcriptions factors BATF3 and HMX2 affecting the most genes. We then explored if the variation of the level of expression of the cis genes were causally affecting the level of expression of the trans genes and discovered several causal relationships between variation in the level of expression of the cis gene and variation of the level of expression of the trans gene. This analysis shows that a large sample size allows the discovery of secondary effects of human variations on gene expression that can be used to construct short directed gene regulatory networks.

  15. Lupus risk variants in the PXK locus alter B-cell receptor internalization

    Directory of Open Access Journals (Sweden)

    Samuel E. Vaughn

    2015-01-01

    Full Text Available Genome wide association studies have identified variants in PXK that confer risk for humoral autoimmune diseases, including systemic lupus erythematosus (SLE or lupus, rheumatoid arthritis and more recently systemic sclerosis. While PXK is involved in trafficking of epidermal growth factor Receptor (EGFR in COS-7 cells, mechanisms linking PXK to lupus pathophysiology have remained undefined. In an effort to uncover the mechanism at this locus that increases lupus-risk, we undertook a fine-mapping analysis in a large multi-ancestral study of lupus patients and controls. We define a large (257kb common haplotype that confers lupus risk detected only in European ancestral populations and spans the promoter through the 3’ UTR of PXK. The strongest association was found at rs6445972 with P < 4.62 x 10-10, OR 0.81 (0.75 – 0.86. Using stepwise logistic regression analysis, we demonstrate that one signal drives the genetic association in the region. Bayesian analysis confirms our results, identifying a 95% credible set consisting of 172 variants spanning 200kb.Functionally, we found that PXK operates on the B-cell antigen receptor (BCR; we confirmed that PXK influenced the rate of BCR internalization. Furthermore, we demonstrate that individuals carrying the risk haplotype exhibited a decreased rate of BCR internalization, a process known to impact B cell survival and cell fate. Taken together, these data define a new candidate mechanism for the genetic association of variants around PXK with lupus risk and highlight the regulation of intracellular trafficking as a genetically regulated pathway mediating human autoimmunity.

  16. Nonrandom Distribution of miRNAs Genes and Single Nucleotide Variants in Keratoconus Loci.

    Directory of Open Access Journals (Sweden)

    Dorota M Nowak

    Full Text Available Despite numerous studies, the causes of both development and progression of keratoconus remain elusive. Previous studies of this disorder focused mainly on one or two genetic factors only. However, in the analysis of such complex diseases all potential factors should be taken into consideration. The purpose of this study was a comprehensive analysis of known keratoconus loci to uncover genetic factors involved in this disease causation in the general population, which could be omitted in the original studies. In this investigation genomic data available in various databases and experimental own data were assessed. The lists of single nucleotide variants and miRNA genes localized in reported keratoconus loci were obtained from Ensembl and miRBase, respectively. The potential impact of nonsynonymous amino acid substitutions on protein structure and function was assessed with PolyPhen-2 and SIFT. For selected protein genes the ranking was made to choose those most promising for keratoconus development. Ranking results were based on topological features in the protein-protein interaction network. High specificity for the populations in which the causative sequence variants have been identified was found. In addition, the possibility of links between previously analyzed keratoconus loci was confirmed including miRNA-gene interactions. Identified number of genes associated with oxidative stress and inflammatory agents corroborated the hypothesis of their effect on the disease etiology. Distribution of the numerous sequences variants within both exons and mature miRNA which forces you to search for a broader look at the determinants of keratoconus. Our findings highlight the complexity of the keratoconus genetics.

  17. Nonrandom Distribution of miRNAs Genes and Single Nucleotide Variants in Keratoconus Loci.

    Science.gov (United States)

    Nowak, Dorota M; Gajecka, Marzena

    2015-01-01

    Despite numerous studies, the causes of both development and progression of keratoconus remain elusive. Previous studies of this disorder focused mainly on one or two genetic factors only. However, in the analysis of such complex diseases all potential factors should be taken into consideration. The purpose of this study was a comprehensive analysis of known keratoconus loci to uncover genetic factors involved in this disease causation in the general population, which could be omitted in the original studies. In this investigation genomic data available in various databases and experimental own data were assessed. The lists of single nucleotide variants and miRNA genes localized in reported keratoconus loci were obtained from Ensembl and miRBase, respectively. The potential impact of nonsynonymous amino acid substitutions on protein structure and function was assessed with PolyPhen-2 and SIFT. For selected protein genes the ranking was made to choose those most promising for keratoconus development. Ranking results were based on topological features in the protein-protein interaction network. High specificity for the populations in which the causative sequence variants have been identified was found. In addition, the possibility of links between previously analyzed keratoconus loci was confirmed including miRNA-gene interactions. Identified number of genes associated with oxidative stress and inflammatory agents corroborated the hypothesis of their effect on the disease etiology. Distribution of the numerous sequences variants within both exons and mature miRNA which forces you to search for a broader look at the determinants of keratoconus. Our findings highlight the complexity of the keratoconus genetics.

  18. Nullification of knots and links

    CERN Document Server

    Diao, Yuanan; Montemayor, Anthony

    2011-01-01

    In this paper, we study a geometric/topological measure of knots and links called the nullification number. The nullification of knots/links is believed to be biologically relevant. For example, in DNA topology, one can intuitively regard it as a way to measure how easily a knotted circular DNA can unknot itself through recombination of its DNA strands. It turns out that there are several different ways to define such a number. These definitions lead to nullification numbers that are related, but different. Our aim is to explore the mathematical properties of these nullification numbers. First, we give specific examples to show that the nullification numbers we defined are different. We provide detailed analysis of the nullification numbers for the well known 2-bridge knots and links. We also explore the relationships among the three nullification numbers, as well as their relationships with other knot invariants. Finally, we study a special class of links, namely those links whose general nullification numbe...

  19. Effects of PCSK1 genetic variants on obesity among Thai children and their family members: in relation to health risk, and biochemical and anthropometric parameters.

    Science.gov (United States)

    Kulanuwat, Sirikul; Phonrat, Benjaluck; Tungtrongchitr, Anchalee; Limwongse, Chanin; Chongviriyaphan, Nalinee; Tungtrongchitr, Rungsunn; Santiprabhob, Jeerunda

    2014-01-01

    Single nucleotide polymorphisms (SNPs) in PCSK1, namely, rs6234, rs6235, and rs271939 have been linked to obesity in European population; and rs3811951 has also been connected to type 2 diabetes and obesity parameters in Chinese population. In this family-based case-control study, we analyzed links between PCSK1 genetic variants and obesity in Thai children and their families. Eleven obese children with a percent weight for height > or = 140 who had family history of obesity and 69 family members were recruited. SNPs rs6234, rs6235, rs3811951, and rs271939 of PCSK1 were analyzed using PCR and gene sequencing methods. DNA of 200 normal weight subjects was used as control. Participants with variant genotypes in the rs6234-6235 pair are at significantly more risk of being obese [OR = 2.44 (1.35-4.43), p = 0.003], and also at increased risk of being severely obese (obese class III) [OR = 3.03 (1.20-7.66), p = 0.015]. Variant rs3811951 showed no association with being obese, but is significantly linked to an increased risk of being severely obese [OR = 3.59 (1.42-9.08) p = 0.005]. Moreover, high density lipoprotein (HDL)-C levels between normal and variant rs3811951 group differed considerably, with patients with variant genotype having a lower HDL-C level (p = 0.037). Thus, Thais carrying SNPs rs6234-5 are at increased risk of being obese, and the risk of severe obesity increases when carrying both rs6234-5 and rs3811951, but not with rs271939. Furthermore, patients with genetic variations at rs3811951 are at risk of having low HDL-C levels.

  20. Association of primary open-angle glaucoma with mitochondrial variants and haplogroups common in African Americans

    Science.gov (United States)

    Gudiseva, Harini V.; Trachtman, Benjamin; Bowman, Anita S.; Sagaser, Anna; Sankar, Prithvi; Miller-Ellis, Eydie; Lehman, Amanda; Addis, Victoria; O'Brien, Joan M.

    2016-01-01

    lineages, associated with Leber hereditary optic neuropathy (LHON) severity, was confirmed to be common (>5%) but was not significantly enriched in the POAG cases. Two variants linked to the composition of the gut microbiome, m.15784T>C (rs527236194, haplogroup L2a1) and m.16390G>A (rs41378955, L2 haplogroups), were also enriched in the case DNA pools. Conclusions These results implicate African mtDNA haplogroups L1c2, L1c2b, and L2 as risk factors for POAG. Approximately one in four African Americans have these mitochondrial ancestries, which may contribute to their elevated glaucoma risk. These haplogroups are defined in part by ancestral variants in the MT-RNR2 and/or MT-CO1 genes, several of which have prior disease associations, such as MT-CO1 missense variants that have been implicated in prostate cancer. PMID:27217714

  1. Alternative Technical Summary Report: Electrometallurgical Treatment Variant

    Energy Technology Data Exchange (ETDEWEB)

    Gray, L.W.

    1995-11-30

    Immobilization is the fixation of the surplus fissile materials in an acceptable matrix such as glass or ceramics to create an environmentally benign form for disposal in a repository. In addition to the traditional characteristics required of an immobilization form to achieve isolation of the fissile material from the biosphere over geologic times, the immobilization form for the Fissile Materials Disposition Program (FMDP) must also possess the property that it is inherently as unattractive and inaccessible as the fissile material from commercial spent fuel. This latter requirement is similar to the wording of the ''spent fuel standard'' invoked in the National Academy of Sciences (NAS) study on plutonium disposition. High-level wastes (HLW) or separated cesium ({sup 137}Cs), can be added with the fissile material into the waste form to create a radiation field that increases the proliferation resistance and decreases reuse by the host nation in the following ways: (1) Plutonium will be diluted with elements that must be removed by extensive chemical processing to return it to weapons-usable purity; (2) The immobilized plutonium canisters will contain approximately 2 tonnes (2000 kg; 2.2 tons) of mass, thereby forcing the use of heavy equipment to move the canisters; (3) A gamma radiation barrier will be added to the immobilized plutonium canisters; the present concept is to add a radiation barrier that is greater than 1 Gy (100 rad) per hour at 1 m (3 ft) 30 years after fabrication; (4) These canisters will then be sealed in casks and emplaced into drifts in a federal repository where they will be monitored for 100 years before the repository is sealed. This immobilization process is shown conceptually in Figure 1. In the electrometallurgical treatment (ET) variant, plutonium-rich residues are shipped to existing Argonne National Laboratory-West (ANL-W) facilities where the plutonium is converted to plutonium chloride, dissolved in a molten

  2. Genetic risk variants for social anxiety.

    Science.gov (United States)

    Stein, Murray B; Chen, Chia-Yen; Jain, Sonia; Jensen, Kevin P; He, Feng; Heeringa, Steven G; Kessler, Ronald C; Maihofer, Adam; Nock, Matthew K; Ripke, Stephan; Sun, Xiaoying; Thomas, Michael L; Ursano, Robert J; Smoller, Jordan W; Gelernter, Joel

    2017-03-01

    Social anxiety is a neurobehavioral trait characterized by fear and reticence in social situations. Twin studies have shown that social anxiety has a heritable basis, shared with neuroticism and extraversion, but genetic studies have yet to demonstrate robust risk variants. We conducted genomewide association analysis (GWAS) of subjects within the Army Study To Assess Risk and Resilience in Servicemembers (Army STARRS) to (i) determine SNP-based heritability of social anxiety; (ii) discern genetic risk loci for social anxiety; and (iii) determine shared genetic risk with neuroticism and extraversion. GWAS were conducted within ancestral groups (EUR, AFR, LAT) using linear regression models for each of the three component studies in Army STARRS, and then meta-analyzed across studies. SNP-based heritability for social anxiety was significant (h(2)g  = 0.12, P = 2.17 × 10(-4) in EUR). One meta-analytically genomewide significant locus was seen in each of EUR (rs708012, Chr 6: BP 36965970, P = 1.55 × 10(-8) ; beta = 0.073) and AFR (rs78924501, Chr 1: BP 88406905, P = 3.58 × 10(-8) ; beta = 0.265) samples. Social anxiety in Army STARRS was significantly genetically correlated (negatively) with extraversion (rg  = -0.52, se = 0.22, P = 0.02) but not with neuroticism (rg  = 0.05, se = 0.22, P = 0.81) or with an anxiety disorder factor score (rg  = 0.02, se = 0.32, P = 0.94) from external GWAS meta-analyses. This first GWAS of social anxiety confirms a genetic basis for social anxiety, shared with extraversion but possibly less so with neuroticism. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  3. Regional brain volume abnormalities in Lesch-Nyhan disease and its variants: a cross-sectional study.

    Science.gov (United States)

    Schretlen, David J; Varvaris, Mark; Ho, Tiffany E; Vannorsdall, Tracy D; Gordon, Barry; Harris, James C; Jinnah, H A

    2013-12-01

    Lesch-Nyhan disease is a rare, X-linked, neurodevelopmental metabolic disorder that is caused by abnormalities in the levels of hypoxanthine-guanine phosphoribosyltransferase enzyme activity. The neural substrates associated with Lesch-Nyhan disease remain poorly understood. We aimed to use voxel-based morphometry to identify affected brain regions in classic Lesch-Nyhan disease and Lesch-Nyhan variant disease, and to identify regions that differ between the two disease types. In this cross-sectional study, we recruited patients with classic Lesch-Nyhan disease or Lesch-Nyhan variant disease from clinics, referrals, the Lesch-Nyhan Syndrome Registry, and the Matheny School and Hospital (Peapack, NJ, USA), and healthy controls from the Baltimore metropolitan area (MD, USA). We used voxel-based morphometry to analyse grey matter volume between groups using a three-group ANCOVA, followed by six pairwise post-hoc group comparisons. Between Oct 3, 1993, and April 29, 2013, we recruited 21 patients with classic Lesch-Nyhan disease, 17 patients with variant disease, and 33 healthy controls. Patients with classic Lesch-Nyhan disease had a 20% reduction in intracranial volume (17% reduction in grey matter volume; 26% reduction in white matter volume) compared with healthy adults. The largest differences were in basal ganglia, and frontotemporal and limbic regions, with sparing of parieto-occipital regions. Grey matter volumes of patients with Lesch-Nyhan variant disease were invariably between those of patients with classic Lesch-Nyhan disease and healthy controls. Compared with healthy controls, patients with classic disease showed additional grey matter volume reductions in the temporal lobe and left lateralised structures, and patients with variant disease showed additional reductions in lingual and precuneus regions with sparing of right frontal and temporal regions. Patients with classic disease had reductions of volume in the ventral striatum and prefrontal areas

  4. Prevalence of common disease-associated variants in Asian Indians

    Directory of Open Access Journals (Sweden)

    Allayee Hooman

    2008-02-01

    Full Text Available Abstract Background Asian Indians display a high prevalence of diseases linked to changes in diet and environment that have arisen as their lifestyle has become more westernized. Using 1200 genome-wide polymorphisms in 432 individuals from 15 Indian language groups, we have recently shown that: (i Indians constitute a distinct population-genetic cluster, and (ii despite the geographic and linguistic diversity of the groups they exhibit a relatively low level of genetic heterogeneity. Results We investigated the prevalence of common polymorphisms that have been associated with diseases, such as atherosclerosis (ALOX5, hypertension (CYP3A5, AGT, GNB3, diabetes (CAPN10, TCF7L2, PTPN22, prostate cancer (DG8S737, rs1447295, Hirschsprung disease (RET, and age-related macular degeneration (CFH, LOC387715. In addition, we examined polymorphisms associated with skin pigmentation (SLC24A5 and with the ability to taste phenylthiocarbamide (TAS2R38. All polymorphisms were studied in a cohort of 576 India-born Asian Indians sampled in the United States. This sample consisted of individuals whose mother tongue is one of 14 of the 22 "official" languages recognized in India as well as individuals whose mother tongue is Parsi, a cultural group that has resided in India for over 1000 years. Analysis of the data revealed that allele frequency differences between the different Indian language groups were small, and interestingly the variant alleles of ALOX5 g.8322G>A and g.50778G>A, and PTPN22 g.36677C>T were present only in a subset of the Indian language groups. Furthermore, a latitudinal cline was identified both for the allele frequencies of the SNPs associated with hypertension (CYP3A5, AGT, GNB3, as well as for those associated with the ability to taste phenylthiocarbamide (TAS2R38. Conclusion Although caution is warranted due to the fact that this US-sampled Indian cohort may not represent a random sample from India, our results will hopefully assist in the

  5. Two insular regions are differentially involved in behavioral variant FTD and nonfluent/agrammatic variant PPA.

    Science.gov (United States)

    Mandelli, Maria Luisa; Vitali, Paolo; Santos, Miguel; Henry, Maya; Gola, Kelly; Rosenberg, Lynne; Dronkers, Nina; Miller, Bruce; Seeley, William W; Gorno-Tempini, Maria Luisa

    2016-01-01

    The non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) and the behavioral variant frontotemporal dementia (bvFTD) are focal neurodegenerative disorders belonging to the FTD-spectrum clinical syndromes. NfvPPA is characterized by effortful speech and/or agrammatism and left frontal atrophy, while bvFTD is characterized by social-emotional dysfunction often accompanied by right-lateralized frontal damage. Despite their contrasting clinical presentations, both disorders show prominent left anterior insula atrophy. We investigated differential patterns of insular sub-region atrophy in nfvPPA and bvFTD. Based on knowledge of insular connectivity and physiology, we hypothesized that the left superior precentral region of the dorsal anterior insula (SPGI) would be more atrophic in nvfPPA due to its critical role in motor speech, whereas the ventral anterior region would be more atrophied in bvFTD reflecting its known role in social-emotional-autonomic functions. Early stage nfvPPA and bvFTD patients matched for disease severity, age, gender and education and healthy controls participated in the study. Detailed clinical history, neurological examination, neuropsychological screening evaluation, and high-resolution T1-weighted brain magnetic resonance imaging (MRI) were collected. Voxel-based morphometry (VBM) was applied to perform group comparisons across the whole brain and in bilateral insula region of interest (ROI). Correlation analyses between insular sub-region atrophy and relevant clinical features were performed. Whole brain group comparisons between nfvPPA and bvFTD showed the expected predominantly left or right anterior insular atrophy pattern. ROI analysis of bilateral insula showed that the left SPGI was significantly more atrophied in nfvPPA compared to bvFTD, while the bilateral ventral anterior and right dorsal anterior insula sub-regions were more atrophied in bvFTD than nfvPPA. Only left SPGI volume correlated with speech production

  6. Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease

    Science.gov (United States)

    Grove, Megan L.; Naj, Adam; Vronskaya, Maria; DeStefano, Anita L.; Brody, Jennifer A.; Smith, Albert V.; Amin, Najaf; Sims, Rebecca; Ibrahim-Verbaas, Carla A.; Choi, Seung-Hoan; Lopez, Oscar L.; Beiser, Alexa; Ikram, M. Arfan; Garcia, Melissa E.; Hayward, Caroline; Ripatti, Samuli; Franks, Paul W.; Hallmans, Göran; Rolandsson, Olov; Jansson, Jan-Håkon; Porteous, David J.; Salomaa, Veikko; Eiriksdottir, Gudny; Rice, Kenneth M.; Bellen, Hugo J.; Levy, Daniel; Uitterlinden, Andre G.; Emilsson, Valur; Rotter, Jerome I.; Aspelund, Thor; O’Donnell, Christopher J.; Fitzpatrick, Annette L.; Launer, Lenore J.; Hofman, Albert; Wang, Li-San; Williams, Julie; Schellenberg, Gerard D.; Boerwinkle, Eric; Psaty, Bruce M.; Seshadri, Sudha; Shulman, Joshua M.; Gudnason, Vilmundur; van Duijn, Cornelia M.

    2016-01-01

    We performed an exome-wide association analysis in 1393 late-onset Alzheimer’s disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5–15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade. PMID:27764101

  7. Structures of the G85R Variant of SOD1 in Familial Amyotrophic Lateral Sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Cao, Xiaohang; Antonyuk, Svetlana V.; Seetharaman, Sai V.; Whitson, Lisa J.; Taylor, Alexander B.; Holloway, Stephen P.; Strange, Richard W.; Doucette, Peter A.; Valentine, Joan Selverstone; Tiwari, Ashutosh; Hayward, Lawrence J.; Padua, Shelby; Cohlberg, Jeffrey A.; Hasnain, S. Samar; Hart, P. John (Texas-HSC); (Cal. State); (UMASS, MED); (UCLA); (Daresbury)

    2008-07-21

    Mutations in the gene encoding human copper-zinc superoxide dismutase (SOD1) cause a dominant form of the progressive neurodegenerative disease amyotrophic lateral sclerosis. Transgenic mice expressing the human G85R SOD1 variant develop paralytic symptoms concomitant with the appearance of SOD1-enriched proteinaceous inclusions in their neural tissues. The process(es) through which misfolding or aggregation of G85R SOD1 induces motor neuron toxicity is not understood. Here we present structures of the human G85R SOD1 variant determined by single crystal x-ray diffraction. Alterations in structure of the metal-binding loop elements relative to the wild type enzyme suggest a molecular basis for the metal ion deficiency of the G85R SOD1 protein observed in the central nervous system of transgenic mice and in purified recombinant G85R SOD1. These findings support the notion that metal-deficient and/or disulfide-reduced mutant SOD1 species contribute to toxicity in SOD1-linked amyotrophic lateral sclerosis.

  8. Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.

    Directory of Open Access Journals (Sweden)

    Johanna Jakobsdottir

    2016-10-01

    Full Text Available We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations. In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI = 7.5 (3.5-15.9, p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade.

  9. Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms.

    Science.gov (United States)

    Rusu, Victor; Hoch, Eitan; Mercader, Josep M; Tenen, Danielle E; Gymrek, Melissa; Hartigan, Christina R; DeRan, Michael; von Grotthuss, Marcin; Fontanillas, Pierre; Spooner, Alexandra; Guzman, Gaelen; Deik, Amy A; Pierce, Kerry A; Dennis, Courtney; Clish, Clary B; Carr, Steven A; Wagner, Bridget K; Schenone, Monica; Ng, Maggie C Y; Chen, Brian H; Centeno-Cruz, Federico; Zerrweck, Carlos; Orozco, Lorena; Altshuler, David M; Schreiber, Stuart L; Florez, Jose C; Jacobs, Suzanne B R; Lander, Eric S

    2017-06-29

    Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ∼20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. VIDEO ABSTRACT. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Vinculin variant M94I identified in sudden unexplained nocturnal death syndrome decreases cardiac sodium current.

    Science.gov (United States)

    Cheng, Jianding; Kyle, John W; Wiedmeyer, Brandi; Lang, Di; Vaidyanathan, Ravi; Makielski, Jonathan C

    2017-02-20

    Sudden unexplained nocturnal death syndrome (SUNDS) remains an autopsy negative disorder with unclear etiology. Vinculin (VCL) was linked to sudden arrhythmia death in VCL knockout mice prior to the appearance of cardiomyopathy. We hypothesized VCL mutations underlie risk for SUNDS. A rare heterozygous variant VCL-M94I was found in a SUNDS victim who suffered sudden nocturnal tachypnea and lacked pathogenic variants in known arrhythmia-causing genes. VCL was identified to interact with SCN5A in vitro/vivo. The VCL-M94I was co-expressed with the cardiac sodium channel in HEK293 cells and also overexpressed in induced pluripotent stem cells derived cardiomyocytes (iPSCs-CM). In HEK293 cells with pH 7.4, VCL-M94I caused ~30% decrease in peak sodium current (INa) amplitude compared to WT; under acidotic conditions (pH 7.0) typically found with hypoxia during sleep apnea, M94I resulted in 37% reduction in peak INa compared to WT and the combination of VCL-M94I and pH 7.0 decreased peak INa by ~56% compared to WT at pH 7.4. In iPSCs-CM, similar effects of M94I on reduction of peak INa were observed. This study initially shows both physical and functional interaction between VCL and cardiac sodium channel, and suggests an important role for respiratory acidosis in triggering the fatal arrhythmia underlying SUNDS.

  11. A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer

    Science.gov (United States)

    Kiemeney, Lambertus A; Sulem, Patrick; Besenbacher, Soren; Vermeulen, Sita H; Sigurdsson, Asgeir; Thorleifsson, Gudmar; Gudbjartsson, Daniel F; Stacey, Simon N; Gudmundsson, Julius; Zanon, Carlo; Kostic, Jelena; Masson, Gisli; Bjarnason, Hjordis; Palsson, Stefan T; Skarphedinsson, Oskar B; Gudjonsson, Sigurjon A; Witjes, J Alfred; Grotenhuis, Anne J; Verhaegh, Gerald W; Bishop, D Timothy; Sak, Sei Chung; Choudhury, Ananya; Elliott, Faye; Barrett, Jennifer H; Hurst, Carolyn D; de Verdier, Petra J; Ryk, Charlotta; Rudnai, Peter; Gurzau, Eugene; Koppova, Kvetoslava; Vineis, Paolo; Polidoro, Silvia; Guarrera, Simonetta; Sacerdote, Carlotta; Campagna, Marcello; Placidi, Donatella; Arici, Cecilia; Zeegers, Maurice P; Kellen, Eliane; Gutierrez, Berta Saez; Sanz-Velez, José I; Sanchez-Zalabardo, Manuel; Valdivia, Gabriel; Garcia-Prats, Maria D; Hengstler, Jan G; Blaszkewicz, Meinolf; Dietrich, Holger; Ophoff, Roel A; van den Berg, Leonard H; Alexiusdottir, Kristin; Kristjansson, Kristleifur; Geirsson, Gudmundur; Nikulasson, Sigfus; Petursdottir, Vigdis; Kong, Augustine; Thorgeirsson, Thorgeir; Mungan, N Aydin; Lindblom, Annika; van Es, Michael A; Porru, Stefano; Buntinx, Frank; Golka, Klaus; Mayordomo, José I; Kumar, Rajiv; Matullo, Giuseppe; Steineck, Gunnar; Kiltie, Anne E; Aben, Katja K H; Jonsson, Eirikur; Thorsteinsdottir, Unnur; Knowles, Margaret A; Rafnar, Thorunn; Stefansson, Kari

    2010-01-01

    Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 × 10−12). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC. PMID:20348956

  12. FTO gene variant modulates the neural correlates of visual food perception.

    Science.gov (United States)

    Kühn, Anne B; Feis, Delia-Lisa; Schilbach, Leonhard; Kracht, Lutz; Hess, Martin E; Mauer, Jan; Brüning, Jens C; Tittgemeyer, Marc

    2016-03-01

    Variations in the fat mass and obesity associated (FTO) gene are currently the strongest known genetic factor predisposing humans to non-monogenic obesity. Recent experiments have linked these variants to a broad spectrum of behavioural alterations, including food choice and substance abuse. Yet, the underlying neurobiological mechanisms by which these genetic variations influence body weight remain elusive. Here, we explore the brain structural substrate of the obesity-predisposing rs9939609 T/A variant of the FTO gene in non-obese subjects by means of multivariate classification and use fMRI to investigate genotype-specific differences in neural food-cue reactivity by analysing correlates of a visual food perception task. Our findings demonstrate that MRI-derived measures of morphology along middle and posterior fusiform gyrus (FFG) are highly predictive for FTO at-risk allele carriers, who also show enhanced neural responses elicited by food cues in the same posterior FFG area. In brief, these findings provide first-time evidence for FTO-specific differences in both brain structure and function already in non-obese individuals, thereby contributing to a mechanistic understanding of why FTO is a predisposing factor for obesity. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. SMIM1 variants rs1175550 and rs143702418 independently modulate Vel blood group antigen expression

    Science.gov (United States)

    Christophersen, Mikael K.; Jöud, Magnus; Ajore, Ram; Vege, Sunitha; Ljungdahl, Klara W.; Westhoff, Connie M.; Olsson, Martin L.; Storry, Jill R.; Nilsson, Björn

    2017-01-01

    The Vel blood group antigen is expressed on the red blood cells of most individuals. Recently, we described that homozygosity for inactivating mutations in SMIM1 defines the rare Vel-negative phenotype. Still, Vel-positive individuals show great variability in Vel antigen expression, creating a risk for Vel blood typing errors and transfusion reactions. We fine-mapped the regulatory region located in SMIM1 intron 2 in Swedish blood donors, and observed a strong correlation between expression and rs1175550 as well as with a previously unreported tri-nucleotide insertion (rs143702418; C > CGCA). While the two variants are tightly linked in Caucasians, we separated their effects in African Americans, and found that rs1175550G and to a lesser extent rs143702418C independently increase SMIM1 and Vel antigen expression. Gel shift and luciferase assays indicate that both variants are transcriptionally active, and we identified binding of the transcription factor TAL1 as a potential mediator of the increased expression associated with rs1175550G. Our results provide insight into the regulatory logic of Vel antigen expression, and extend the set of markers for genetic Vel blood group typing. PMID:28084402

  14. MSV3d: database of human MisSense Variants mapped to 3D protein structure.

    Science.gov (United States)

    Luu, Tien-Dao; Rusu, Alin-Mihai; Walter, Vincent; Ripp, Raymond; Moulinier, Luc; Muller, Jean; Toursel, Thierry; Thompson, Julie D; Poch, Olivier; Nguyen, Hoan

    2012-01-01

    The elucidation of the complex relationships linking genotypic and phenotypic variations to protein structure is a major challenge in the post-genomic era. We present MSV3d (Database of human MisSense Variants mapped to 3D protein structure), a new database that contains detailed annotation of missense variants of all human proteins (20 199 proteins). The multi-level characterization includes details of the physico-chemical changes induced by amino acid modification, as well as information related to the conservation of the mutated residue and its position relative to functional features in the available or predicted 3D model. Major releases of the database are automatically generated and updated regularly in line with the dbSNP (database of Single Nucleotide Polymorphism) and SwissVar releases, by exploiting the extensive Décrypthon computational grid resources. The database (http://decrypthon.igbmc.fr/msv3d) is easily accessible through a simple web interface coupled to a powerful query engine and a standard web service. The content is completely or partially downloadable in XML or flat file formats. Database URL: http://decrypthon.igbmc.fr/msv3d.

  15. Dark Variants of Luminous Bacteria Whole Cell Bioluminescent Optical Fiber Sensor to Genotoxicants

    Institute of Scientific and Technical Information of China (English)

    孙雅量; 周铁波; 过健俐; 李义勇

    2004-01-01

    A stable dark variant separated from photobacterium phosphoreum (A2) was fixed in agar-gel membrane and immobilized onto an exposed end of a fiber-optic linked with bioluminometer. The variant could emit a luminescent signal in the presence of genotoxic agents, such as Mitomycin C (MC). The performance of this whole-cell optical fiber sensor system was examined as a function of several parameters, including gel probe thickness, bacterial cell density, and diameter of the fiber-optic core and working temperature. An optimal response to a model genotoxicant, Mitomycin C, was achieved with agar-bacterial gel membrane: the thickness of gel membrane was about 5 mm; the cell density of bacteria in gel membranewas about 2.0 × 107/ml; the diameter of fiberoptic core was 5.0 mm; the working temperature was 25℃. Under these optimized conditions, the response time was less than 10 h to Mitomycin C, with a lower detection threshold of 0.1 mg/L.

  16. A Bioinformatics Approach to the Identification of Variants Associated with Type 1 and Type 2 Diabetes Mellitus that Reside in Functionally Validated miRNAs Binding Sites.

    Science.gov (United States)

    Ghaedi, Hamid; Bastami, Milad; Jahani, Mohammad Mehdi; Alipoor, Behnam; Tabasinezhad, Maryam; Ghaderi, Omar; Nariman-Saleh-Fam, Ziba; Mirfakhraie, Reza; Movafagh, Abolfazl; Omrani, Mir Davood; Masotti, Andrea

    2016-06-01

    The present work is aimed at finding variants associated with Type 1 and Type 2 diabetes mellitus (DM) that reside in functionally validated miRNAs binding sites and that can have a functional role in determining diabetes and related pathologies. Using bioinformatics analyses we obtained a database of validated polymorphic miRNA binding sites which has been intersected with genes related to DM or to variants associated and/or in linkage disequilibrium (LD) with it and is reported in genome-wide association studies (GWAS). The workflow we followed allowed us to find variants associated with DM that also reside in functional miRNA binding sites. These data have been demonstrated to have a functional role by impairing the functions of genes implicated in biological processes linked to DM. In conclusion, our work emphasized the importance of SNPs located in miRNA binding sites. The results discussed in this work may constitute the basis of further works aimed at finding functional candidates and variants affecting protein structure and function, transcription factor binding sites, and non-coding epigenetic variants, contributing to widen the knowledge about the pathogenesis of this important disease.

  17. Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels

    Science.gov (United States)

    van Leeuwen, Elisabeth M; Sabo, Aniko; Bis, Joshua C; Huffman, Jennifer E; Manichaikul, Ani; Smith, Albert V; Feitosa, Mary F; Demissie, Serkalem; Joshi, Peter K; Duan, Qing; Marten, Jonathan; van Klinken, Jan B; Surakka, Ida; Nolte, Ilja M; Zhang, Weihua; Mbarek, Hamdi; Li-Gao, Ruifang; Trompet, Stella; Verweij, Niek; Evangelou, Evangelos; Lyytikäinen, Leo-Pekka; Tayo, Bamidele O; Deelen, Joris; van der Most, Peter J; van der Laan, Sander W; Arking, Dan E; Morrison, Alanna; Dehghan, Abbas; Franco, Oscar H; Hofman, Albert; Rivadeneira, Fernando; Sijbrands, Eric J; Uitterlinden, Andre G; Mychaleckyj, Josyf C; Campbell, Archie; Hocking, Lynne J; Padmanabhan, Sandosh; Brody, Jennifer A; Rice, Kenneth M; White, Charles C; Harris, Tamara; Isaacs, Aaron; Campbell, Harry; Lange, Leslie A; Rudan, Igor; Kolcic, Ivana; Navarro, Pau; Zemunik, Tatijana; Salomaa, Veikko; Kooner, Angad S; Kooner, Jaspal S; Lehne, Benjamin; Scott, William R; Tan, Sian-Tsung; de Geus, Eco J; Milaneschi, Yuri; Penninx, Brenda W J H; Willemsen, Gonneke; de Mutsert, Renée; Ford, Ian; Gansevoort, Ron T; Segura-Lepe, Marcelo P; Raitakari, Olli T; Viikari, Jorma S; Nikus, Kjell; Forrester, Terrence; McKenzie, Colin A; de Craen, Anton J M; de Ruijter, Hester M; Pasterkamp, Gerard; Snieder, Harold; Oldehinkel, Albertine J; Slagboom, P Eline; Cooper, Richard S; Kähönen, Mika; Lehtimäki, Terho; Elliott, Paul; van der Harst, Pim; Jukema, J Wouter; Mook-Kanamori, Dennis O; Boomsma, Dorret I; Chambers, John C; Swertz, Morris; Ripatti, Samuli; Willems van Dijk, Ko; Vitart, Veronique; Polasek, Ozren; Hayward, Caroline; Wilson, James G; Wilson, James F; Gudnason, Vilmundur; Rich, Stephen S; Psaty, Bruce M; Borecki, Ingrid B; Boerwinkle, Eric; Rotter, Jerome I; Cupples, L Adrienne; van Duijn, Cornelia M

    2016-01-01

    Background So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels. Methods We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage. Results Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene. Conclusions This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels. PMID:27036123

  18. M89V Sialic acid Acetyl Esterase (SIAE) and all other non-synonymous common variants of this gene are catalytically normal.

    Science.gov (United States)

    Chellappa, Vasant; Taylor, Kendra N; Pedrick, Kathryn; Donado, Carlos; Netravali, Ilka Arun; Haider, Khaleda; Cariappa, Annaiah; Dalomba, Natasha F; Pillai, Shiv

    2013-01-01

    Catalytically defective rare variants of Sialic acid Acetyl Esterase (SIAE) have previously been linked to autoimmunity. Studies presented here confirm that the M89V SIAE protein and all other products of common variant alleles of SIAE are catalytically normal. Although overexpressing transfected non-lymphoid cells secrete small amounts of SIAE that can associate with the cell surface, normal human lymphocytes do not exhibit cell surface SIAE, supporting genetic evidence in mice that indicates that this protein functions in a lymphocyte intrinsic manner. Analyses of the plasma proteome also indicate that SIAE is not secreted in vivo. A re-analysis exclusively of catalytically defective rare variant alleles of SIAE in subjects in which this gene was completely sequenced confirmed an association of SIAE with autoimmunity. A subset of catalytically defective rare variant SIAE alleles has previously been typed in a large genotyping study comparing a diverse group of disease subjects and controls; our re-analysis of this data shows that catalytically defective alleles are enriched in disease subjects. These data suggest that SIAE may be associated with autoimmunity and that further study of catalytically defective rare variant SIAE alleles in terms of autoimmune disease susceptibility is strongly warranted.

  19. M89V Sialic acid Acetyl Esterase (SIAE and all other non-synonymous common variants of this gene are catalytically normal.

    Directory of Open Access Journals (Sweden)

    Vasant Chellappa

    Full Text Available Catalytically defective rare variants of Sialic acid Acetyl Esterase (SIAE have previously been linked to autoimmunity. Studies presented here confirm that the M89V SIAE protein and all other products of common variant alleles of SIAE are catalytically normal. Although overexpressing transfected non-lymphoid cells secrete small amounts of SIAE that can associate with the cell surface, normal human lymphocytes do not exhibit cell surface SIAE, supporting genetic evidence in mice that indicates that this protein functions in a lymphocyte intrinsic manner. Analyses of the plasma proteome also indicate that SIAE is not secreted in vivo. A re-analysis exclusively of catalytically defective rare variant alleles of SIAE in subjects in which this gene was completely sequenced confirmed an association of SIAE with autoimmunity. A subset of catalytically defective rare variant SIAE alleles has previously been typed in a large genotyping study comparing a diverse group of disease subjects and controls; our re-analysis of this data shows that catalytically defective alleles are enriched in disease subjects. These data suggest that SIAE may be associated with autoimmunity and that further study of catalytically defective rare variant SIAE alleles in terms of autoimmune disease susceptibility is strongly warranted.

  20. Divergence in the plasminogen-binding group a streptococcal M protein family: functional conservation of binding site and potential role for immune selection of variants.

    Science.gov (United States)

    Sanderson-Smith, Martina; Batzloff, Michael; Sriprakash, Kabada S; Dowton, Mark; Ranson, Marie; Walker, Mark J

    2006-02-10

    Group A streptococci (GAS) display receptors for the human zymogen plasminogen on the cell surface, one of which is the plasminogen-binding group A streptococcal M protein (PAM). Characterization of PAM genes from 12 GAS isolates showed significant variation within the plasminogen-binding repeat motifs (a1/a2) of this protein. To determine the impact of sequence variation on protein function, recombinant proteins representing five naturally occurring variants of PAM, together with a recombinant M1 protein, were expressed and purified. Equilibrium dissociation constants for the interaction of PAM variants with biotinylated Glu-plasminogen ranged from 1.58 to 4.99 nm. Effective concentrations of prototype PAM required for 50% inhibition of plasminogen binding to immobilized PAM variants ranged from 0.68 to 22.06 nm. These results suggest that although variation in the a1/a2 region of the PAM protein does affect the comparative affinity of PAM variants, the functional capacity to bind plasminogen is conserved. Additionally, a potential role for the a1 region of PAM in eliciting a protective immune response was investigated by using a mouse model for GAS infection. The a1 region of PAM was found to protect immunized mice challenged with a PAM-positive GAS strain. These data suggest a link between selective immune pressure against the plasminogen-binding repeats and the functional conservation of the binding domain in PAM variants.

  1. Further Evidence That the CFTR Variant c.2620-6T>C Is Benign.

    Science.gov (United States)

    Wallerstein, Violet I; Wallerstein, Robert

    2017-01-01

    The c.2620-6T>C variant in the CFTR gene is a rare variant about which little is known. We present an asymptomatic adult who has this variant as well as the well described delta F508 pathogenic variant in transpresentation. This patient provides additional evidence that this is a benign polymorphism.

  2. Further Evidence That the CFTR Variant c.2620-6T>C Is Benign

    Science.gov (United States)

    Wallerstein, Violet I.

    2017-01-01

    The c.2620-6T>C variant in the CFTR gene is a rare variant about which little is known. We present an asymptomatic adult who has this variant as well as the well described delta F508 pathogenic variant in transpresentation. This patient provides additional evidence that this is a benign polymorphism. PMID:28163942

  3. Cellulase variants with improved expression, activity and stability, and use thereof

    Energy Technology Data Exchange (ETDEWEB)

    Aehle, Wolfgang; Bott, Richard R.; Bower, Benjamin S.; Caspi, Jonathan; Goedegebuur, Frits; Hommes, Ronaldus Wilhelmus Joannes; Kaper, Thijs; Kelemen, Bradley R.; Kralj, Slavko; Van Lieshout, Johannes Franciscus Thomas; Nikolaev, Igor; Wallace, Louise; Van Stigt Thans, Sander; Vogtentanz, Gudrun; Sandgren, Mats

    2016-12-20

    The present disclosure relates to cellulase variants. In particular the present disclosure relates to cellulase variants having improved expression, activity and/or stability. Also described are nucleic acids encoding the cellulase variants, compositions comprising the cellulase variants, and methods of use thereof.

  4. Further Evidence That the CFTR Variant c.2620-6T>C Is Benign

    Directory of Open Access Journals (Sweden)

    Violet I. Wallerstein

    2017-01-01

    Full Text Available The c.2620-6T>C variant in the CFTR gene is a rare variant about which little is known. We present an asymptomatic adult who has this variant as well as the well described delta F508 pathogenic variant in transpresentation. This patient provides additional evidence that this is a benign polymorphism.

  5. Riboflavin cross-linking of collagen porous scaffolds for periodontal regeneration

    Directory of Open Access Journals (Sweden)

    Seciu A-M.

    2016-05-01

    Full Text Available Periodontitis treatment using occlusive membranes presented variable efficacy due to their rapid degradation in the complex biologic environment of the damaged periodontium. The aim of this study was to prepare novel composites based on collagen, chondroitin sulfate and fibronectin, and to establish the optimal parameters for their photochemical cross-linking using riboflavin and UV exposure. The degree of cross-linking, biodegradability and density of all scaffold variants were investigated. Their cytotoxicity was evaluated in a culture of gingival fibroblasts by MTT assay and light microscopy. The results indicated that the higher the cross-linking degree, the lower was the scaffold biodegradation. Cell culture studies showed that composite scaffolds were favorable for cellular survival. In conclusion, the cross-linking method using riboflavin and UV exposure resulted in stable and biocompatible collagen-based composite scaffolds that could be used for periodontitis treatment.

  6. Acute fibrinous and organising pneumonia: a rare histopathological variant of chemotherapy-induced lung injury.

    Science.gov (United States)

    Gupta, Arjun; Sen, Shiraj; Naina, Harris

    2016-04-06

    Bleomycin-induced lung injury is the most common chemotherapy-associated lung disease, and is linked with several histopathological patterns. Acute fibrinous and organising pneumonia (AFOP) is a relatively new and rare histological pattern of diffuse lung injury. We report the first known case of bleomycin-induced AFOP. A 36-year-old man with metastatic testicular cancer received three cycles of bleomycin, etoposide and cisplatin, before being transitioned to paclitaxel, ifosfamide and cisplatin. He subsequently presented with exertional dyspnoea, cough and pleuritic chest pain. CT of the chest demonstrated bilateral ground glass opacities with peribronchovascular distribution and pulmonary function tests demonstrated a restrictive pattern of lung disease with impaired diffusion. Transbronchial biopsy revealed intra-alveolar fibrin deposits with organising pneumonia, consisting of intraluminal loose connective tissue consistent with AFOP. The patient received high-dose corticosteroids with symptomatic and radiographic improvement. AFOP should be recognised as a histopathological variant of bleomycin-induced lung injury.

  7. ALKBH7 Variant Related to Prostate Cancer Exhibits Altered Substrate Binding

    Science.gov (United States)

    Müller, Tina A.; Podolsky, Robert H.; Dyson, Gregory; Cisneros, Gerardo Andrés

    2017-01-01

    The search for prostate cancer biomarkers has received increased attention and several DNA repair related enzymes have been linked to this dysfunction. Here we report a targeted search for single nucleotide polymorphisms (SNPs) and functional impact characterization of human ALKBH family dioxygenases related to prostate cancer. Our results uncovered a SNP of ALKBH7, rs7540, which is associated with prostate cancer disease in a statistically significantly manner in two separate cohorts, and maintained in African American men. Comparisons of molecular dynamics (MD) simulations on the wild-type and variant protein structures indicate that the resulting alteration in the enzyme induces a significant structural change that reduces ALKBH7’s ability to bind its cosubstrate. Experimental spectroscopy studies with purified proteins validate our MD predictions and corroborate the conclusion that this cancer-associated mutation affects productive cosubstrate binding in ALKBH7. PMID:28231280

  8. Combined effects of thrombosis pathway gene variants predict cardiovascular events.

    Directory of Open Access Journals (Sweden)

    Kirsi Auro

    2007-07-01

    Full Text Available The genetic background of complex diseases is proposed to consist of several low-penetrance risk loci. Addressing this complexity likely requires both large sample size and simultaneous analysis of different predisposing variants. We investigated the role of four thrombosis genes: coagulation factor V (F5, intercellular adhesion molecule 1 (ICAM1, protein C (PROC, and thrombomodulin (THBD in cardiovascular diseases. Single allelic gene variants and their pair-wise combinations were analyzed in two independently sampled population cohorts from Finland. From among 14,140 FINRISK participants (FINRISK-92, n = 5,999 and FINRISK-97, n = 8,141, we selected for genotyping a sample of 2,222, including 528 incident cardiovascular disease (CVD cases and random subcohorts totaling 786. To cover all known common haplotypes (>10%, 54 single nucleotide polymorphisms (SNPs were genotyped. Classification-tree analysis identified 11 SNPs that were further analyzed in Cox's proportional hazard model as single variants and pair-wise combinations. Multiple testing was controlled by use of two independent cohorts and with false-discovery rate. Several CVD risk variants were identified: In women, the combination of F5 rs7542281 x THBD rs1042580, together with three single F5 SNPs, was associated with CVD events. Among men, PROC rs1041296, when combined with either ICAM1 rs5030341 or F5 rs2269648, was associated with total mortality. As a single variant, PROC rs1401296, together with the F5 Leiden mutation, was associated with ischemic stroke events. Our strategy to combine the classification-tree analysis with more traditional genetic models was successful in identifying SNPs-acting either in combination or as single variants--predisposing to CVD, and produced consistent results in two independent cohorts. These results suggest that variants in these four thrombosis genes contribute to arterial cardiovascular events at population level.

  9. Functionally significant, rare transcription factor variants in tetralogy of Fallot.

    Directory of Open Access Journals (Sweden)

    Ana Töpf

    Full Text Available Rare variants in certain transcription factors involved in cardiac development cause Mendelian forms of congenital heart disease. The purpose of this study was to systematically assess the frequency of rare transcription factor variants in sporadic patients with the cardiac outflow tract malformation tetralogy of Fallot (TOF.We sequenced the coding, 5'UTR, and 3'UTR regions of twelve transcription factor genes implicated in cardiac outflow tract development (NKX2.5, GATA4, ISL1, TBX20, MEF2C, BOP/SMYD1, HAND2, FOXC1, FOXC2, FOXH, FOXA2 and TBX1 in 93 non-syndromic, non-Mendelian TOF cases. We also analysed Illumina Human 660W-Quad SNP Array data for copy number variants in these genes; none were detected. Four of the rare variants detected have previously been shown to affect transactivation in in vitro reporter assays: FOXC1 p.P297S, FOXC2 p.Q444R, FOXH1 p.S113T and TBX1 p.P43_G61del PPPPRYDPCAAAAPGAPGP. Two further rare variants, HAND2 p.A25_A26insAA and FOXC1 p.G378_G380delGGG, A488_491delAAAA, affected transactivation in in vitro reporter assays. Each of these six functionally significant variants was present in a single patient in the heterozygous state; each of the four for which parental samples were available were maternally inherited. Thus in the 93 TOF cases we identified six functionally significant mutations in the secondary heart field transcriptional network.This study indicates that rare genetic variants in the secondary heart field transcriptional network with functional effects on protein function occur in 3-13% of patients with TOF. This is the first report of a functionally significant HAND2 mutation in a patient with congenital heart disease.

  10. MEFV Variants in Patients with PFAPA Syndrome in Japan.

    Science.gov (United States)

    Taniuchi, Shoichiro; Nishikomori, Ryuta; Iharada, Anna; Tuji, Shoji; Heike, Toshio; Kaneko, Kazunari

    2013-01-01

    The pathogenesis of PFAPA (periodic fever, aphthous stomatitis, pharyngitis, adenitis) syndrome is unknown as yet. In order to understand whether genes implicated in other auto-inflammatory diseases might be involved in the pathogenesis of PFAPA, all variants in the genes causing familial Mediterranean fever (FMF), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), and Hyper IgD syndrome were analyzed in children with PFAPA. All variants in MEFV, TNFRSF1A, and MVK were analyzed in 20 patients with PFAPA. PFAPA were diagnosed by previous published criteria. The findings of all analyses in PFAPA patients were compared with those of unaffected normal subjects (n=62). In the 13 children of 20 with PFAPA, the heterozygous variants of MEFV (5 patients: E148Q-L110P, 2 patients: E148Q, 1 patient: E148Q-L110P/E148Q, 1 patient: E148Q-P369S-R408Q-E84K, 1 patient: E148Q-L110P-P369S-A408G, 1 patient: R202Q, 1 patient: P115R) were found. No variants belonging to TNFRSF1A or MVK were detected in children with PFAPA. The frequency of the E148Q-L110P variants in children with PFAPA was significantly higher than that observed in unaffected normal subjects (7/20 versus 8/62). The duration of the episodes of illness in PFAPA children with MEFV variants was shorter than that of patients without variants. Genes involved in the development and progression of MEFV may affect the incidence and the phenotype of PFAPA in children.

  11. Mendelian randomization analysis with multiple genetic variants using summarized data.

    Science.gov (United States)

    Burgess, Stephen; Butterworth, Adam; Thompson, Simon G

    2013-11-01

    Genome-wide association studies, which typically report regression coefficients summarizing the associations of many genetic variants with various traits, are potentially a powerful source of data for Mendelian randomization investigations. We demonstrate how such coefficients from multiple variants can be combined in a Mendelian randomization analysis to estimate the causal effect of a risk factor on an outcome. The bias and efficiency of estimates based on summarized data are compared to those based on individual-level data in simulation studies. We investigate the impact of gene-gene interactions, linkage disequilibrium, and 'weak instruments' on these estimates. Both an inverse-variance weighted average of variant-specific associations and a likelihood-based approach for summarized data give similar estimates and precision to the two-stage least squares method for individual-level data, even when there are gene-gene interactions. However, these summarized data methods overstate precision when variants are in linkage disequilibrium. If the P-value in a linear regression of the risk factor for each variant is less than 1×10⁻⁵, then weak instrument bias will be small. We use these methods to estimate the causal association of low-density lipoprotein cholesterol (LDL-C) on coronary artery disease using published data on five genetic variants. A 30% reduction in LDL-C is estimated to reduce coronary artery disease risk by 67% (95% CI: 54% to 76%). We conclude that Mendelian randomization investigations using summarized data from uncorrelated variants are similarly efficient to those using individual-level data, although the necessary assumptions cannot be so fully assessed. © 2013 WILEY PERIODICALS, INC.

  12. Functionally significant, rare transcription factor variants in tetralogy of Fallot.

    Science.gov (United States)

    Töpf, Ana; Griffin, Helen R; Glen, Elise; Soemedi, Rachel; Brown, Danielle L; Hall, Darroch; Rahman, Thahira J; Eloranta, Jyrki J; Jüngst, Christoph; Stuart, A Graham; O'Sullivan, John; Keavney, Bernard D; Goodship, Judith A

    2014-01-01

    Rare variants in certain transcription factors involved in cardiac development cause Mendelian forms of congenital heart disease. The purpose of this study was to systematically assess the frequency of rare transcription factor variants in sporadic patients with the cardiac outflow tract malformation tetralogy of Fallot (TOF). We sequenced the coding, 5'UTR, and 3'UTR regions of twelve transcription factor genes implicated in cardiac outflow tract development (NKX2.5, GATA4, ISL1, TBX20, MEF2C, BOP/SMYD1, HAND2, FOXC1, FOXC2, FOXH, FOXA2 and TBX1) in 93 non-syndromic, non-Mendelian TOF cases. We also analysed Illumina Human 660W-Quad SNP Array data for copy number variants in these genes; none were detected. Four of the rare variants detected have previously been shown to affect transactivation in in vitro reporter assays: FOXC1 p.P297S, FOXC2 p.Q444R, FOXH1 p.S113T and TBX1 p.P43_G61del PPPPRYDPCAAAAPGAPGP. Two further rare variants, HAND2 p.A25_A26insAA and FOXC1 p.G378_G380delGGG, A488_491delAAAA, affected transactivation in in vitro reporter assays. Each of these six functionally significant variants was present in a single patient in the heterozygous state; each of the four for which parental samples were available were maternally inherited. Thus in the 93 TOF cases we identified six functionally significant mutations in the secondary heart field transcriptional network. This study indicates that rare genetic variants in the secondary heart field transcriptional network with functional effects on protein function occur in 3-13% of patients with TOF. This is the first report of a functionally significant HAND2 mutation in a patient with congenital heart disease.

  13. HABP2 G534E Variant in Papillary Thyroid Carcinoma.

    Science.gov (United States)

    Tomsic, Jerneja; Fultz, Rebecca; Liyanarachchi, Sandya; He, Huiling; Senter, Leigha; de la Chapelle, Albert

    2016-01-01

    The main nonmedullary form of thyroid cancer is papillary thyroid carcinoma (PTC) that accounts for 80-90% of all thyroid malignancies. Only 3-10% of PTC patients have a positive family history of PTC yet the familiality is one of the highest of all cancers as measured by case control studies. A handful of genes have been implicated accounting for a small fraction of this genetic predisposition. It was therefore of considerable interest that a mutation in the HABP2 gene was recently implicated in familial PTC. The present work was undertaken to examine the extent of HABP2 variant involvement in PTC. The HABP2 G534E variant (rs7080536) was genotyped in blood DNA from 179 PTC families (one affected individual per family), 1160 sporadic PTC cases and 1395 controls. RNA expression of HABP2 was tested by qPCR in RNA extracted from tumor and normal thyroid tissue from individuals that are homozygous wild-type or heterozygous for the variant. The variant was found to be present in 6.1% familial cases, 8.0% sporadic cases (2 individuals were homozygous for the variant) and 8.7% controls. The variant did not segregate with PTC in one large and 6 smaller families in which it occurred. In keeping with data from the literature and databases the expression of HABP2 was highest in the liver, much lower in 3 other tested tissues (breast, kidney, brain) but not found in thyroid. Given these results showing lack of any involvement we suggest that the putative role of variant HABP2 in PTC should be carefully scrutinized.

  14. HABP2 G534E Variant in Papillary Thyroid Carcinoma.

    Directory of Open Access Journals (Sweden)

    Jerneja Tomsic

    Full Text Available The main nonmedullary form of thyroid cancer is papillary thyroid carcinoma (PTC that accounts for 80-90% of all thyroid malignancies. Only 3-10% of PTC patients have a positive family history of PTC yet the familiality is one of the highest of all cancers as measured by case control studies. A handful of genes have been implicated accounting for a small fraction of this genetic predisposition. It was therefore of considerable interest that a mutation in the HABP2 gene was recently implicated in familial PTC. The present work was undertaken to examine the extent of HABP2 variant involvement in PTC. The HABP2 G534E variant (rs7080536 was genotyped in blood DNA from 179 PTC families (one affected individual per family, 1160 sporadic PTC cases and 1395 controls. RNA expression of HABP2 was tested by qPCR in RNA extracted from tumor and normal thyroid tissue from individuals that are homozygous wild-type or heterozygous for the variant. The variant was found to be present in 6.1% familial cases, 8.0% sporadic cases (2 individuals were homozygous for the variant and 8.7% controls. The variant did not segregate with PTC in one large and 6 smaller families in which it occurred. In keeping with data from the literature and databases the expression of HABP2 was highest in the liver, much lower in 3 other tested tissues (breast, kidney, brain but not found in thyroid. Given these results showing lack of any involvement we suggest that the putative role of variant HABP2 in PTC should be carefully scrutinized.

  15. Integrating Linked Data into Discovery

    Directory of Open Access Journals (Sweden)

    Götz Hatop

    2013-07-01

    Full Text Available Although the Linked Data paradigm has evolved from a research idea to a practical approach for publishing structured data on the web, the performance gap between currently available RDF data stores and the somewhat older search technologies could not be closed. The combination of Linked Data with a search engine can help to improve ad-hoc retrieval. This article presents and documents the process of building a search index for the Solr search engine from bibliographic records published as linked open data.

  16. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... Prevention Recovery Substance Use and SUDs in LGBT Populations Treatment Trends & Statistics Women and Drugs Publications Search ... the link between drug abuse and HIV/AIDS, populations most at risk, trends in HIV/AIDS, and ...

  17. Medicare and Medicaid Linked Files

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Medicare-Medicaid Linked Enrollee Analytic Data Source (MMLEADS) has been developed to allow for the examination of all Medicare and Medicaid enrollment and...

  18. Drugs + HIV, Learn the Link

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    Full Text Available ... affect anyone. Watch the “d’cisions” Videos Campaign Materials After the Party Posters: We have developed posters ... the Learn the Link message. Campaign messages and materials were tested among various groups of young people, ...

  19. Drugs + HIV, Learn the Link

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    Full Text Available ... Drugs and HIV Learn the Link - Drugs and HIV Email Facebook Twitter 2005 –Ongoing Behaviors associated with ... Send the Message . Get the Facts What are HIV and AIDS? HIV (human immunodeficiency virus) is the ...

  20. Drugs + HIV, Learn the Link

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    Full Text Available Skip to main content En español Researchers Medical & Health Professionals Patients & Families Parents & Educators Children & Teens Search Connect with NIDA : Facebook LinkedIn Twitter YouTube Flickr RSS Menu ...

  1. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... other organizations in your tweets to spread the word even further. Tweet About Learn the Link To ... other organizations in your tweets to spread the word even further. Share with Flickr, Pinterest or Instagram ...

  2. Drugs + HIV, Learn the Link

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    Full Text Available ... Researchers Medical & Health Professionals Patients & Families Parents & Educators Children & Teens Search Connect with NIDA : Facebook LinkedIn Twitter ... Network TV Organizations: AIDS.gov AIDS Alliance for Children, Youth and Families The American Academy of Child & ...

  3. Drugs + HIV, Learn the Link

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    Full Text Available ... Drugs and HIV Learn the Link - Drugs and HIV Email Facebook Twitter 2005 –Ongoing Behaviors associated with ... Send the Message . Get the Facts What are HIV and AIDS? HIV (human immunodeficiency virus) is the ...

  4. Decouplink: Dynamic Links for Java

    DEFF Research Database (Denmark)

    Jensen, Martin Lykke Rytter; Jørgensen, Bo Nørregaard

    2011-01-01

    -based systems: On the one hand, violating the open/closed principle by allowing for modification compromises independent extensibility. On the other hand, trying to enforce the open/closed principle by prohibiting modification precludes unanticipated dimensions of extension. Dynamic links increase the number...... of dimensions of extension that can be exploited without performing modification of existing types. Thus, dynamic links make it possible to enforce the open/closed principle in situations where it would otherwise not be possible. We present Decouplink – a library-based implementation of dynamic links for Java.......We also present experience with the use of dynamic links during the evolution of a component-based control system....

  5. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... NIDA’s "Learn the Link" campaign continues to raise awareness among this generation of the real risks of ... Collaborators Thanks to Those Who Have Helped Raise Awareness of Our Campaign! NIDA acknowledges the following television ...

  6. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... Military Opioid Overdose Reversal with Naloxone (Narcan, Evzio) Pain Prevention Recovery Treatment Trends & Statistics Women and Drugs ... to your Web site. Please link these banners back to this site at: http://www.drugabuse.gov/ ...

  7. Advanced solderless flexible thermal link

    Science.gov (United States)

    Williams, Brian G.; Jensen, Scott M.; Batty, J. Clair

    1996-10-01

    Flexible thermal links play an important role int he thermal management of cryogenically cooled components. The purpose of these links is to provide a means of transferring heat from a cooled component to a cooler reservoir with little increase in temperature. The standard soldered approach although effective proves to be time consuming and contributes to added thermal impedances which degrade the performance of the link. For system with little tolerance for temperature differences between cooled components and a cooling source this is undesirable. The authors of this paper have developed a technique by which thin metal foil or braided wire can be attached to metal end blocks without any solder using the swaging process. Swaging provides a fast, simple method for providing a low thermal impedance between the foils and blocks. This paper describes the characteristics of these thermal links in terms of length, mass, thermal resistance, flexibility, and survivability.

  8. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... the message to young people and to parents, teachers, and the media about the link between ... status updates that you can easily copy and paste to help show your support for ...

  9. Linking Ethics and Economic Growth

    DEFF Research Database (Denmark)

    Foss, Nicolai Juul

    2012-01-01

    Hunt (2012) builds on his work concerning ethics and resource-advantage theory to link personal ethical standards, societal norms, and economic growth but offers few details concerning the precise mechanisms that link ethics and growth. This comment suggests a number of such mechanisms – for exam......Hunt (2012) builds on his work concerning ethics and resource-advantage theory to link personal ethical standards, societal norms, and economic growth but offers few details concerning the precise mechanisms that link ethics and growth. This comment suggests a number of such mechanisms...... – for example, the influence of prevailing ethical norms on the aggregate elasticity of substitution and, therefore, total factor productivity and growth....

  10. Study Links Disasters to Dementia

    Science.gov (United States)

    ... news/fullstory_161672.html Study Links Disasters to Dementia Losing home was tied to greater mental decline ... Earthquakes, floods and other natural disasters may raise dementia risk for seniors forced to leave their homes, ...

  11. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... affect anyone. Watch the “d’cisions” Videos Campaign Materials After the Party Posters: We have developed posters ... behaviors. NIDA researchers have studied and continue to study the links between drug abuse and HIV/AIDS. ...

  12. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... abuse and HIV infection. It contains information for young people, parents and teachers, and the media with links ... 177(1):355-361. How are Teens Affected? Young people are at risk for contracting HIV. In general, ...

  13. Protein Linked to Atopic Dermatitis

    Science.gov (United States)

    ... Research Matters NIH Research Matters January 14, 2013 Protein Linked to Atopic Dermatitis Normal skin from a ... in mice suggests that lack of a certain protein may trigger atopic dermatitis, the most common type ...

  14. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... patients who do not abuse drugs. In animal studies, methamphetamine has been shown to increase the amount ... behaviors. NIDA researchers have studied and continue to study the links between drug abuse and HIV/AIDS. ...

  15. Drugs + HIV, Learn the Link

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    Full Text Available ... Addiction Science Adolescent Brain Comorbidity College-Age & Young Adults Criminal Justice Drugged Driving Drug Testing Drugs and ... Link campaign. This campaign shows teens and young adults that non-injection drug use and alcohol use ...

  16. Drugs + HIV, Learn the Link

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    Full Text Available ... are at risk for contracting HIV. In general, middle and late teen years are when young people ... link between drug abuse and HIV. Post on Facebook or Twitter ; add photos to your Flickr , Pinterest , ...

  17. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... of HIV infection in the United States. Drugs can change the way the brain works, disrupting the ... linked and referred to as "HIV/AIDS." HIV can be transferred between people if an infected person's ...

  18. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... other organizations in your tweets to spread the word even further. Tweet About Learn the Link To ... other organizations in your tweets to spread the word even further. Share with Flickr, Pinterest or Instagram ...

  19. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... teens and young adults have never known a world without it. NIDA’s "Learn the Link" campaign continues ... NIDA TV PEERx Drugs & Health Blog The NIDA Science Fair Award for Addiction Science USA Science & Engineering ...

  20. Study Links Celiac Disease, Anorexia

    Science.gov (United States)

    ... medlineplus.gov/news/fullstory_164453.html Study Links Celiac Disease, Anorexia Chances of being diagnosed with eating ... April 4, 2017 (HealthDay News) -- Young women with celiac disease may face a heightened risk of being ...