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Sample records for challenged heterozygous watanabe

  1. Increased plant sterol and stanol levels in brain of Watanabe rabbits fed rapeseed oil derived plant sterol or stanol esters

    DEFF Research Database (Denmark)

    Fricke, Christiane B.; Schrøder, Malene; Poulsen, Morten

    2007-01-01

    . Cholesterol synthesis in brain, indicated by lathosterol, a local surrogate cholesterol synthesis marker, does not seem to be affected by plant sterol or stanol ester feeding. We conclude that high dose intake of plant sterol and stanol esters in Watanabe rabbits results in elevated concentrations...... of these components not only in the periphery but also in the central nervous system....... of these components in brain tissue of homozygous and heterozygous Watanabe rabbits, an animal model for familial hypercholesterolemia. Homozygous animals received either a standard diet, RSO stanol or RSO sterol ester while heterozygous animals were additionally fed with 2 g cholesterol/kg to the respective diet...

  2. Effect of rapeseed oil derived plant sterol and stanol esters on atherosclerosis parameters in cholesterol challenged heterozygous Watanabe Heritable Hyperlipidemic rabbits

    DEFF Research Database (Denmark)

    Schrøder, Malene; Fricke, Christiane; Pilegaard, Kirsten

    2009-01-01

    Watanabe heritable hyperlipidaemic (Hh-WHHL) rabbits. Four groups (n 18 per group) received a cholesterol-added (2 g/kg) standard chow or this diet with added RSO stanol esters (17 g/kg), RSO stanol esters (34 g/kg) or RSO sterol esters (34 g/kg) for 18 weeks. Feeding RSO stanol esters increased plasma...... campestanol (P Feeding RSO sterol esters increased concentrations of plasma campesterol (P ... of the RSO stanol ester groups and in one in the RSO sterol ester group. Aortic cholesterol was decreased in the treated groups (P response to lowering of plasma cholesterol induced by RSO sterol and stanol esters. In conclusion, RSO stanol and sterol esters with a high concentration...

  3. A correction to the Watanabe potential

    International Nuclear Information System (INIS)

    Abul-Magd, A.Y.; Rabie, A.; El-Gazzar, M.A.

    1980-10-01

    Using the adiabatic approximation, an analytic expression for the correction to the Watanabe potential was obtained. In addition, we have corrected through a proper choice of the energy at which the potential parameters of the constituents of 6 Li should be taken. (author)

  4. The Watanabe model for 6Li-nucleus optical potential

    International Nuclear Information System (INIS)

    Abul-Magd, A.Y.; Rabie, A.; El-Gazzar, M.A.

    1980-09-01

    Optical potentials for the scattering of 6 Li projectiles are calculated using the Watanabe model and an α+d cluster model wave function for 6 Li. Reasonable fits to the elastic differential cross-section and vector polarization are obtained. (author)

  5. Effects of red grape skin and seed extract supplementation on atherosclerosis in Watanabe heritable hyperlipidemic rabbits

    DEFF Research Database (Denmark)

    Frederiksen, Hanne; Mortensen, Alicja; Schrøder, Malene

    2007-01-01

    Epidemiological studies have suggested an association between consumption of red wine and other polyphenolic compounds and prevention of cardiovascular diseases. In the present study, Watanabe heritable hyperlipidemic (WHHL) rabbits were used to investigate the effects of polyphenols in a red gra...

  6. The Female Images in Junichi Watanabe's Works%简析渡边淳一作品中的女性形象

    Institute of Scientific and Technical Information of China (English)

    刘娜

    2014-01-01

    As“the first person of Japanese middle literature”,Junichi Watanabe has a great influence in Japan and even in the world. Some Japanese media evaluates him as the“voice”of modern man,but in his literary works he created many beautiful female images with distinct personality. The various female images reflect Watanabe's concern over modern women. This article,through anal-ysis of specific images in Watanabe literature,explores the essence of Watanabe literature,and analyzes the status of men and women and gender consciousness in literature from the perspective of feminism.%作为“日本中间文学第一人”的渡边淳一在日本乃至世界范围内影响巨大,有些日本媒体评价他为“现代男人的代言人”,但是他在文学作品中塑造了许多美丽动人、个性鲜明的女性形象,这些形形色色的女性形象都体现了渡边文学对现代女性的关注。基于此,通过对渡边文学中女性具体形象的分析,来探索渡边文学的精髓,进而从女性主义视角浅析渡边文学中男女两性地位及性别意识等问题。

  7. Compound-heterozygous Marfan syndrome

    NARCIS (Netherlands)

    van Dijk, F. S.; Hamel, B. C.; Hilhorst-Hofstee, Y.; Mulder, B. J. M.; Timmermans, J.; Pals, G.; Cobben, J. M.

    2009-01-01

    We report two families in which the probands have compound-heterozygous Marfan syndrome (MFS). The proband of family I has the R2726W FBN1 mutation associated with isolated skeletal features on one allele and a pathogenic FBN1 mutation on the other allele. The phenotype of the compound-heterozygous

  8. Estrogen and phytoestrogens: Effect on eNOS expression and in vitro vasodilation in cerebral arteries in ovariectomized Watanabe heritable hyperlipidemic rabbits

    DEFF Research Database (Denmark)

    Lund, Claus Otto; Mortensen, A; Nilas, Lisbeth

    2007-01-01

    -six female ovariectomized Watanabe heritable hyperlipidemic (WHHL) rabbits were randomised to treatment with 17beta-estradiol (17beta-E(2)), SoyLife 150 or control for 16 weeks. Ring segments of basilar artery (BA) and posterior cerebral artery (PCA) were mounted in myographs for isometric tension recordings...

  9. Probucol selectively increases oxidation of atherogenic lipoproteins in cholesterol-fed mice and in Watanabe heritable hyperlipidemic rabbits

    DEFF Research Database (Denmark)

    Lauridsen, S.T.; Mortensen, Alicja

    1999-01-01

    The anti-atherogenic and cholesterol-lowering drug probucol (0.5-1%) or quercetin (1%), a natural antioxidant, was given to cholesterol-fed (1.5%) mice for a period of 6 weeks and to Watanabe heritable hyperlipidemic (WHHL) rabbits for a period of 8 weeks to investigate the oxidative changes.......001) and cholesterol-fed mice (579.7 +/- 47.3 nmol/g vs. 408.1 +/- 85.8 nmol/g, P mice: P ... and thereby leads to a decrease in cholesterol levels....

  10. Mixed Sequence Reader: A Program for Analyzing DNA Sequences with Heterozygous Base Calling

    Science.gov (United States)

    Chang, Chun-Tien; Tsai, Chi-Neu; Tang, Chuan Yi; Chen, Chun-Houh; Lian, Jang-Hau; Hu, Chi-Yu; Tsai, Chia-Lung; Chao, Angel; Lai, Chyong-Huey; Wang, Tzu-Hao; Lee, Yun-Shien

    2012-01-01

    The direct sequencing of PCR products generates heterozygous base-calling fluorescence chromatograms that are useful for identifying single-nucleotide polymorphisms (SNPs), insertion-deletions (indels), short tandem repeats (STRs), and paralogous genes. Indels and STRs can be easily detected using the currently available Indelligent or ShiftDetector programs, which do not search reference sequences. However, the detection of other genomic variants remains a challenge due to the lack of appropriate tools for heterozygous base-calling fluorescence chromatogram data analysis. In this study, we developed a free web-based program, Mixed Sequence Reader (MSR), which can directly analyze heterozygous base-calling fluorescence chromatogram data in .abi file format using comparisons with reference sequences. The heterozygous sequences are identified as two distinct sequences and aligned with reference sequences. Our results showed that MSR may be used to (i) physically locate indel and STR sequences and determine STR copy number by searching NCBI reference sequences; (ii) predict combinations of microsatellite patterns using the Federal Bureau of Investigation Combined DNA Index System (CODIS); (iii) determine human papilloma virus (HPV) genotypes by searching current viral databases in cases of double infections; (iv) estimate the copy number of paralogous genes, such as β-defensin 4 (DEFB4) and its paralog HSPDP3. PMID:22778697

  11. Is the Watanabe heritable hyperlipidemic rabbit a suitable experimental model for percutaneous transluminal coronary angioplasty in humans? A light microscopic, immunohistochemical and ultrastructural study

    NARCIS (Netherlands)

    Wanibuchi, H.; Dingemans, K. P.; Becker, A. E.; Ueda, M.; Naruko, T.; Tanizawa, S.; Nakamura, K.

    1993-01-01

    This study was designed to assess an experimental model for the study of mechanisms that underlie restenosis after percutaneous transluminal coronary angioplasty. The Watanabe heritable hyperlipidemic (WHHL) rabbit lacks the receptor for low density lipoproteins, produces atherosclerotic lesions

  12. Hemigrapsus takanoi Asakura and Watanabe, 2005 (Crustacea: Decapoda: Brachyura: Grapsoidea): first records of the brush-clawed shore crab from Great Britain

    OpenAIRE

    Wood, C. A.; Bishop, J. D. D.; Davies, Clare J.; Delduca, E. L.; Hatton, J. C.; Herbert, Roger J.H.; Clark, P. F.

    2015-01-01

    The brush-clawed shore crab is reported from the River Medway, Kent and the River Colne, Essex, England. These represent the first records of Hemigrapsus takanoi Asakura and Watanabe, 2005 from Great Britain. If H. takanoi becomes established in GB, it may pose a threat to populations of the native shore crab Carcinus maenas.

  13. Classical phenotype of Laron syndrome in a girl with a heterozygous mutation and heterozygous polymorphism of the growth hormone receptor gene.

    Science.gov (United States)

    Shevah, Orit; Galli-Tsinopoulou, Assimina; Rubinstein, Menachem; Nousia-Arvanitakis, Sanda; Laron, Zvi

    2004-03-01

    We describe here a 19 month-old girl with classical Laron syndrome (LS). Molecular analysis of the GH receptor gene in the patient and her parents was performed. The patient was found to be heterozygous for a mutation in exon 4 (R43X) and heterozygous for a polymorphism in exon 6 (Gly168Gly). Her mother was also heterozygous for R43X but homozygous for the polymorphism. In the father, a heterozygous polymorphism was found. Contrary to previous assumptions that only homozygous patients express the typical phenotype, this patient shows all the classical features of LS, despite being a heterozygote for a pathological defect.

  14. Fundus albipunctatus associated with compound heterozygous mutations in RPE65

    DEFF Research Database (Denmark)

    Schatz, Patrik; Preising, Markus; Lorenz, Birgit

    2011-01-01

    To describe a family with an 18-year-old woman with fundus albipunctatus and compound heterozygous mutations in RPE65 whose unaffected parents and 1 female sibling harbored single heterozygous RPE65 mutations.......To describe a family with an 18-year-old woman with fundus albipunctatus and compound heterozygous mutations in RPE65 whose unaffected parents and 1 female sibling harbored single heterozygous RPE65 mutations....

  15. If Auditors Are Like Belgian Beers, Which Style Would You Prefer? : Discussion of “Auditor Style and Financial Statement Comparability” by Francis, Pinnuck, and Watanabe .

    NARCIS (Netherlands)

    Bruynseels, L.M.L.; Brenk, van H.M.

    2016-01-01

    Recent research by Francis, Pinnuck, and Watanabe (2014) has shown that financial reporting outcomes are influenced by the audit firm’s unique audit style. They argue that audit firm styles are driven by their “unique set of internal working rules that guide the auditor’s application of accounting

  16. Penetrance of eye defects in mice heterozygous for mutation of Gli3 is enhanced by heterozygous mutation of Pax6

    Directory of Open Access Journals (Sweden)

    Price David J

    2006-10-01

    Full Text Available Abstract Background Knowledge of the consequences of heterozygous mutations of developmentally important genes is important for understanding human genetic disorders. The Gli3 gene encodes a zinc finger transcription factor and homozygous loss-of-function mutations of Gli3 are lethal. Humans heterozygous for mutations in this gene suffer Greig cephalopolysyndactyly or Pallister-Hall syndromes, in which limb defects are prominent, and mice heterozygous for similar mutations have extra digits. Here we examined whether eye development, which is abnormal in mice lacking functional Gli3, is defective in Gli3+/- mice. Results We showed that Gli3 is expressed in the developing eye but that Gli3+/- mice have only very subtle eye defects. We then generated mice compound heterozygous for mutations in both Gli3 and Pax6, which encodes another developmentally important transcription factor known to be crucial for eye development. Pax6+/-; Gli3+/- eyes were compared to the eyes of wild-type, Pax6+/- or Gli3+/- siblings. They exhibited a range of abnormalities of the retina, iris, lens and cornea that was more extensive than in single Gli3+/- or Pax6+/- mutants or than would be predicted by addition of their phenotypes. Conclusion These findings indicate that heterozygous mutations of Gli3 can impact on eye development. The importance of a normal Gli3 gene dosage becomes greater in the absence of a normal Pax6 gene dosage, suggesting that the two genes co-operate during eye morphogenesis.

  17. Dynamics of weakly inhomogeneous oscillator populations: perturbation theory on top of Watanabe-Strogatz integrability

    Science.gov (United States)

    Vlasov, Vladimir; Rosenblum, Michael; Pikovsky, Arkady

    2016-08-01

    As has been shown by Watanabe and Strogatz (WS) (1993 Phys. Rev. Lett. 70 2391), a population of identical phase oscillators, sine-coupled to a common field, is a partially integrable system: for any ensemble size its dynamics reduce to equations for three collective variables. Here we develop a perturbation approach for weakly nonidentical ensembles. We calculate corrections to the WS dynamics for two types of perturbations: those due to a distribution of natural frequencies and of forcing terms, and those due to small white noise. We demonstrate that in both cases, the complex mean field for which the dynamical equations are written is close to the Kuramoto order parameter, up to the leading order in the perturbation. This supports the validity of the dynamical reduction suggested by Ott and Antonsen (2008 Chaos 18 037113) for weakly inhomogeneous populations.

  18. Orthology Guided Assembly in highly heterozygous crops

    DEFF Research Database (Denmark)

    Ruttink, Tom; Sterck, Lieven; Rohde, Antje

    2013-01-01

    to outbreeding crop species hamper De Bruijn Graph-based de novo assembly algorithms, causing transcript fragmentation and the redundant assembly of allelic contigs. If multiple genotypes are sequenced to study genetic diversity, primary de novo assembly is best performed per genotype to limit the level......Despite current advances in next-generation sequencing data analysis procedures, de novo assembly of a reference sequence required for SNP discovery and expression analysis is still a major challenge in genetically uncharacterized, highly heterozygous species. High levels of polymorphism inherent...... of polymorphism and avoid transcript fragmentation. Here, we propose an Orthology Guided Assembly procedure that first uses sequence similarity (tBLASTn) to proteins of a model species to select allelic and fragmented contigs from all genotypes and then performs CAP3 clustering on a gene-by-gene basis. Thus, we...

  19. Diskriminasi Gender dalam Novel Ginko Karya Junichi Watanabe

    Directory of Open Access Journals (Sweden)

    Linda Unsriana

    2014-05-01

    Full Text Available Discrimination is an attitude and behavior that violates human rights. Discrimination can also be interpreted as a treatment for individuals differently based on race, religion, or gender. Any harassment, restriction, or exclusion to race, religion, or gender includes discriminatory actions. The theme of discrimination experienced by many women made the writer want to examine it from literature point of view, especially Japanese literature. The problem in this paper is gender discrimination experienced by the main character in novel Ginko. In Ginko novel written by Junichi Watanabe, the theme of discrimination against women is very strong, as experienced by the main character named Gin Ogino. This study used feminist standpoint research with the assumption that gender discrimination in society in the novel cannot be separated from women’s real experiences perceived by the author. In addition to stand on or derived from real experiences from the first woman doctor in Japan, which with all her efforts to break away from discrimination against women endured throughout her life: before marriage, divorce, attending medical school to become a doctor, even after she was graduated from medical school, she still experienced gender discrimination. This study found that gender discrimination experienced by Ginko because she is a woman, in which at that time (the Meiji era there were clear boundaries between men and women. Difficulty and discrimination experienced are because Ginko’s ideals were considered impossible, because she wanted to become a doctor. Her ability and cleverness were obstructed just because she is a woman. It can be concluded in the Meiji era, there was discrimination against women reflected in the Novel Ginko.

  20. Absorption and excretion of black currant anthocyanins in human and Watanabe Heritable Hyperlipidemic rabbits

    DEFF Research Database (Denmark)

    Nielsen, I. L.. F.; Ravn-Haren, Gitte; Dragsted, L. O.

    2003-01-01

    Anthocyanins are thought to protect against cardiovascular diseases. Watanabe heritable hyperlipidemic (WHHL) rabbits are hypercholesterolemic and used as a model of the development of atherosclerosis. To compare the uptake and excretion of anthocyanins in humans and WHHL rabbits, single-dose black......). The excretion and absorption of anthocyanins from black currant juice were found to be within the same order of magnitude in the two species regarding urinary excretion within the first 4 h (rabbits, 0.035%; humans, 0.072%) and t(ma)x (rabbits, similar to30 min; humans, similar to45 min). A food matrix effect...... was detected in rabbits, resulting in the absorption of a higher proportion of the anthocyanins from black currant juice than from an aqueous citric acid matrix. In humans the absorption and urinary excretion of anthocyanins from black currant juice were found to be proportional with dose and not influenced...

  1. HbA1c levels in individuals heterozygous for hemoglobin variants.

    Science.gov (United States)

    Tavares, Ricardo Silva; Souza, Fábio Oliveira de; Francescantonio, Isabel Cristina Carvalho Medeiros; Soares, Weslley Carvalho; Mesquita, Mauro Meira

    2017-04-01

    To evaluate the levels of glycated hemoglobin (HbA1c) in patients heterozygous for hemoglobin variants and compare the results of this test with those of a control group. This was an experimental study based on the comparison of HbA1c tests in two different populations, with a test group represented by individuals heterozygous for hemoglobin variants (AS and AC) and a control group consisting of people with electrophoretic profile AA. The two populations were required to meet the following inclusion criteria: Normal levels of fasting glucose, hemoglobin, urea and triglycerides, bilirubin > 20 mg/dL and non-use of acetylsalicylic acid. 50 heterozygous subjects and 50 controls were evaluated between August 2013 and May 2014. The comparison of HbA1c levels between heterozygous individuals and control subjects was performed based on standard deviation, mean and G-Test. The study assessed a test group and a control group, both with 39 adults and 11 children. The mean among heterozygous adults for HbA1c was 5.0%, while the control group showed a rate of 5.74%. Heterozygous children presented mean HbA1c at 5.11%, while the controls were at 5.78%. G-Test yielded p=0.93 for children and p=0.89 for adults. Our study evaluated HbA1c using ion exchange chromatography resins, and the patients heterozygous for hemoglobin variants showed no significant difference from the control group.

  2. Adenosine-induced coronary flow reserve in Watanabe heritable hyperlipidemic rabbits

    Energy Technology Data Exchange (ETDEWEB)

    Shimada, Kazuhiro; Yoshida, Katsuya [Chiba Univ. (Japan). School of Medicine; Tadokoro, Hiroyuki [and others

    2000-12-01

    The Watanabe heritable hyperlipidemic (WHHL) rabbit develops coronary atherosclerosis and hypercholesterolemia because of a genetic deficiency of low-density lipoprotein receptors and is therefore a good animal model for studying the relationships of coronary atherosclerosis, hypercholesterolemia and coronary flow reserve. The aim of the present study was to assess myocardial perfusion at baseline and during adenosine infusion (0.2 mg{center_dot}kg{sup -1}{center_dot}min{sup -1}) in 8 WHHL rabbits (13.8{+-}0.5 months) with {sup 13}N-ammonia, small-animal positron emission tomography (PET) and colored microspheres. Results were compared with those from 6 age-matched Japanese white rabbits. Plaque distribution was also examined in the extramural coronary arteries. All 8 WHHL rabbits had coronary plaques, with 6 showing multiple plaques. Mean global myocardial blood flow (ml{center_dot}min{sup -1}{center_dot}g{sup -1}) did not differ significantly between control and WHHL groups both at baseline (3.67{+-}0.72 vs 4.26{+-}1.12 ml{center_dot}min{sup -1}{center_dot}g{sup -1}, p=NS) and with adenosine (7.92{+-}2.00 vs 9.27{+-}2.91 ml{center_dot}min{sup -1}{center_dot}g{sup -1}, p=NS), nor did coronary flow reserve (2.16{+-}0.37 vs 2.18{+-}0.41, p=NS). None showed evidence of regional perfusion abnormalities by visual and semiquantitative analyses of PET images. It was concluded that WHHL rabbits preserve adenosine-induced coronary flow reserve despite coronary atherosclerosis and hypercholesterolemia, suggesting that a compensatory mechanism develops in this animal model. (author)

  3. Adenosine-induced coronary flow reserve in Watanabe heritable hyperlipidemic rabbits

    International Nuclear Information System (INIS)

    Shimada, Kazuhiro; Yoshida, Katsuya; Tadokoro, Hiroyuki

    2000-01-01

    The Watanabe heritable hyperlipidemic (WHHL) rabbit develops coronary atherosclerosis and hypercholesterolemia because of a genetic deficiency of low-density lipoprotein receptors and is therefore a good animal model for studying the relationships of coronary atherosclerosis, hypercholesterolemia and coronary flow reserve. The aim of the present study was to assess myocardial perfusion at baseline and during adenosine infusion (0.2 mg·kg -1 ·min -1 ) in 8 WHHL rabbits (13.8±0.5 months) with 13 N-ammonia, small-animal positron emission tomography (PET) and colored microspheres. Results were compared with those from 6 age-matched Japanese white rabbits. Plaque distribution was also examined in the extramural coronary arteries. All 8 WHHL rabbits had coronary plaques, with 6 showing multiple plaques. Mean global myocardial blood flow (ml·min -1 ·g -1 ) did not differ significantly between control and WHHL groups both at baseline (3.67±0.72 vs 4.26±1.12 ml·min -1 ·g -1 , p=NS) and with adenosine (7.92±2.00 vs 9.27±2.91 ml·min -1 ·g -1 , p=NS), nor did coronary flow reserve (2.16±0.37 vs 2.18±0.41, p=NS). None showed evidence of regional perfusion abnormalities by visual and semiquantitative analyses of PET images. It was concluded that WHHL rabbits preserve adenosine-induced coronary flow reserve despite coronary atherosclerosis and hypercholesterolemia, suggesting that a compensatory mechanism develops in this animal model. (author)

  4. Heterozygous effects of irradiated chromosomes on viability in Drosophila melanogaster

    International Nuclear Information System (INIS)

    Simmons, M.J.

    1976-01-01

    Two large experiments were conducted in order to evaluate the heterozygous effects of irradiated chromosomes on viability. Mutations were accumulated on several hundred second chromosomes by delivering doses of 2,500R over either two or four generations for total x-ray exposures of 5,000R or 10,000R. Chromosomes treated with 5,000R were screened for lethals after the first treatment, and surviving nonlethals were used to generate families of fully treated chromosomes. The members of these families shared the effects of the first irradiation, but differed with respect to those of the second. The chromosomes treated with 10,000R were not grouped into families since mutations were accumulated independently on each chromosome in that experiment. Heterozygous effects on viability of the irradiated chromosomes were tested in both isogenic (homozygous) and nonisogenic (heterozygous) genetic backgrounds. In conjunction with these tests, homozygous viabilities were determined by the marked-inversion technique. This permitted a separation of the irradiated chromosomes into those which were drastic when made homozygous and those which were not. The results indicate that drastic chromosomes have deleterious effects in heterozygous condition, since viability was reduced by 2 to 4 percent in tests performed with the 10,000R chromosomes, and by 1 percent in those involving the 5,000R material. Within a series of tests, the effects were more pronounced when the genetic background was homozygous. These results suggest that the mutants induced by high doses of x-rays are principally drastic ones which show deleterious effects on viability in heterozygous condition

  5. Behavioral and electrophysiological characterization of Dyt1 heterozygous knockout mice.

    Science.gov (United States)

    Yokoi, Fumiaki; Chen, Huan-Xin; Dang, Mai Tu; Cheetham, Chad C; Campbell, Susan L; Roper, Steven N; Sweatt, J David; Li, Yuqing

    2015-01-01

    DYT1 dystonia is an inherited movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Most of the patients have a trinucleotide deletion (ΔGAG) corresponding to a glutamic acid in the C-terminal region (torsinA(ΔE)). Dyt1 ΔGAG heterozygous knock-in (KI) mice, which mimic ΔGAG mutation in the endogenous gene, exhibit motor deficits and deceased frequency of spontaneous excitatory post-synaptic currents (sEPSCs) and normal theta-burst-induced long-term potentiation (LTP) in the hippocampal CA1 region. Although Dyt1 KI mice show decreased hippocampal torsinA levels, it is not clear whether the decreased torsinA level itself affects the synaptic plasticity or torsinA(ΔE) does it. To analyze the effect of partial torsinA loss on motor behaviors and synaptic transmission, Dyt1 heterozygous knock-out (KO) mice were examined as a model of a frame-shift DYT1 mutation in patients. Consistent with Dyt1 KI mice, Dyt1 heterozygous KO mice showed motor deficits in the beam-walking test. Dyt1 heterozygous KO mice showed decreased hippocampal torsinA levels lower than those in Dyt1 KI mice. Reduced sEPSCs and normal miniature excitatory post-synaptic currents (mEPSCs) were also observed in the acute hippocampal brain slices from Dyt1 heterozygous KO mice, suggesting that the partial loss of torsinA function in Dyt1 KI mice causes action potential-dependent neurotransmitter release deficits. On the other hand, Dyt1 heterozygous KO mice showed enhanced hippocampal LTP, normal input-output relations and paired pulse ratios in the extracellular field recordings. The results suggest that maintaining an appropriate torsinA level is important to sustain normal motor performance, synaptic transmission and plasticity. Developing therapeutics to restore a normal torsinA level may help to prevent and treat the symptoms in DYT1 dystonia.

  6. Behavioral and electrophysiological characterization of Dyt1 heterozygous knockout mice.

    Directory of Open Access Journals (Sweden)

    Fumiaki Yokoi

    Full Text Available DYT1 dystonia is an inherited movement disorder caused by mutations in DYT1 (TOR1A, which codes for torsinA. Most of the patients have a trinucleotide deletion (ΔGAG corresponding to a glutamic acid in the C-terminal region (torsinA(ΔE. Dyt1 ΔGAG heterozygous knock-in (KI mice, which mimic ΔGAG mutation in the endogenous gene, exhibit motor deficits and deceased frequency of spontaneous excitatory post-synaptic currents (sEPSCs and normal theta-burst-induced long-term potentiation (LTP in the hippocampal CA1 region. Although Dyt1 KI mice show decreased hippocampal torsinA levels, it is not clear whether the decreased torsinA level itself affects the synaptic plasticity or torsinA(ΔE does it. To analyze the effect of partial torsinA loss on motor behaviors and synaptic transmission, Dyt1 heterozygous knock-out (KO mice were examined as a model of a frame-shift DYT1 mutation in patients. Consistent with Dyt1 KI mice, Dyt1 heterozygous KO mice showed motor deficits in the beam-walking test. Dyt1 heterozygous KO mice showed decreased hippocampal torsinA levels lower than those in Dyt1 KI mice. Reduced sEPSCs and normal miniature excitatory post-synaptic currents (mEPSCs were also observed in the acute hippocampal brain slices from Dyt1 heterozygous KO mice, suggesting that the partial loss of torsinA function in Dyt1 KI mice causes action potential-dependent neurotransmitter release deficits. On the other hand, Dyt1 heterozygous KO mice showed enhanced hippocampal LTP, normal input-output relations and paired pulse ratios in the extracellular field recordings. The results suggest that maintaining an appropriate torsinA level is important to sustain normal motor performance, synaptic transmission and plasticity. Developing therapeutics to restore a normal torsinA level may help to prevent and treat the symptoms in DYT1 dystonia.

  7. Dietary supplementation with an extract of lycopene-rich tomatoes does not reduce atherosclerosis in Watanabe Heritable Hyperlipidemic rabbits

    DEFF Research Database (Denmark)

    Frederiksen, H.; Rasmussen, S.E.; Schrøder, Malene

    2007-01-01

    Tomatoes are rich in lycopene and other carotenoids which have shown beneficial effects on CVD in epidemiological and intervention studies. In the present study the effect of an extract of lycopene-rich tomatoes, Lyc-O-Mato (R) on atherosclerosis was studied in Watanabe Heritable Hyperlipidemic...... rabbits. The rabbits were fed a control diet, a control diet supplemented with the tomato extract or a control diet supplemented with a mixture of plant oils for 16 weeks. Lycopene was detected only in plasma of rabbits receiving tomato extract. The tomato extract had no effect on cholesterol...... and triacylglycerol levels measured in total plasma, lipoprotein fractions and on aortic atherosclerosis evaluated biochemically and by microscopy. Oxidation of lipids in unfractionated plasma also was unaffected by the intake of tomato extract. In conclusion, the tomato extract increased plasma levels of lycopene...

  8. PINK1 heterozygous mutations induce subtle alterations in dopamine-dependent synaptic plasticity

    Science.gov (United States)

    Madeo, G.; Schirinzi, T.; Martella, G.; Latagliata, E.C.; Puglisi, F.; Shen, J.; Valente, E.M.; Federici, M.; Mercuri, N.B.; Puglisi-Allegra, S.; Bonsi, P.; Pisani, A.

    2014-01-01

    Background Homozygous or compound heterozygous mutations in the PTEN-induced kinase 1 (PINK1) gene are causative of autosomal recessive, early onset PD. Single heterozygous mutations have been repeatedly detected in a subset of patients as well as in non-affected subjects, and their significance has long been debated. Several neurophysiological studies from non-manifesting PINK1 heterozygotes have shown the existence of neural plasticity abnormalities, indicating the presence of specific endophenotypic traits in the heterozygous state. Methods In the present study, we performed a functional analysis of corticostriatal synaptic plasticity in heterozygous PINK1 knock-out (PINK1+/−) mice by a multidisciplinary approach. Results We found that, despite a normal motor behavior, repetitive activation of cortical inputs to striatal neurons failed to induce long-term potentiation (LTP), whereas long-term depression (LTD) was normal. Although nigral dopaminergic neurons exhibited normal morphological and electrophysiological properties with normal responses to dopamine receptor activation, we measured a significantly lower dopamine release in the striatum of PINK1+/−, compared to control mice, suggesting that a decrease in stimulus-evoked dopamine overflow acts as a major determinant for the LTP deficit. Accordingly, pharmacological agents capable of increasing the availability of dopamine in the synaptic cleft restored a normal LTP in heterozygous mice. Moreover, MAO-B inhibitors rescued a physiological LTP and a normal dopamine release. Conclusions Our results provide novel evidence for striatal plasticity abnormalities even in the heterozygous disease state. These alterations might be considered an endophenotype to this monogenic form of PD, and a valid tool to characterize early disease stage and design possible disease-modifying therapies. PMID:24167038

  9. EDNRB mutations cause Waardenburg syndrome type II in the heterozygous state.

    Science.gov (United States)

    Issa, Sarah; Bondurand, Nadege; Faubert, Emmanuelle; Poisson, Sylvain; Lecerf, Laure; Nitschke, Patrick; Deggouj, Naima; Loundon, Natalie; Jonard, Laurence; David, Albert; Sznajer, Yves; Blanchet, Patricia; Marlin, Sandrine; Pingault, Veronique

    2017-05-01

    Waardenburg syndrome (WS) is a genetic disorder characterized by sensorineural hearing loss and pigmentation anomalies. The clinical definition of four WS types is based on additional features due to defects in structures mostly arising from the neural crest, with type I and type II being the most frequent. While type I is tightly associated to PAX3 mutations, WS type II (WS2) remains partly enigmatic with mutations in known genes (MITF, SOX10) accounting for only 30% of the cases. We performed exome sequencing in a WS2 index case and identified a heterozygous missense variation in EDNRB. Interestingly, homozygous (and very rare heterozygous) EDNRB mutations are already described in type IV WS (i.e., in association with Hirschsprung disease [HD]) and heterozygous mutations in isolated HD. Screening of a WS2 cohort led to the identification of an overall of six heterozygous EDNRB variations. Clinical phenotypes, pedigrees and molecular segregation investigations unraveled a dominant mode of inheritance with incomplete penetrance. In parallel, cellular and functional studies showed that each of the mutations impairs the subcellular localization of the receptor or induces a defective downstream signaling pathway. Based on our results, we now estimate EDNRB mutations to be responsible for 5%-6% of WS2. © 2017 Wiley Periodicals, Inc.

  10. Characterization of Heterozygous HTRA1 Mutations in Taiwanese Patients With Cerebral Small Vessel Disease.

    Science.gov (United States)

    Lee, Yi-Chung; Chung, Chih-Ping; Chao, Nai-Chen; Fuh, Jong-Ling; Chang, Feng-Chi; Soong, Bing-Wing; Liao, Yi-Chu

    2018-07-01

    Homozygous and compound heterozygous mutations in the high temperature requirement serine peptidase A1 gene ( HTRA1 ) cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. However, heterozygous HTRA1 mutations were recently identified to be associated with autosomal dominant cerebral small vessel disease (SVD). The present study aims at investigating the clinical features, frequency, and spectrum of HTRA1 mutations in a Taiwanese cohort with SVD. Mutational analyses of HTRA1 were performed by Sanger sequencing in 222 subjects, selected from a cohort of 337 unrelated patients with SVD after excluding those harboring a NOTCH3 mutation. The influence of these mutations on HTRA1 protease activities was characterized. Seven novel heterozygous mutations in HTRA1 were identified, including p.Gly120Asp, p.Ile179Asn, p.Ala182Profs*33, p.Ile256Thr, p.Gly276Ala, p.Gln289Ter, and p.Asn324Thr, and each was identified in 1 single index patient. All mutations significantly compromise the HTRA1 protease activities. For the 7 index cases and another 2 affected siblings carrying a heterozygous HTRA1 mutation, the common clinical presentations include lacunar infarction, intracerebral hemorrhage, cognitive decline, and spondylosis at the fifth to sixth decade of life. Among the 9 patients, 4 have psychiatric symptoms as delusion, depression, and compulsive behavior, 3 have leukoencephalopathy in anterior temporal poles, and 2 patients have alopecia. Heterozygous HTRA1 mutations account for 2.08% (7 of 337) of SVD in Taiwan. The clinical and neuroradiological features of HTRA1 -related SVD and sporadic SVD are similar. These findings broaden the mutational spectrum of HTRA1 and highlight the pathogenic role of heterozygous HTRA1 mutations in SVD. © 2018 American Heart Association, Inc.

  11. Heterozygous RTEL1 mutations are associated with familial pulmonary fibrosis.

    Science.gov (United States)

    Kannengiesser, Caroline; Borie, Raphael; Ménard, Christelle; Réocreux, Marion; Nitschké, Patrick; Gazal, Steven; Mal, Hervé; Taillé, Camille; Cadranel, Jacques; Nunes, Hilario; Valeyre, Dominique; Cordier, Jean François; Callebaut, Isabelle; Boileau, Catherine; Cottin, Vincent; Grandchamp, Bernard; Revy, Patrick; Crestani, Bruno

    2015-08-01

    Pulmonary fibrosis is a fatal disease with progressive loss of respiratory function. Defective telomere maintenance leading to telomere shortening is a cause of pulmonary fibrosis, as mutations in the telomerase component genes TERT (reverse transcriptase) and TERC (RNA component) are found in 15% of familial pulmonary fibrosis (FPF) cases. However, so far, about 85% of FPF remain genetically uncharacterised.Here, in order to identify new genetic causes of FPF, we performed whole-exome sequencing, with a candidate-gene approach, of 47 affected subjects from 35 families with FPF without TERT and TERC mutations.We identified heterozygous mutations in regulator of telomere elongation helicase 1 (RTEL1) in four families. RTEL1 is a DNA helicase with roles in DNA replication, genome stability, DNA repair and telomere maintenance. The heterozygous RTEL1 mutations segregated as an autosomal dominant trait in FPF, and were predicted by structural analyses to severely affect the function and/or stability of RTEL1. In agreement with this, RTEL1-mutated patients exhibited short telomeres in comparison with age-matched controls.Our results provide evidence that heterozygous RTEL1 mutations are responsible for FPF and, thereby, extend the clinical spectrum of RTEL1 deficiency. Thus, RTEL1 enlarges the number of telomere-associated genes implicated in FPF. Copyright ©ERS 2015.

  12. A Novel Double Heterozygous Hb D-Punjab/Hb J-Meerut Hemoglobinopathy.

    Science.gov (United States)

    Chandra, Dinesh; Tyagi, Seema; Deka, Roopam; Chauhan, Richa; Seth, Tulika; Saxena, Renu; Pati, H P

    2017-12-01

    A comprehensive laboratory diagnosis of hemoglobinopathies forms an integral part in workup of disorders of globin chain synthesis. Clinical findings, complete blood counts, peripheral smear examination along with hemoglobin (Hb) electrophoresis and/or cation exchange high performance liquid chromatography findings and parental study helps to clinch a final diagnosis. Compound heterozygous hemoglobinopathy presents with variable clinical findings and some of them are picked up on screening tests done as part of routine antenatal workup. Here we report a rare double heterozygous hemoglobinopathy of Hb D-Punjab and Hb J-Meerut in a 35 year antenatal female.

  13. Filaggrin compound heterozygous patients carry mutations in trans position

    DEFF Research Database (Denmark)

    Carlsen, Berit C; Meldgaard, Michael; Johansen, Jeanne D

    2013-01-01

    by means of allele-specific PCR amplification and analysis of PCR products by agarose gel electrophoresis. All R501X/2282del4 compound heterozygous samples collected over a 4-year period of routine FLG mutation testing were investigated. In total, 37 samples were tested. All thirty-seven R501X/2282del4......More than 40 null mutations in the filaggrin (FLG) gene are described. It is therefore possible to find two different null mutations in one individual (compound heterozygosity). It has been generally perceived that homozygous and compound heterozygous individuals were genotypically comparable......; however, this has not been scientifically investigated. Two different FLG null mutations in the same individual may be in trans position, meaning that each mutation locates to a different allele functionally equivalent to homozygosity, or may be in cis position, meaning that both mutations locate...

  14. Pentosan polysulfate inhibits atherosclerosis in Watanabe heritable hyperlipidemic rabbits: differential modulation of metalloproteinase-2 and -9.

    Science.gov (United States)

    Lupia, Enrico; Zheng, Feng; Grosjean, Fabrizio; Tack, Ivan; Doublier, Sophie; Elliot, Sharon J; Vlassara, Helen; Striker, Gary E

    2012-02-01

    Pentosan polysulfate (PPS), a heparinoid compound essentially devoid of anticoagulant activity, modulates cell growth and decreases inflammation. We investigated the effect of PPS on the progression of established atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbits. After severe atherosclerosis developed on an atherogenic diet, WHHL rabbits were treated with oral PPS or tap water for 1 month. The aortic intima-to-media ratio and macrophage infiltration were reduced, plaque collagen content was increased, and plaque fibrous caps were preserved by PPS treatment. Plasma lipid levels and post-heparin hepatic lipase activity remained unchanged. However, net collagenolytic activity in aortic extracts was decreased, and the levels of matrix metalloproteinase (MMP)-2 and tissue inhibitor of metalloproteinase (TIMP) activity were increased by PPS. Moreover, PPS treatment decreased tumor necrosis factor α (TNFα)-stimulated proinflammatory responses, in particular activation of nuclear factor-κB and p38, and activation of MMPs in macrophages. In conclusion, oral PPS treatment prevents progression of established atherosclerosis in WHHL rabbits. This effect may be partially mediated by increased MMP-2 and TIMP activities in the aortic wall and reduced TNFα-stimulated inflammation and MMP activation in macrophages. Thus, PPS may be a useful agent in inhibiting the progression of atherosclerosis.

  15. Heterozygous CDKL5 Knockout Female Mice Are a Valuable Animal Model for CDKL5 Disorder

    Directory of Open Access Journals (Sweden)

    Claudia Fuchs

    2018-01-01

    Full Text Available CDKL5 disorder is a severe neurodevelopmental disorder caused by mutations in the X-linked CDKL5 (cyclin-dependent kinase-like five gene. CDKL5 disorder primarily affects girls and is characterized by early-onset epileptic seizures, gross motor impairment, intellectual disability, and autistic features. Although all CDKL5 female patients are heterozygous, the most valid disease-related model, the heterozygous female Cdkl5 knockout (Cdkl5 +/− mouse, has been little characterized. The lack of detailed behavioral profiling of this model remains a crucial gap that must be addressed in order to advance preclinical studies. Here, we provide a behavioral and molecular characterization of heterozygous Cdkl5 +/− mice. We found that Cdkl5 +/− mice reliably recapitulate several aspects of CDKL5 disorder, including autistic-like behaviors, defects in motor coordination and memory performance, and breathing abnormalities. These defects are associated with neuroanatomical alterations, such as reduced dendritic arborization and spine density of hippocampal neurons. Interestingly, Cdkl5 +/− mice show age-related alterations in protein kinase B (AKT and extracellular signal-regulated kinase (ERK signaling, two crucial signaling pathways involved in many neurodevelopmental processes. In conclusion, our study provides a comprehensive overview of neurobehavioral phenotypes of heterozygous female Cdkl5 +/− mice and demonstrates that the heterozygous female might be a valuable animal model in preclinical studies on CDKL5 disorder.

  16. Risk of asthma in heterozygous carriers for cystic fibrosis

    DEFF Research Database (Denmark)

    Nielsen, Anne Orholm; Qayum, Sadaf; Bouchelouche, Pierre Nourdine

    2016-01-01

    Background Patients with cystic fibrosis (CF) have a higher prevalence of asthma than the background population, however, it is unclear whether heterozygous CF carriers are susceptible to asthma. Given this, a meta-analysis is necessary to determine the veracity of the association of CF...

  17. Premature cardiovascular disease in young women with heterozygous familial hypercholesterolemia

    NARCIS (Netherlands)

    van der Graaf, Anouk; Hutten, Barbara A.; Kastelein, John J. P.; Vissers, Maud N.

    2006-01-01

    Heterozygous familial hypercholesterolemia is associated with elevated low-density lipoprotein cholesterol levels and the development of premature cardiovascular disease. Despite this general statement, data regarding the incidence of cardiovascular disease in young women with familial

  18. Heterozygous defects in PAX6 gene and congenital hypopituitarism.

    Science.gov (United States)

    Takagi, Masaki; Nagasaki, Keisuke; Fujiwara, Ikuma; Ishii, Tomohiro; Amano, Naoko; Asakura, Yumi; Muroya, Koji; Hasegawa, Yukihiro; Adachi, Masanori; Hasegawa, Tomonobu

    2015-01-01

    The prevalence of congenital hypopituitarism (CH) attributable to known transcription factor mutations appears to be rare and other causative genes for CH remain to be identified. Due to the sporadic occurrence of CH, de novo chromosomal rearrangements could be one of the molecular mechanisms participating in its etiology, especially in syndromic cases. To identify the role of copy number variations (CNVs) in the etiology of CH and to identify novel genes implicated in CH. We enrolled 88 (syndromic: 30; non-syndromic: 58) Japanese CH patients. We performed an array comparative genomic hybridization screening in the 30 syndromic CH patients. For all the 88 patients, we analyzed PAX6 by PCR-based sequencing. We identified one heterozygous 310-kb deletion of the PAX6 enhancer region in one patient showing isolated GH deficiency (IGHD), cleft palate, and optic disc cupping. We also identified one heterozygous 6.5-Mb deletion encompassing OTX2 in a patient with bilateral anophthalmia and multiple pituitary hormone deficiency. We identified a novel PAX6 mutation, namely p.N116S in one non-syndromic CH patient showing IGHD. The p.N116S PAX6 was associated with an impairment of the transactivation capacities of the PAX6-binding elements. This study showed that heterozygous PAX6 mutations are associated with CH patients. PAX6 mutations may be associated with diverse clinical features ranging from severely impaired ocular and pituitary development to apparently normal phenotype. Overall, this study identified causative CNVs with a possible role in the etiology of CH in <10% of syndromic CH patients. © 2015 European Society of Endocrinology.

  19. Arterial intima-media thickness in children heterozygous for familial hypercholesterolaemia

    NARCIS (Netherlands)

    Wiegman, Albert; de Groot, Eric; Hutten, Barbara A.; Rodenburg, Jessica; Gort, Johan; Bakker, Henk D.; Sijbrands, Eric J. G.; Kastelein, John J. P.

    2004-01-01

    Patients with familial hypercholesterolaemia have severe coronary-artery disease early in adult life. Whether lipid-lowering treatment should be started in childhood remains to be established. We therefore assessed 201 children heterozygous for familial hypercholesterolaemia and 80 unaffected

  20. Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome

    NARCIS (Netherlands)

    Van Houdt, Jeroen K. J.; Nowakowska, Beata Anna; Sousa, Sergio B.; van Schaik, Barbera D. C.; Seuntjens, Eve; Avonce, Nelson; Sifrim, Alejandro; Abdul-Rahman, Omar A.; van den Boogaard, Marie-Jose H.; Bottani, Armand; Castori, Marco; Cormier-Daire, Valerie; Deardorff, Matthew A.; Filges, Isabel; Fryer, Alan; Fryns, Jean-Pierre; Gana, Simone; Garavelli, Livia; Gillessen-Kaesbach, Gabriele; Hall, Bryan D.; Horn, Denise; Huylebroeck, Danny; Klapecki, Jakub; Krajewska-Walasek, Malgorzata; Kuechler, Alma; Lines, Matthew A.; Maas, Saskia; MacDermot, Kay D.; McKee, Shane; Magee, Alex; de Man, Stella A.; Moreau, Yves; Morice-Picard, Fanny; Obersztyn, Ewa; Pilch, Jacek; Rosser, Elizabeth; Shannon, Nora; Stolte-Dijkstra, Irene; Van Dijck, Patrick; Vilain, Catheline; Vogels, Annick; Wakeling, Emma; Wieczorek, Dagmar; Wilson, Louise; Zuffardi, Orsetta; van Kampen, Antoine H. C.; Devriendt, Koenraad; Hennekam, Raoul; Vermeesch, Joris Robert

    Nicolaides-Baraitser syndrome (NBS) is characterized by sparse hair, distinctive facial morphology, distal-limb anomalies and intellectual disability. We sequenced the exomes of ten individuals with NBS and identified heterozygous variants in SMARCA2 in eight of them. Extended molecular screening

  1. Homozygous and compound heterozygous mutations in the FBN1 gene: unexpected findings in molecular diagnosis of Marfan syndrome.

    Science.gov (United States)

    Arnaud, Pauline; Hanna, Nadine; Aubart, Mélodie; Leheup, Bruno; Dupuis-Girod, Sophie; Naudion, Sophie; Lacombe, Didier; Milleron, Olivier; Odent, Sylvie; Faivre, Laurence; Bal, Laurence; Edouard, Thomas; Collod-Beroud, Gwenaëlle; Langeois, Maud; Spentchian, Myrtille; Gouya, Laurent; Jondeau, Guillaume; Boileau, Catherine

    2017-02-01

    Marfan syndrome (MFS) is an autosomal-dominant connective tissue disorder usually associated with heterozygous mutations in the gene encoding fibrillin-1 (FBN1). Homozygous and compound heterozygous cases are rare events and have been associated with a clinical severe presentation. Report unexpected findings of homozygosity and compound heterozygosity in the course of molecular diagnosis of heterozygous MFS and compare the findings with published cases. In the context of molecular diagnosis of heterozygous MFS, systematic sequencing of the FBN1 gene was performed in 2500 probands referred nationwide. 1400 probands carried a heterozygous mutation in this gene. Unexpectedly, among them four homozygous cases (0.29%) and five compound heterozygous cases (0.36%) were identified (total: 0.64%). Interestingly, none of these cases carried two premature termination codon mutations in the FBN1 gene. Clinical features for these carriers and their families were gathered and compared. There was a large spectrum of severity of the disease in probands carrying two mutated FBN1 alleles, but none of them presented extremely severe manifestations of MFS in any system compared with carriers of only one mutated FBN1 allele. This observation is not in line with the severe clinical features reported in the literature for four homozygous and three compound heterozygous probands. Homozygotes and compound heterozygotes were unexpectedly identified in the course of molecular diagnosis of MFS. Contrary to previous reports, the presence of two mutated alleles was not associated with severe forms of MFS. Although homozygosity and compound heterozygosity are rarely found in molecular diagnosis, they should not be overlooked, especially among consanguineous families. However, no predictive evaluation of severity should be provided. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  2. Neurochemical and behavioral characterization of neuronal glutamate transporter EAAT3 heterozygous mice

    Directory of Open Access Journals (Sweden)

    Luis F. González

    2017-10-01

    Full Text Available Abstract Background Obsessive–compulsive disorder (OCD is a severe neuropsychiatric condition affecting 1–3% of the worldwide population. OCD has a strong genetic component, and the SLC1A1 gene that encodes neuronal glutamate transporter EAAT3 is a strong candidate for this disorder. To evaluate the impact of reduced EAAT3 expression in vivo, we studied male EAAT3 heterozygous and wild-type littermate mice using a battery of behavioral paradigms relevant to anxiety (open field test, elevated plus maze and compulsivity (marble burying, as well as locomotor activity induced by amphetamine. Using high-performance liquid chromatography, we also determined tissue neurotransmitter levels in cortex, striatum and thalamus—brain areas that are relevant to OCD. Results Compared to wild-type littermates, EAAT3 heterozygous male mice have unaltered baseline anxiety-like, compulsive-like behavior and locomotor activity. Administration of acute amphetamine (5 mg/kg intraperitoneally increased locomotion with no differences across genotypes. Tissue levels of glutamate, GABA, dopamine and serotonin did not vary between EAAT3 heterozygous and wild-type mice. Conclusions Our results indicate that reduced EAAT3 expression does not impact neurotransmitter content in the corticostriatal circuit nor alter anxiety or compulsive-like behaviors.

  3. A novel double heterozygous Hb Fontainebleau/HbD Punjab hemoglobinopathy.

    Science.gov (United States)

    Rodríguez-Capote, Karina; Estey, Mathew P; Barakauskas, Vilte; Bordeleau, Pierre; Christensen, Cathie-Lou; Zuberbuhler, Peter; Higgins, Trefor N

    2015-09-01

    To report the finding of a novel double heterozygous hemoglobinopathy, the coinheritance of Hb Fontainebleau (α-chain variant) with HbD-Punjab (β-chain variant) discovered upon investigation of unexplained microcytosis in an infant. Hemoglobinopathy investigation was performed by high performance liquid chromatography (HPLC) using the β-thalassemia Short Program on the Bio-Rad Variant II(TM) followed by gel electrophoresis at alkaline and acid pH (Sebia Hydrasys 2 Electrophoresis System) and molecular diagnostic testing. This study complied with our institutional board ethics requirements. HPLC and electrophoresis suggested a complex α- and β-chain hemoglobinopathy with presumptive identification of the beta Hb variant as Hb D-Punjab. DNA sequencing analysis revealed the presence of a double heterozygous status for Hb Fontainebleau/Hb D-Punjab. In this paper we report the coinheritance of Hb Fontainebleau with Hb D-Punjab. Copyright © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  4. Clinical and functional characterization of a patient carrying a compound heterozygous pericentrin mutation and a heterozygous IGF1 receptor mutation.

    Directory of Open Access Journals (Sweden)

    Eva Müller

    Full Text Available Intrauterine and postnatal longitudinal growth is controlled by a strong genetic component that regulates a complex network of endocrine factors integrating them with cellular proliferation, differentiation and apoptotic processes in target tissues, particularly the growth centers of the long bones. Here we report on a patient born small for gestational age (SGA with severe, proportionate postnatal growth retardation, discreet signs of skeletal dysplasia, microcephaly and moyamoya disease. Initial genetic evaluation revealed a novel heterozygous IGF1R p.Leu1361Arg mutation affecting a highly conserved residue with the insulin-like growth factor type 1 receptor suggestive for a disturbance within the somatotropic axis. However, because the mutation did not co-segregate with the phenotype and functional characterization did not reveal an obvious impairment of the ligand depending major IGF1R signaling capabilities a second-site mutation was assumed. Mutational screening of components of the somatotropic axis, constituents of the IGF signaling system and factors involved in cellular proliferation, which are described or suggested to provoke syndromic dwarfism phenotypes, was performed. Two compound heterozygous PCNT mutations (p.[Arg585X];[Glu1774X] were identified leading to the specification of the diagnosis to MOPD II. These investigations underline the need for careful assessment of all available information to derive a firm diagnosis from a sequence aberration.

  5. Clinical and functional characterization of a patient carrying a compound heterozygous pericentrin mutation and a heterozygous IGF1 receptor mutation.

    Science.gov (United States)

    Müller, Eva; Dunstheimer, Desiree; Klammt, Jürgen; Friebe, Daniela; Kiess, Wieland; Kratzsch, Jürgen; Kruis, Tassilo; Laue, Sandy; Pfäffle, Roland; Wallborn, Tillmann; Heidemann, Peter H

    2012-01-01

    Intrauterine and postnatal longitudinal growth is controlled by a strong genetic component that regulates a complex network of endocrine factors integrating them with cellular proliferation, differentiation and apoptotic processes in target tissues, particularly the growth centers of the long bones. Here we report on a patient born small for gestational age (SGA) with severe, proportionate postnatal growth retardation, discreet signs of skeletal dysplasia, microcephaly and moyamoya disease. Initial genetic evaluation revealed a novel heterozygous IGF1R p.Leu1361Arg mutation affecting a highly conserved residue with the insulin-like growth factor type 1 receptor suggestive for a disturbance within the somatotropic axis. However, because the mutation did not co-segregate with the phenotype and functional characterization did not reveal an obvious impairment of the ligand depending major IGF1R signaling capabilities a second-site mutation was assumed. Mutational screening of components of the somatotropic axis, constituents of the IGF signaling system and factors involved in cellular proliferation, which are described or suggested to provoke syndromic dwarfism phenotypes, was performed. Two compound heterozygous PCNT mutations (p.[Arg585X];[Glu1774X]) were identified leading to the specification of the diagnosis to MOPD II. These investigations underline the need for careful assessment of all available information to derive a firm diagnosis from a sequence aberration.

  6. Heterozygous CDKL5 Knockout Female Mice Are a Valuable Animal Model for CDKL5 Disorder

    OpenAIRE

    Fuchs, Claudia; Gennaccaro, Laura; Trazzi, Stefania; Bastianini, Stefano; Bettini, Simone; Martire, Viviana Lo; Ren, Elisa; Medici, Giorgio; Zoccoli, Giovanna; Rimondini, Roberto; Ciani, Elisabetta

    2018-01-01

    CDKL5 disorder is a severe neurodevelopmental disorder caused by mutations in the X-linked CDKL5 (cyclin-dependent kinase-like five) gene. CDKL5 disorder primarily affects girls and is characterized by early-onset epileptic seizures, gross motor impairment, intellectual disability, and autistic features. Although all CDKL5 female patients are heterozygous, the most valid disease-related model, the heterozygous female Cdkl5 knockout (Cdkl5 +/−) mouse, has been little characterized. The lack of...

  7. Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms.

    Science.gov (United States)

    Marsh, Judith C W; Gutierrez-Rodrigues, Fernanda; Cooper, James; Jiang, Jie; Gandhi, Shreyans; Kajigaya, Sachiko; Feng, Xingmin; Ibanez, Maria Del Pilar F; Donaires, Flávia S; Lopes da Silva, João P; Li, Zejuan; Das, Soma; Ibanez, Maria; Smith, Alexander E; Lea, Nicholas; Best, Steven; Ireland, Robin; Kulasekararaj, Austin G; McLornan, Donal P; Pagliuca, Anthony; Callebaut, Isabelle; Young, Neal S; Calado, Rodrigo T; Townsley, Danielle M; Mufti, Ghulam J

    2018-01-09

    Biallelic germline mutations in RTEL1 (regulator of telomere elongation helicase 1) result in pathologic telomere erosion and cause dyskeratosis congenita. However, the role of RTEL1 mutations in other bone marrow failure (BMF) syndromes and myeloid neoplasms, and the contribution of monoallelic RTEL1 mutations to disease development are not well defined. We screened 516 patients for germline mutations in telomere-associated genes by next-generation sequencing in 2 independent cohorts; one constituting unselected patients with idiopathic BMF, unexplained cytopenia, or myeloid neoplasms (n = 457) and a second cohort comprising selected patients on the basis of the suspicion of constitutional/familial BMF (n = 59). Twenty-three RTEL1 variants were identified in 27 unrelated patients from both cohorts: 7 variants were likely pathogenic, 13 were of uncertain significance, and 3 were likely benign. Likely pathogenic RTEL1 variants were identified in 9 unrelated patients (7 heterozygous and 2 biallelic). Most patients were suspected to have constitutional BMF, which included aplastic anemia (AA), unexplained cytopenia, hypoplastic myelodysplastic syndrome, and macrocytosis with hypocellular bone marrow. In the other 18 patients, RTEL1 variants were likely benign or of uncertain significance. Telomeres were short in 21 patients (78%), and 3' telomeric overhangs were significantly eroded in 4. In summary, heterozygous RTEL1 variants were associated with marrow failure, and telomere length measurement alone may not identify patients with telomere dysfunction carrying RTEL1 variants. Pathogenicity assessment of heterozygous RTEL1 variants relied on a combination of clinical, computational, and functional data required to avoid misinterpretation of common variants.

  8. [Molecular characterization of heterozygous beta-thalassemia in Lanzarote, Spain].

    Science.gov (United States)

    Calvo-Villas, José Manuel; de la Iglesia Iñigo, Silvia; Ropero Gradilla, Paloma; Zapata Ramos, María Francisca; Cuesta Tovar, Jorge; Sicilia Guillén, Francisco

    2008-04-05

    The aim of this study was to determine the molecular defects of heterozygous beta thalassaemia and to ascertain their distribution in Lanzarote. Molecular characterization was achieved by real time polymerase chain reaction (RT-PCR LightCycler, Roche), PCR-ARMS (PCR-amplification reaction mutations system) and DNA sequencing on an automated DNA sequencer. Two hundred forty-three heterozygous beta thalassaemia carriers were included between July 1991 and February 2007. RT-PCR detected the molecular defect in 81% of the beta thalassaemia chromosomes analyzed [113 codon CD 39 (C --> T); 41 IVS-1-nt-110 (G --> A), 25 IVS 1-nt-1 (G --> A) and 19 IVS 1-nt-6 (T --> C)]. The remaining 12 molecular defects included the deletion 619 bp (7.8%) and the mutations -28 (A --> G), IVS1-nt-2 (T --> G), CD 41/42 (-TTCT), CD 8/9 (+G), CD 51 (-C), CD 22 (G --> T) and CD 24 (T --> A), CD 67 (-TG) and the novel mutation CD 20/21-TGGA. The distribution of the mutations is similar to that found in the Mediterranean area. The increasing migratory flow received in the Canary Islands may explain the emergence of new mutations not reported before in our area.

  9. Quantitating PrP Polymorphisms Present in Prions from Heterozygous Scrapie-Infected Sheep.

    Science.gov (United States)

    Silva, Christopher J; Erickson-Beltran, Melissa L; Hui, Colleen; Badiola, Juan José; Nicholson, Eric M; Requena, Jesús R; Bolea, Rosa

    2017-01-03

    Scrapie is a prion (PrP Sc ) disease of sheep. The incubation period of sheep scrapie is strongly influenced by polymorphisms at positions 136, 154, and 171 of a sheep's normal cellular prion protein (PrP C ). Chymotrypsin was used to digest sheep recombinant PrP to identify a set of characteristic peptides [M 132 LGSXMSRPL 141 (X = A or V), Y 153 XENMY 158 (X,= H or R), and Y 166 RPVDXY 172 (X = H, K, Q, or R)] that could be used to detect and quantitate polymorphisms at positions 136, 154, and 171 of sheep PrP C or PrP Sc . These peptides were used to develop a multiple reaction monitoring method (MRM) to detect the amounts of a particular polymorphism in a sample of PrP Sc isolated from sheep heterozygous for their PrP C proteins. The limit of detection for these peptides was less than 50 attomole. Spinal cord tissue from heterozygous (ARQ/VRQ or ARH/ARQ) scrapie-infected Rasa Aragonesa sheep was analyzed using this MRM method. Both sets of heterozygotes show the presence of both polymorphisms in PrP Sc . This was true for samples containing both proteinase K (PK)-sensitive and PK-resistant PrP Sc and samples containing only the PK-resistant PrP Sc . These results show that heterozygous animals contain PrP Sc that is composed of significant amounts of both PrP polymorphisms.

  10. Modulation of repetitive genes in the parent forms of heterozygous corn hybrids

    International Nuclear Information System (INIS)

    Gilyazetdinov, S.Ya.; Zimnitskii, A.N.; Yakhin, I.A.; Bikbaeva, E.S.

    1987-01-01

    The number of copies of the genes of high-molecular-weight rRNA, 5 S r RNA, and certain other families of repetitive sequences of DNA in the genome of different forms of corn is not coordinated but is stably inherited in the same strains. The authors present the results of their investigations into the repetition of the genes of tRNA, 5 S rRNA, histones, and the controlling element Ds of corn for the highly heterozygous hybrid Slava (VIR 44 x VIR 38), the medium-heterozygous hybrid Svetoch (VIR 40 x VIR 43), the low heterozygous hybrid Iskra (VIR 26 x VIR 27), and their parent strains. The relative content of these sequences was studied by the molecular hybridization of DNA immobilized on nitrocellulose filters with [ 125 I]tRNA labeled in vitro, 5 S rRNA, histone DNA of Drosophila, and the Ds-element of corn. The DNA preparations were isolated from the zones of the meristem (1.5-2mm), elongation (4-5mm), differentiation of the roots (3 cm), of 3-4 day seedlings, and from isolated embryos of 4 h and 24 h seedlings. The DNA of the embryos immobilized on the filters was preliminarily incubated with unlabeled high-molecular-weight rRNA in the experiments with tRNA and 5 S rRNA, while when histone DNA and the Ds element of corn were used in the hybridization reaction, it was preliminary incubated with plasmid DNA

  11. X-linked adrenoleukodystrophy in heterozygous female patients: women are not just carriers

    Directory of Open Access Journals (Sweden)

    Charles Marques Lourenço

    2012-07-01

    Full Text Available X-linked adrenoleukodystrophy (X-ALD is a recessive X-linked disorder associated with marked phenotypic variability. Female carriers are commonly thought to be normal or only mildly affected, but their disease still needs to be better described and systematized. OBJECTIVES: To review and systematize the clinical features of heterozygous women followed in a Neurogenetics Clinic. METHODS: We reviewed the clinical, biochemical, and neuroradiological data of all women known to have X-ADL. RESULTS: The nine women identified were classified into three groups: with severe and aggressive diseases; with slowly progressive, spastic paraplegia; and with mildly decreased vibratory sensation, brisk reflexes, and no complaints. Many of these women did not have a known family history of X-ALD. CONCLUSIONS: Heterozygous women with X-ADL have a wide spectrum of clinical manifestations, ranging from mild to severe phenotypes.

  12. Assay for identification of heterozygous single-nucleotide polymorphism (Ala67Thr in human poliovirus receptor gene

    Directory of Open Access Journals (Sweden)

    Shyam Sundar Nandi

    2016-01-01

    Results: A new SNP assay for detection of heterozygous Ala67Thr genotype was developed and validated by testing 150 DNA samples. Heterozygous CD155 was detected in 27.33 per cent (41/150 of DNA samples tested by both SNP detection assay and sequencing. Interpretation & conclusions: The SNP detection assay was successfully developed for identification of Ala67Thr polymorphism in human PVR/CD155 gene. The SNP assay will be useful for large scale screening of DNA samples.

  13. Frequency of Gγ-globin promoter -158 (C>T) XmnI polymorphism in patients with homozygous/compound heterozygous beta thalassaemia.

    Science.gov (United States)

    Ali, Nadir; Ayyub, Muhammad; Khan, Saleem Ahmed; Ahmed, Suhaib; Abbas, Kazim; Malik, Hamid Saeed; Tashfeen, Sunila

    2015-03-01

    Response to hydroxyurea therapy in homozygous or compound heterozygous beta thalassaemia (BT) has been reported as more favourable in the presence of XmnI polymorphism. The prevalence of XmnI polymorphism may vary with BT phenotypes and genotypes, and differs geographically in distribution. Prevalence of XmnI polymorphism is not known in northern Pakistan. To determine the frequency of Gγ-globin promoter -158 (C>T) XmnI polymorphism (XmnI polymorphism) in patients with homozygous or compound heterozygous beta thalassaemia. Polymerase chain reaction (PCR) for common beta thalassaemia mutations and Gγ-globin promoter -158 (C>T) XmnI polymorphism was performed on 107 blood samples of transfusion dependent beta thalassaemia (BT) patients in Pakistan. One hundred samples of unrelated BT traits and 94 samples of healthy subjects as controls were also analysed for BT mutations and XmnI polymorphism. Out of 301 DNA samples, XmnI polymorphism was detected in 71(24%); in normal controls, XmnI polymorphism was detected in 34/94 (36%) subjects; while in homozygous/compound heterozygous BT, it was detected in 14/107(13%) patients (Fisher's exact test, p=.0002). In heterozygous BT group, XmnI polymorphism was detected in 23/100 subjects (Fisher's exact test, p=.03 with normal controls, and p=.049 with homozygous/compound heterozygous BT). The most common BT genotype was Frame Shift (Fr) 8-9/Fr 8-9, and none of the patients with this genotype had XmnI polymorphism. The second most common genotype was IVSI-5/IVSI-5; 4/26 (15%). Cases with this genotype had XmnI polymorphism. XmnI polymorphism in homozygous/compound heterozygous BT group is 13%. The most common genotype associated with XmnI polymorphism was IVSI-5/IVSI-5. Copyright © 2015 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.

  14. The Nance-Horan syndrome: a rare X-linked ocular-dental trait with expression in heterozygous females.

    Science.gov (United States)

    Bixler, D; Higgins, M; Hartsfield, J

    1984-07-01

    This report describes two families with the Nance-Horan syndrome, an X-linked trait featuring lenticular cataracts and anomalies of tooth shape and number. Previous reports have described blindness in affected males but posterior sutural cataracts with normal vision as the primary ocular expression in heterozygous females. In one of these two families, the affected female is not only blind in one eye but reportedly had supernumerary central incisors (mesiodens) removed. This constitutes the most severe ocular and dental expression of this gene in heterozygous females yet reported.

  15. Heterozygous Mutations in TREX1 Cause Familial Chilblain Lupus and Dominant Aicardi-Goutières Syndrome

    Science.gov (United States)

    Rice, Gillian; Newman, William G.; Dean, John; Patrick, Teresa; Parmar, Rekha; Flintoff, Kim; Robins, Peter; Harvey, Scott; Hollis, Thomas; O’Hara, Ann; Herrick, Ariane L.; Bowden, Andrew P.; Perrino, Fred W.; Lindahl, Tomas; Barnes, Deborah E.; Crow, Yanick J.

    2007-01-01

    TREX1 constitutes the major 3′→5′ DNA exonuclease activity measured in mammalian cells. Recently, biallelic mutations in TREX1 have been shown to cause Aicardi-Goutières syndrome at the AGS1 locus. Interestingly, Aicardi-Goutières syndrome shows overlap with systemic lupus erythematosus at both clinical and pathological levels. Here, we report a heterozygous TREX1 mutation causing familial chilblain lupus. Additionally, we describe a de novo heterozygous mutation, affecting a critical catalytic residue in TREX1, that results in typical Aicardi-Goutières syndrome. PMID:17357087

  16. Novel compound heterozygous mutations in SERPINH1 cause rare autosomal recessive osteogenesis imperfecta type X.

    Science.gov (United States)

    Song, Y; Zhao, D; Xu, X; Lv, F; Li, L; Jiang, Y; Wang, O; Xia, W; Xing, X; Li, M

    2018-03-09

    We identified novel compound heterozygous mutations in SERPINH1 in a Chinese boy suffering from recurrent fractures, femoral deformities, and growth retardation, which resulted in extremely rare autosomal recessive OI type X. Long-term treatment of BPs was effective in increasing BMD Z-score, reducing fracture incidence and reshaping vertebrae compression. Osteogenesis imperfecta (OI) is a heritable bone disorder characterized by low bone mineral density, recurrent fractures, and progressive bone deformities. Mutation in serpin peptidase inhibitor clade H, member 1 (SERPINH1), which encodes heat shock protein 47 (HSP47), leads to rare autosomal recessive OI type X. We aimed to detect the phenotype and the pathogenic mutation of OI type X in a boy from a non-consanguineous Chinese family. We investigated the pathogenic mutations and analyzed their relationship with the phenotype in the patient using next-generation sequencing (NGS) and Sanger sequencing. Moreover, the efficacy of long-term bisphosphonate treatment in this patient was evaluated. The patient suffered from multiple fractures, low bone mass, and bone deformities in the femur, without dentinogenesis imperfecta or hearing loss. Compound heterozygous variants were found in SERPINH1 as follows: c.149 T>G in exon 2 and c.1214G>A in exon 5. His parents were heterozygous carriers of each of these mutations, respectively. Bisphosphonates could be helpful in increasing BMD Z-score, reducing bone fracture risk and reshaping the compressed vertebral bodies of this patient. We reported novel compound heterozygous mutations in SERPINH1 in a Chinese OI patient for the first time, which expanded the spectrum of phenotype and genotype of extremely rare OI type X.

  17. Altered social cognition in male BDNF heterozygous mice and following chronic methamphetamine exposure.

    Science.gov (United States)

    Manning, Elizabeth E; van den Buuse, Maarten

    2016-05-15

    Growing clinical evidence suggests that persistent psychosis which occurs in methamphetamine users is closely related to schizophrenia. However, preclinical studies in animal models have focussed on psychosis-related behaviours following methamphetamine, and less work has been done to assess endophenotypes relevant to other deficits observed in schizophrenia. Altered social behaviour is a feature of both the negative symptoms and cognitive deficits in schizophrenia, and significantly impacts patient functioning. We recently found that brain-derived neurotrophic factor (BDNF) heterozygous mice show disrupted sensitization to methamphetamine, supporting other work suggesting an important role of this neurotrophin in the pathophysiology of psychosis and the neuronal response to stimulant drugs. In the current study, we assessed social and cognitive behaviours in methamphetamine-treated BDNF heterozygous mice and wildtype littermate controls. Following chronic methamphetamine exposure male wildtype mice showed a 50% reduction in social novelty preference. Vehicle-treated male BDNF heterozygous mice showed a similar impairment in social novelty preference, with a trend for no further disruption by methamphetamine exposure. Female mice were unaffected in this task, and no groups showed any changes in sociability or short-term spatial memory. These findings suggest that chronic methamphetamine alters behaviour relevant to disruption of social cognition in schizophrenia, supporting other studies which demonstrate a close resemblance between persistent methamphetamine psychosis and schizophrenia. Together these findings suggest that dynamic regulation of BDNF signalling is necessary to mediate the effects of methamphetamine on behaviours relevant to schizophrenia. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.

    Science.gov (United States)

    Patel, Kashyap A; Kettunen, Jarno; Laakso, Markku; Stančáková, Alena; Laver, Thomas W; Colclough, Kevin; Johnson, Matthew B; Abramowicz, Marc; Groop, Leif; Miettinen, Päivi J; Shepherd, Maggie H; Flanagan, Sarah E; Ellard, Sian; Inagaki, Nobuya; Hattersley, Andrew T; Tuomi, Tiinamaija; Cnop, Miriam; Weedon, Michael N

    2017-10-12

    Finding new causes of monogenic diabetes helps understand glycaemic regulation in humans. To find novel genetic causes of maturity-onset diabetes of the young (MODY), we sequenced MODY cases with unknown aetiology and compared variant frequencies to large public databases. From 36 European patients, we identify two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants are enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio = 131, P = 1 × 10 -4 ). We find similar results in non-Finnish European (n = 348, odds ratio = 43, P = 5 × 10 -5 ) and Finnish (n = 80, odds ratio = 22, P = 1 × 10 -6 ) replication cohorts. RFX6 heterozygotes have reduced penetrance of diabetes compared to common HNF1A and HNF4A-MODY mutations (27, 70 and 55% at 25 years of age, respectively). The hyperglycaemia results from beta-cell dysfunction and is associated with lower fasting and stimulated gastric inhibitory polypeptide (GIP) levels. Our study demonstrates that heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.Maturity-onset diabetes of the young (MODY) is the most common subtype of familial diabetes. Here, Patel et al. use targeted DNA sequencing of MODY patients and large-scale publically available data to show that RFX6 heterozygous protein truncating variants cause reduced penetrance MODY.

  19. The effect of social environment on markers of vascular oxidative stress and inflammation in the Watanabe heritable hyperlipidemic rabbit.

    Science.gov (United States)

    Nation, Daniel A; Gonzales, Julie A; Mendez, Armando J; Zaias, Julia; Szeto, Angela; Brooks, Larry G; Paredes, Jamespaul; D'Angola, Alyssa; Schneiderman, Neil; McCabe, Philip M

    2008-04-01

    Previous research demonstrated that social environment can influence progression of atherosclerosis in the Watanabe Heritable Hyperlipidemic (WHHL) rabbit. This study examined the effect of social environment on markers of oxidative stress and inflammation to clarify the physiological pathways potentially responsible for the influence of social environment on disease. WHHL rabbits were assigned to 1 of 3 social groups: an unstable group, in which unfamiliar rabbits were paired daily, with the pairing switched each week; a stable group, in which littermates were paired daily; and an individually-caged group. The stable group engaged in more affiliative social behavior than the unstable group. The unstable group showed more agonistic behavior compared with the stable group and higher C-reactive protein levels than the individually caged group. The individually caged group was behaviorally sedentary, had higher 24-hour urinary catecholamine levels than the other groups, and exhibited higher NAD(P)H-oxidase activity in the aortic arch relative to the stable group. The results suggest that social environment creates distinct behavioral contexts that can affect markers of inflammation and oxidative stress early in the development of atherosclerosis. Specifically, physical inactivity associated with individual caging affects indices of oxidative stress and inflammation. These pathophysiological markers may help to explain behaviorally related differences in the extent of atherosclerosis observed in prior studies.

  20. Age-Dependent Deficits in Fear Learning in Heterozygous BDNF Knock-Out Mice

    Science.gov (United States)

    Endres, Thomas; Lessmann, Volkmar

    2012-01-01

    Beyond its trophic function, the neurotrophin BDNF (brain-derived neurotrophic factor) is well known to crucially mediate synaptic plasticity and memory formation. Whereas recent studies suggested that acute BDNF/TrkB signaling regulates amygdala-dependent fear learning, no impairments of cued fear learning were reported in heterozygous BDNF…

  1. Atm heterozygous mice are more sensitive to radiation-induced cataracts than are their wild-type counterparts

    Science.gov (United States)

    Worgul, Basil V.; Smilenov, Lubomir; Brenner, David J.; Junk, Anna; Zhou, Wei; Hall, Eric J.

    2002-01-01

    It is important to know whether the human population includes genetically predisposed radiosensitive subsets. In vitro studies have shown that cells from individuals homozygous for ataxia telangiectasia (A-T) are much more radiosensitive than cells from unaffected individuals. Although cells heterozygous for the ATM gene (ATM(+/-)) may be slightly more radiosensitive in vitro, it remained to be determined whether the greater susceptibility of ATM(+/-) cells translates into an increased sensitivity for late effects in vivo, though there is a suggestion that radiotherapy patients that are heterozygous for the ATM gene may be more at risk of developing late normal tissue damage. We chose cataractogenesis in the lens as a means to assay for the effects of ATM deficiency in a late-responding tissue. One eye of wild-type, Atm heterozygous and homozygous knockout mice was exposed to 0.5-, 1.0-, 2.0-, or 4.0-Gy x rays. The animals were followed weekly for cataract development by conventional slit-lamp biomicroscopy. Cataract development in the animals of all three groups was strongly dependent on dose. The lenses of homozygous mice were the first to opacify at any given dose. Most important in the present context is that cataracts appeared earlier in the heterozygous versus wild-type animals. The data suggest that ATM heterozygotes in the human population may also be radiosensitive. This may influence the choice of individuals destined to be exposed to higher than normal doses of radiation, such as astronauts, and may also suggest that radiotherapy patients who are ATM heterozygotes could be predisposed to increased late normal tissue damage.

  2. Heterozygous Che-1 KO mice show deficiencies in object recognition memory persistence.

    Science.gov (United States)

    Zalcman, Gisela; Corbi, Nicoletta; Di Certo, Maria Grazia; Mattei, Elisabetta; Federman, Noel; Romano, Arturo

    2016-10-06

    Transcriptional regulation is a key process in the formation of long-term memories. Che-1 is a protein involved in the regulation of gene transcription that has recently been proved to bind the transcription factor NF-κB, which is known to be involved in many memory-related molecular events. This evidence prompted us to investigate the putative role of Che-1 in memory processes. For this study we newly generated a line of Che-1(+/-) heterozygous mice. Che-1 homozygous KO mouse is lethal during development, but Che-1(+/-) heterozygous mouse is normal in its general anatomical and physiological characteristics. We analyzed the behavioral characteristic and memory performance of Che-1(+/-) mice in two NF-κB dependent types of memory. We found that Che-1(+/-) mice show similar locomotor activity and thigmotactic behavior than wild type (WT) mice in an open field. In a similar way, no differences were found in anxiety-like behavior between Che-1(+/-) and WT mice in an elevated plus maze as well as in fear response in a contextual fear conditioning (CFC) and object exploration in a novel object recognition (NOR) task. No differences were found between WT and Che-1(+/-) mice performance in CFC training and when tested at 24h or 7days after training. Similar performance was found between groups in NOR task, both in training and 24h testing performance. However, we found that object recognition memory persistence at 7days was impaired in Che-1(+/-) heterozygous mice. This is the first evidence showing that Che-1 is involved in memory processes. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  3. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype

    NARCIS (Netherlands)

    Toubiana, Julie; Okada, Satoshi; Hiller, Julia; Oleastro, Matias; Lagos Gomez, Macarena; Aldave Becerra, Juan Carlos; Ouachée-Chardin, Marie; Fouyssac, Fanny; Girisha, Katta Mohan; Etzioni, Amos; van Montfrans, Joris M.; Camcioglu, Yildiz; Kerns, Leigh Ann; Belohradsky, Bernd; Blanche, Stéphane; Bousfiha, Aziz; Rodriguez-Gallego, Carlos; Meyts, Isabelle; Kisand, Kai; Reichenbach, Janine; Renner, Ellen D; Rosenzweig, Sergio; Grimbacher, Bodo; van de Veerdonk, Frank L; Traidl-Hoffmann, Claudia; Picard, Capucine; Marodi, Laszlo; Morio, Tomohiro; Kobayashi, Masao; Lilic, Desa; Milner, Joshua D; Holland, Steven; Casanova, Jean-Laurent; Puel, Anne

    2016-01-01

    Since their discovery in patients with autosomal dominant (AD) chronic mucocutaneous candidiasis (CMC) in 2011, heterozygous STAT1 gain-of-function (GOF) mutations have increasingly been identified worldwide. The clinical spectrum associated with them needed to be delineated. We enrolled 274

  4. Whole Genome Sequence of the Heterozygous Clinical Isolate Candida krusei 81-B-5

    Directory of Open Access Journals (Sweden)

    Christina A. Cuomo

    2017-09-01

    Full Text Available Candida krusei is a diploid, heterozygous yeast that is an opportunistic fungal pathogen in immunocompromised patients. This species also is utilized for fermenting cocoa beans during chocolate production. One major concern in the clinical setting is the innate resistance of this species to the most commonly used antifungal drug fluconazole. Here, we report a high-quality genome sequence and assembly for the first clinical isolate of C. krusei, strain 81-B-5, into 11 scaffolds generated with PacBio sequencing technology. Gene annotation and comparative analysis revealed a unique profile of transporters that could play a role in drug resistance or adaptation to different environments. In addition, we show that, while 82% of the genome is highly heterozygous, a 2.0 Mb region of the largest scaffold has undergone loss of heterozygosity. This genome will serve as a reference for further genetic studies of this pathogen.

  5. Novel CLCN7 compound heterozygous mutations in intermediate autosomal recessive osteopetrosis.

    Science.gov (United States)

    Okamoto, Nana; Kohmoto, Tomohiro; Naruto, Takuya; Masuda, Kiyoshi; Komori, Takahide; Imoto, Issei

    2017-01-01

    Osteopetrosis is a heritable disorder of the skeleton that is characterized by increased bone density on radiographs caused by defects in osteoclast formation and function. Mutations in >10 genes are identified as causative for this clinically and genetically heterogeneous disease in humans. We report two novel missense variations in a compound heterozygous state in the CLCN7 gene, detected through targeted exome sequencing, in a 15-year-old Japanese female with intermediate autosomal recessive osteopetrosis.

  6. [A clinical and hereditary analysis of novel complex heterozygous KCNJ1 mutation in a Bartter syndrome type Ⅱ patient].

    Science.gov (United States)

    Li, X Y; Jiang, Y; Xu, L J; Duan, L; Peng, X Y; Chen, L M; Xia, W B; Xing, X P

    2017-10-01

    Bartter syndrome (BS) is a hereditary condition transmitted as an autosomal recessive (Bartter type 1 to 4) or dominant trait (Bartter type 5). The disease associates hypokalemic alkalosis with varying degrees of hypercalciuria. Here we presented a case (BS type Ⅱ) of a 17 years old female presented with polyhydramnios, polyuria, nephrocalcinosis and hypokalemia, which was alleviated after treatment with celecoxib and vitamin D(3). DNA sequencing identified compound heterozygous KCNJ 1 gene mutations, c. 931C >T (p.R311W) and c. 445-446insCCTGAACAC (p.V149Afs, 150X), with the latter a novel mutation. Her father and mother were heterozygous carriers of c. 931C >T (p.R311W) and c. 445-446insCCTGAACAC (p.V149Afs, 150X), respectively. In conclusion, this case of BS type Ⅱ is caused by a novel compound heterozygous KCNJ 1 mutation. Further studies are needed to verify the effect of celecoxib in BS patients.

  7. Primary microcephaly caused by novel compound heterozygous mutations in ASPM.

    Science.gov (United States)

    Okamoto, Nobuhiko; Kohmoto, Tomohiro; Naruto, Takuya; Masuda, Kiyoshi; Imoto, Issei

    2018-01-01

    Autosomal recessive primary microcephaly (microcephaly primary hereditary, MCPH) is a genetically heterogeneous rare developmental disorder that is characterized by prenatal onset of abnormal brain growth, which leads to intellectual disability of variable severity. We report a 5-year-old male who presented with a severe form of primary microcephaly. Targeted panel sequencing revealed compound heterozygous truncating mutations of the abnormal spindle-like microcephaly-associated ( ASPM ) gene, which confirmed the MCPH5 diagnosis. A novel NM_018136.4: c.9742_9745del (p.Lys3248Serfs*13) deletion mutation was identified.

  8. Efficient introduction of specific homozygous and heterozygous mutations using CRISPR/Cas9.

    Science.gov (United States)

    Paquet, Dominik; Kwart, Dylan; Chen, Antonia; Sproul, Andrew; Jacob, Samson; Teo, Shaun; Olsen, Kimberly Moore; Gregg, Andrew; Noggle, Scott; Tessier-Lavigne, Marc

    2016-05-05

    The bacterial CRISPR/Cas9 system allows sequence-specific gene editing in many organisms and holds promise as a tool to generate models of human diseases, for example, in human pluripotent stem cells. CRISPR/Cas9 introduces targeted double-stranded breaks (DSBs) with high efficiency, which are typically repaired by non-homologous end-joining (NHEJ) resulting in nonspecific insertions, deletions or other mutations (indels). DSBs may also be repaired by homology-directed repair (HDR) using a DNA repair template, such as an introduced single-stranded oligo DNA nucleotide (ssODN), allowing knock-in of specific mutations. Although CRISPR/Cas9 is used extensively to engineer gene knockouts through NHEJ, editing by HDR remains inefficient and can be corrupted by additional indels, preventing its widespread use for modelling genetic disorders through introducing disease-associated mutations. Furthermore, targeted mutational knock-in at single alleles to model diseases caused by heterozygous mutations has not been reported. Here we describe a CRISPR/Cas9-based genome-editing framework that allows selective introduction of mono- and bi-allelic sequence changes with high efficiency and accuracy. We show that HDR accuracy is increased dramatically by incorporating silent CRISPR/Cas-blocking mutations along with pathogenic mutations, and establish a method termed 'CORRECT' for scarless genome editing. By characterizing and exploiting a stereotyped inverse relationship between a mutation's incorporation rate and its distance to the DSB, we achieve predictable control of zygosity. Homozygous introduction requires a guide RNA targeting close to the intended mutation, whereas heterozygous introduction can be accomplished by distance-dependent suboptimal mutation incorporation or by use of mixed repair templates. Using this approach, we generated human induced pluripotent stem cells with heterozygous and homozygous dominant early onset Alzheimer's disease-causing mutations in

  9. Heterozygous CAV1 frameshift mutations (MIM 601047 in patients with atypical partial lipodystrophy and hypertriglyceridemia

    Directory of Open Access Journals (Sweden)

    Alston Lindsay

    2008-01-01

    Full Text Available Abstract Background Mice with a deleted Cav1 gene encoding caveolin-1 develop adipocyte abnormalities and insulin resistance. From genomic DNA of patients with atypical lipodystrophy and hypertriglyceridemia who had no mutations in any known lipodystrophy gene, we used DNA sequence analysis to screen the coding regions of human CAV1 (MIM 601047. Results We found a heterozygous frameshift mutation in CAV1, designated I134fsdelA-X137, in a female patient who had atypical partial lipodystrophy, with subcutaneous fat loss affecting the upper part of her body and face, but sparing her legs, gluteal region and visceral fat stores. She had severe type 5 hyperlipoproteinemia, with recurrent pancreatitis. In addition, she had some atypical features, including congenital cataracts and neurological findings. Her father was also heterozygous for this mutation, and had a similar pattern of fat redistribution, hypertriglyceridemia and congenital cataracts, with milder neurological involvement. An unrelated patient had a different heterozygous frameshift mutation in the CAV1 gene, designated -88delC. He also had a partial lipodystrophy phenotype, with subcutaneous fat loss affecting the arms, legs and gluteal region, but sparing his face, neck and visceral fat stores. He also had severe type 5 hyperlipoproteinemia, with recurrent pancreatitis; however he had no clinically apparent neurological manifestations. The mutations were absent from the genomes of 1063 healthy individuals. Conclusion Thus, very rare CAV1 frameshift mutations appear to be associated with atypical lipodystrophy and hypertriglyceridemia.

  10. Phytosterols and atherosclerosis

    DEFF Research Database (Denmark)

    Schrøder, Malene

    Cardiovascular disease (CVD) is the major cause of premature deaths worldwide. Coronary heart disease is the most common CVD, caused by atherosclerosis in the coronary arteries. Atherosclerosis is a multifactorial disease influenced by both genetic and environmental factors. WHO has in 2007 listed...... in its “Guidelines for assessment and management of cardiovascular risk” the following risk factors to influence progressive atherosclerosis: hypertension, abnormal blood lipids, diabetes, unhealthy diet, physical inactivity and smoking. Phytosterols (plant sterols and plant stanols) are known...... their blood cholesterol levels. The aim of this Ph.D. project was to investigate the effects of phytosterols on the development of atherosclerosis in the aorta of heterozygous Watanabe Heritable Hyperlipidemic (WHHL) rabbits. The main advantage of animal studies to human studies in atherosclerosis research...

  11. Heterozygous deficiency of endoglin decreases insulin and hepatic triglyceride levels during high fat diet.

    Directory of Open Access Journals (Sweden)

    Daniel Beiroa

    Full Text Available Endoglin is a transmembrane auxiliary receptor for transforming growth factor-beta (TGF-beta that is predominantly expressed on proliferating endothelial cells. It plays a wide range of physiological roles but its importance on energy balance or insulin sensitivity has been unexplored. Endoglin deficient mice die during midgestation due to cardiovascular defects. Here we report for first time that heterozygous endoglin deficiency in mice decreases high fat diet-induced hepatic triglyceride content and insulin levels. Importantly, these effects are independent of changes in body weight or adiposity. At molecular level, we failed to detect relevant changes in the insulin signalling pathway at basal levels in liver, muscle or adipose tissues that could explain the insulin-dependent effect. However, we found decreased triglyceride content in the liver of endoglin heterozygous mice fed a high fat diet in comparison to their wild type littermates. Overall, our findings indicate that endoglin is a potentially important physiological mediator of insulin levels and hepatic lipid metabolism.

  12. Heterozygous deletion at the SOX10 gene locus in two patients from a Chinese family with Waardenburg syndrome type II.

    Science.gov (United States)

    Wenzhi, He; Ruijin, Wen; Jieliang, Li; Xiaoyan, Ma; Haibo, Liu; Xiaoman, Wang; Jiajia, Xian; Shaoying, Li; Shuanglin, Li; Qing, Li

    2015-10-01

    Waardenburg syndrome (WS) is a rare disease characterized by sensorineural deafness and pigment disturbance. To date, almost 100 mutations have been reported, but few reports on cases with SOX10 gene deletion. The inheritance pattern of SOX10 gene deletion is still unclear. Our objective was to identify the genetic causes of Waardenburg syndrome type II in a two-generation Chinese family. Clinical evaluations were conducted in both of the patients. Microarray analysis and multiplex ligation-dependent probe amplification (MLPA) were performed to identify disease-related copy number variants (CNVs). DNA sequencing of the SOX10, MITF and SNAI2 genes was performed to identify the pathogenic mutation responsible for WS2. A 280kb heterozygous deletion at the 22q13.1 chromosome region (including SOX10) was detected in both of the patients. No mutation was found in the patients, unaffected family members and 30 unrelated healthy controls. This report is the first to describe SOX10 heterozygous deletions in Chinese WS2 patients. Our result conform the thesis that heterozygous deletions at SOX10 is an important pathogenicity for WS, and present as autosomal dominant inheritance. Nevertheless, heterozygous deletion of the SOX10 gene would be worth investigating to understand their functions and contributions to neurologic phenotypes. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  13. Electroclinical presentation and genotype-phenotype relationships in patients with Unverricht-Lundborg disease carrying compound heterozygous CSTB point and indel mutations.

    Science.gov (United States)

    Canafoglia, Laura; Gennaro, Elena; Capovilla, Giuseppe; Gobbi, Giuseppe; Boni, Antonella; Beccaria, Francesca; Viri, Maurizio; Michelucci, Roberto; Agazzi, Pamela; Assereto, Stefania; Coviello, Domenico A; Di Stefano, Maria; Rossi Sebastiano, Davide; Franceschetti, Silvana; Zara, Federico

    2012-12-01

    Unverricht-Lundborg disease (EPM1A) is frequently due to an unstable expansion of a dodecamer repeat in the CSTB gene, whereas other types of mutations are rare. EPM1A due to homozygous expansion has a rather stereotyped presentation with prominent action myoclonus. We describe eight patients with five different compound heterozygous CSTB point or indel mutations in order to highlight their particular phenotypical presentations and evaluate their genotype-phenotype relationships. We screened CSTB mutations by means of Southern blotting and the sequencing of the genomic DNA of each proband. CSTB messenger RNA (mRNA) aberrations were characterized by sequencing the complementary DNA (cDNA) of lymphoblastoid cells, and assessing the protein concentrations in the lymphoblasts. The patient evaluations included the use of a simplified myoclonus severity rating scale, multiple neurophysiologic tests, and electroencephalography (EEG)-polygraphic recordings. To highlight the particular clinical features and disease time-course in compound heterozygous patients, we compared some of their characteristics with those observed in a series of 40 patients carrying the common homozygous expansion mutation observed at the C. Besta Foundation, Milan, Italy. The eight compound heterozygous patients belong to six EPM1A families (out of 52; 11.5%) diagnosed at the Laboratory of Genetics of the Galliera Hospitals in Genoa, Italy. They segregated five different heterozygous point or indel mutations in association with the common dodecamer expansion. Four patients from three families had previously reported CSTB mutations (c.67-1G>C and c.168+1_18del); one had a novel nonsense mutation at the first exon (c.133C>T) leading to a premature stop codon predicting a short peptide; the other three patients from two families had a complex novel indel mutation involving the donor splice site of intron 2 (c.168+2_169+21delinsAA) and leading to an aberrant transcript with a partially retained intron

  14. A novel heterozygous SOX2 mutation causing congenital bilateral anophthalmia, hypogonadotropic hypogonadism and growth hormone deficiency.

    Science.gov (United States)

    Macchiaroli, Annamaria; Kelberman, Daniel; Auriemma, Renata Simona; Drury, Suzanne; Islam, Lily; Giangiobbe, Sara; Ironi, Gabriele; Lench, Nicholas; Sowden, Jane C; Colao, Annamaria; Pivonello, Rosario; Cavallo, Luciano; Gasperi, Maurizio; Faienza, Maria Felicia

    2014-01-25

    Heterozygous de novo mutations in SOX2 have been reported in approximately 10-20% of patients with unilateral or bilateral anophthalmia or microphthalmia. An additional phenotype of hypopituitarism, with anterior pituitary hypoplasia and hypogonadotropic hypogonadism, has been reported in patients carrying SOX2 alterations. We report a novel heterozygous mutation in the SOX2 gene in a male affected with congenital bilateral anophthalmia, hypogonadotrophic hypogonadism and growth hormone deficiency. The mutation we describe is a cytosine deletion in position 905 (c905delC) which causes frameshift and an aberrant C-terminal domain. Our report highlights the fact that subjects affected with eye anomalies and harboring SOX2 mutations are at high risk for gonadotropin deficiency, which has important implications for their clinical management. Copyright © 2013 Elsevier B.V. All rights reserved.

  15. Atherosclerosis in Watanabe heritable hyperlipidaemic rabbits. Evaluation by macroscopic, microscopic and biochemical methods and comparison of atherosclerosis variables

    DEFF Research Database (Denmark)

    Hansen, B F; Mortensen, A; Hansen, J F

    1994-01-01

    estimation of aortic atherosclerosis extent and by biochemical analysis of aortic cholesterol content. No noteworthy atherosclerosis was demonstrated within 19 months in heterozygous rabbits. In homozygous rabbits, atherosclerotic lesions were seen from the age of 4 months and progressed with age. All 19......-month-old rabbits had severe atherosclerotic disease. As much as 64% of the variation in atherosclerosis extent/severity could be explained by serum cholesterol and age. A highly significant correlation between the various methods for quantitation of atherosclerosis extent and/or severity...... was demonstrated, suggesting that quantitative microscopy, macroscopic morphometry and determination of aortic cholesterol content may be equally valid as a measure of atherosclerosis in WHHL rabbits and are therefore interchangeable....

  16. Duchenne muscular dystrophy in a female with compound heterozygous contiguous exon deletions.

    Science.gov (United States)

    Takeshita, Eri; Minami, Narihiro; Minami, Kumiko; Suzuki, Mikiya; Awashima, Takeya; Ishiyama, Akihiko; Komaki, Hirofumi; Nishino, Ichizo; Sasaki, Masayuki

    2017-06-01

    Females with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) mutations rarely exhibit clinical symptoms from childhood, although potential mechanisms for symptoms associated with DMD and BMD in females have been reported. We report the case of a female DMD patient with a clinical course indistinguishable from that of a male DMD patient, and who possessed compound heterozygous contiguous exon deletions in the dystrophin gene. She exhibited Gowers' sign, calf muscle hypertrophy, and a high serum creatine kinase level at 2 years. Her muscle pathology showed most of the fibers were negative for dystrophin immunohistochemical staining. She lost ambulation at 11 years. Multiplex ligation-dependent probe amplification analysis of this gene detected one copy of exons 48-53; she was found to be a BMD carrier with an in-frame deletion. Messenger RNA from her muscle demonstrated out-of-frame deletions of exons 48-50 and 51-53 occurring on separate alleles. Genomic DNA from her lymphocytes demonstrated the accurate deletion region on each allele. To our knowledge, this is the first report on a female patient possessing compound heterozygous contiguous exon deletions in the dystrophin gene, leading to DMD. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Intrafamiliar clinical variability of circumferential skin creases Kunze type caused by a novel heterozygous mutation of N-terminal TUBB gene.

    Science.gov (United States)

    Dentici, M L; Terracciano, A; Bellacchio, E; Capolino, R; Novelli, A; Digilio, M C; Dallapiccola, B

    2018-02-10

    Circumferential skin creases Kunze type (CSC-KT; OMIM 156610, 616734) is a rare disorder characterized by folding of excess skin, which leads to ringed creases, known as Michelin Tire Baby Syndrome (MTBS). CSC-KT patients also exhibit facial dysmorphism, growth retardation, intellectual disability (ID) and multiple congenital malformations. Recently, 2 heterozygous mutations in TUBB gene and 4 mutations (both homozygous and heterozygous) in MAPRE2 gene were identified in 3 and 4 CSC-KT patients, respectively. In the 3 TUBB gene-related CSC-KT patients, all mutations fall in the N-terminal gene domain and were de novo. Mutations in the C-terminal of TUBB gene have been associated to microcephaly and structural brain malformation, in the absence of CSC-KT features. We report a 9-year-old boy with a diagnosis of CSC-KT based on MTBS, facial dysmorphism, microcephaly, severe ID, cortical atrophy and corpus callosum hypoplasia. Sanger sequencing identified a novel heterozygous c.218T>C (p.Met73Thr) mutation in the N-terminal of TUBB gene, that was inherited from the mother affected by isolated MTBS. This is the first report of inherited TUBB gene-related CSC-KT resulting from a novel heterozygous mutation in the N-terminal domain. Present data support the role of TUBB mutations in CSC-KT and definitely includes CSC-KT syndrome within the tubulinopathies. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. A new compound heterozygous CFTR mutation in a Chinese family with cystic fibrosis.

    Science.gov (United States)

    Xie, Yingjun; Huang, Xueqiong; Liang, Yujian; Xu, Lingling; Pei, Yuxin; Cheng, Yucai; Zhang, Lidan; Tang, Wen

    2017-11-01

    Cystic fibrosis (CF) is the most common autosomal recessive disease among Caucasians but is rarer in the Chinese population, because mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. To elucidate the causative role of a novel compound heterozygous mutation of CF. In this study, clinical samples were obtained from two siblings with recurrent airway infections, clubbed fingers, salt-sweat and failure to gain weight in a non-consanguineous Chinese family. Next-generation sequencing was performed on the 27 coding exons of CFTR in both children, with confirmation by Sanger sequencing. Next-generation sequencing showed the same compound heterozygous CFTR mutation (c.865A>T p.Arg289X and c.3651_3652insAAAT p.Tyr1219X) in both children. As this mutation is consistent with the clinical manifestations of CF and no other mutations were detected after scanning the gene sequence, we suggest that the CF phenotype is caused by compound heterozygosity for c.865A>T and c.3651_3652insAAAT. As c865A>T is not currently listed in the "Cystic Fibrosis Mutation Database", this information about CF in a Chinese population is of interest. © 2015 John Wiley & Sons Ltd.

  19. Compound heterozygous ASPM mutations in Pakistani MCPH families

    DEFF Research Database (Denmark)

    Muhammad, Farooq; Mahmood Baig, Shahid; Hansen, Lars

    2009-01-01

    Autosomal recessive primary microcephaly (MCPH) is characterized by reduced head circumference (50% of all reported families. In spite of the high frequency of MCPH in Pakistan only one case of compound heterozygosity for mutations in ASPM has been reported yet. In this large MCPH study we...... confirmed compound heterozygosity in two and homozygous mutations in 20 families, respectively, showing that up to 10% of families with MCPH caused by ASPM are compound heterozygous. In total we identified 16 different nonsense or frameshift mutations of which 12 were novel thereby increasing the number...... of mutations in ASPM significantly from 35 to 47. We found no correlation between the severity of the condition and the site of truncation. We suggest that the high frequency of compound heterozygosity observed in this study is taken into consideration as part of future genetic testing and counseling...

  20. Early-Onset X-Linked Retinitis Pigmentosa in a Heterozygous Female Harboring an Intronic Donor Splice Site Mutation in the Retinitis Pigmentosa GTPase Regulator Gene.

    Science.gov (United States)

    Shifera, Amde Selassie; Kay, Christine Nichols

    2015-01-01

    To report a heterozygous female presenting with an early-onset and severe form of X-linked retinitis pigmentosa (XLRP). This is a case series presenting the clinical findings in a heterozygous female with XLRP and two of her family members. Fundus photography, fundus autofluorescence, ocular coherence tomography, and visual perimetry are presented. The proband reported here is a heterozygous female who presented at the age of 8 years with an early onset and aggressive form of XLRP. The patient belongs to a four-generation family with a total of three affected females and four affected males. The patient was initially diagnosed with retinitis pigmentosa (RP) at the age of 4 years. Genetic testing identified a heterozygous donor splice site mutation in intron 1 (IVS1 + 1G > A) of the retinitis pigmentosa GTPase regulator gene. The father of the proband was diagnosed with RP when he was a young child. The sister of the proband, evaluated at the age of 6 years, showed macular pigmentary changes. Although carriers of XLRP are usually asymptomatic or have a mild disease of late onset, the proband presented here exhibited an early-onset, aggressive form of the disease. It is not clear why some carrier females manifest a severe phenotype. A better understanding of the genetic processes involved in the penetrance and expressivity of XLRP in heterozygous females could assist in providing the appropriate counseling to affected families.

  1. A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis.

    Science.gov (United States)

    Olson, Heather E; Jean-Marçais, Nolwenn; Yang, Edward; Heron, Delphine; Tatton-Brown, Katrina; van der Zwaag, Paul A; Bijlsma, Emilia K; Krock, Bryan L; Backer, E; Kamsteeg, Erik-Jan; Sinnema, Margje; Reijnders, Margot R F; Bearden, David; Begtrup, Amber; Telegrafi, Aida; Lunsing, Roelineke J; Burglen, Lydie; Lesca, Gaetan; Cho, Megan T; Smith, Lacey A; Sheidley, Beth R; Moufawad El Achkar, Christelle; Pearl, Phillip L; Poduri, Annapurna; Skraban, Cara M; Tarpinian, Jennifer; Nesbitt, Addie I; Fransen van de Putte, Dietje E; Ruivenkamp, Claudia A L; Rump, Patrick; Chatron, Nicolas; Sabatier, Isabelle; De Bellescize, Julitta; Guibaud, Laurent; Sweetser, David A; Waxler, Jessica L; Wierenga, Klaas J; Donadieu, Jean; Narayanan, Vinodh; Ramsey, Keri M; Nava, Caroline; Rivière, Jean-Baptiste; Vitobello, Antonio; Tran Mau-Them, Frédéric; Philippe, Christophe; Bruel, Ange-Line; Duffourd, Yannis; Thomas, Laurel; Lelieveld, Stefan H; Schuurs-Hoeijmakers, Janneke; Brunner, Han G; Keren, Boris; Thevenon, Julien; Faivre, Laurence; Thomas, Gary; Thauvin-Robinet, Christel

    2018-05-03

    Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Both proteins harbor cargo(furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase. Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control. Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function. These findings support the causality of this recurrent de novo PACS2 heterozygous missense in DEEs with facial dysmorphim and cerebellar dysgenesis. Copyright © 2018 American Society of Human Genetics. All rights reserved.

  2. Novel compound heterozygous mutations of ALDH1A3 contribute to anophthalmia in a non-consanguineous Chinese family

    Directory of Open Access Journals (Sweden)

    Yunqiang Liu

    2017-06-01

    Full Text Available Abstract Anophthalmia is a rare eye development anomaly resulting in absent ocular globes or tissue in the orbit since birth. Here, we investigated a newborn with bilateral anophthalmia in a Chinese family. Exome sequencing revealed that compound heterozygous mutations c.287G > A (p.(Arg96His and c.709G > A (p.(Gly237Arg of the ALDH1A3 gene were present in the affected newborn. Both mutations were absent in all of the searched databases, including 10,000 in-house Chinese exome sequences, and these mutations were confirmed as having been transmitted from the parents. Comparative amino acid sequence analysis across distantly related species revealed that the residues at positions 96 and 234 were evolutionarily highly conserved. In silico analysis predicted these changes to be damaging, and in vitro expression analysis revealed that the mutated alleles were associated with decreased protein production and impaired tetrameric protein formation. This study firstly reported that compound heterozygous mutations of the ALDH1A3 gene can result in anophthalmia in humans, thus highlighting those heterozygous mutations in ALDH1A3 should be considered for molecular screening in anophthalmia, particularly in cases from families without consanguineous relationships.

  3. Comparison of Spectrophotometry, Chromate Inhibition, and Cytofluorometry Versus Gene Sequencing for Detection of Heterozygously Glucose-6-Phosphate Dehydrogenase-Deficient Females.

    Science.gov (United States)

    Peters, Anna L; Veldthuis, Martijn; van Leeuwen, Karin; Bossuyt, Patrick M M; Vlaar, Alexander P J; van Bruggen, Robin; de Korte, Dirk; Van Noorden, Cornelis J F; van Zwieten, Rob

    2017-11-01

    Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme deficiency worldwide. Detection of heterozygously deficient females can be difficult as residual activity in G6PD-sufficient red blood cells (RBCs) can mask deficiency. In this study, we compared accuracy of 4 methods for detection of G6PD deficiency in females. Blood samples from females more than 3 months of age were used for spectrophotometric measurement of G6PD activity and for determination of the percentage G6PD-negative RBCs by cytofluorometry. An additional sample from females suspected to have G6PD deficiency based on the spectrophotometric G6PD activity was used for measuring chromate inhibition and sequencing of the G6PD gene. Of 165 included females, 114 were suspected to have heterozygous deficiency. From 75 females, an extra sample was obtained. In this group, mutation analysis detected 27 heterozygously deficient females. The sensitivity of spectrophotometry, cytofluorometry, and chromate inhibition was calculated to be 0.52 (confidence interval [CI]: 0.32-0.71), 0.85 (CI: 0.66-0.96), and 0.96 (CI: 0.71-1.00, respectively, and the specificity was 1.00 (CI: 0.93-1.00), 0.88 (CI: 0.75-0.95), and 0.98 (CI: 0.89-1.00), respectively. Heterozygously G6PD-deficient females with a larger percentage of G6PD-sufficient RBCs are missed by routine methods measuring total G6PD activity. However, the majority of these females can be detected with both chromate inhibition and cytofluorometry.

  4. Heterozygous Hfe gene deletion leads to impaired glucose homeostasis, but not liver injury in mice fed a high-calorie diet.

    Science.gov (United States)

    Britton, Laurence; Jaskowski, Lesley; Bridle, Kim; Santrampurwala, Nishreen; Reiling, Janske; Musgrave, Nick; Subramaniam, V Nathan; Crawford, Darrell

    2016-06-01

    Heterozygous mutations of the Hfe gene have been proposed as cofactors in the development and progression of nonalcoholic fatty liver disease (NAFLD). Homozygous Hfe deletion previously has been shown to lead to dysregulated hepatic lipid metabolism and accentuated liver injury in a dietary mouse model of NAFLD We sought to establish whether heterozygous deletion of Hfe is sufficient to promote liver injury when mice are exposed to a high-calorie diet (HCD). Eight-week-old wild-type and Hfe(+/-) mice received 8 weeks of a control diet or HCD Liver histology and pathways of lipid and iron metabolism were analyzed. Liver histology demonstrated that mice fed a HCD had increased NAFLD activity score (NAS), steatosis, and hepatocyte ballooning. However, liver injury was unaffected by Hfe genotype. Hepatic iron concentration (HIC) was increased in Hfe(+/-) mice of both dietary groups. HCD resulted in a hepcidin-independent reduction in HIC Hfe(+/-) mice demonstrated raised fasting serum glucose concentrations and HOMA-IR score, despite unaltered serum adiponectin concentrations. Downstream regulators of hepatic de novo lipogenesis (pAKT, SREBP-1, Fas, Scd1) and fatty acid oxidation (AdipoR2, Pparα, Cpt1) were largely unaffected by genotype. In summary, heterozygous Hfe gene deletion is associated with impaired iron and glucose metabolism. However, unlike homozygous Hfe deletion, heterozygous gene deletion did not affect lipid metabolism pathways or liver injury in this model. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  5. Novel compound heterozygous mutations in MYO7A gene associated with autosomal recessive sensorineural hearing loss in a Chinese family.

    Science.gov (United States)

    Ma, Yalin; Xiao, Yun; Zhang, Fengguo; Han, Yuechen; Li, Jianfeng; Xu, Lei; Bai, Xiaohui; Wang, Haibo

    2016-04-01

    Mutations in MYO7A gene have been reported to be associated with Usher Syndrome type 1B (USH1B) and nonsyndromic hearing loss (DFNB2, DFNA11). Most mutations in MYO7A gene caused USH1B, whereas only a few reported mutations led to DFNB2 and DFNA11. The current study was designed to investigate the mutations among a Chinese family with autosomal recessive hearing loss. In this study, we present the clinical, genetic and molecular characteristics of a Chinese family. Targeted capture of 127 known deafness genes and next-generation sequencing were employed to study the genetic causes of two siblings in the Chinese family. Sanger sequencing was employed to examine those variant mutations in the members of this family and other ethnicity-matched controls. We identified the novel compound heterozygous mutant alleles of MYO7A gene: a novel missense mutation c.3671C>A (p.A1224D) and a reported insert mutation c.390_391insC (p.P131PfsX9). Variants were further confirmed by Sanger sequencing. These two compound heterozygous variants were co-segregated with autosomal recessive hearing loss phenotype. The gene mutation analysis and protein sequence alignment further supported that the novel compound heterozygous mutations were pathogenic. The novel compound heterozygous mutations (c.3671C>A and c.390_391insC) in MYO7A gene identified in this study were responsible for the autosomal recessive sensorineural hearing loss of this Chinese family. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  6. The Coexpression of Reelin and Neuronal Nitric Oxide Synthase in a Subpopulation of Dentate Gyrus Neurons Is Downregulated in Heterozygous Reeler Mice

    Directory of Open Access Journals (Sweden)

    Raquel Romay-Tallón

    2010-01-01

    Full Text Available Reelin is an extracellular matrix protein expressed in several interneuron subtypes in the hippocampus and dentate gyrus. Neuronal nitric oxide synthase (nNOS is also expressed by interneurons in these areas. We investigated whether reelin and nNOS are co-localized in the same population of hippocampal interneurons, and whether this colocalization is altered in the heterozygous reeler mouse. We found colocalization of nNOS in reelin-positive cells in the CA1 stratum radiatum and lacunosum moleculare, the CA3 stratum radiatum, and the dentate gyrus subgranular zone, molecular layer, and hilus. In heterozygous reeler mice, the colocalization of nNOS in reelin-positive cells was significantly decreased only in the subgranular zone and molecular layer. The coexpression of reelin and nNOS in several hippocampal regions suggests that reelin and nNOS may work synergistically to promote glutamatergic function, and the loss of this coexpression in heterozygous reeler mice may underlie some of the behavioral deficits observed in these animals.

  7. Heterozygous loss of TSC2 alters p53 signaling and human stem cell reprogramming.

    Science.gov (United States)

    Armstrong, Laura C; Westlake, Grant; Snow, John P; Cawthon, Bryan; Armour, Eric; Bowman, Aaron B; Ess, Kevin C

    2017-12-01

    Tuberous sclerosis complex (TSC) is a pediatric disorder of dysregulated growth and differentiation caused by loss of function mutations in either the TSC1 or TSC2 genes, which regulate mTOR kinase activity. To study aberrations of early development in TSC, we generated induced pluripotent stem cells using dermal fibroblasts obtained from patients with TSC. During validation, we found that stem cells generated from TSC patients had a very high rate of integration of the reprogramming plasmid containing a shRNA against TP53. We also found that loss of one allele of TSC2 in human fibroblasts is sufficient to increase p53 levels and impair stem cell reprogramming. Increased p53 was also observed in TSC2 heterozygous and homozygous mutant human stem cells, suggesting that the interactions between TSC2 and p53 are consistent across cell types and gene dosage. These results support important contributions of TSC2 heterozygous and homozygous mutant cells to the pathogenesis of TSC and the important role of p53 during reprogramming. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  8. Unusual xanthomas in a young patient with heterozygous familial hypercholesterolemia and type III hyperlipoproteinemia

    Energy Technology Data Exchange (ETDEWEB)

    Feussner, G.; Dobmeyer, J. [Univ. of Heidelberg (Germany); Nissen, H.; Hansen, T.S. [Odense Univ. Hospital (Denmark)

    1996-10-16

    We report on a 20-year-old man with the combination of two independent familial lipoprotein disorders: heterozygous familial hypercholesterolemia (FH) and type III hyperlipoproteinemia (HLP). Familial hypercholesterolemia was diagnosed by elevated total and low density lipoprotein cholesterol levels and family history. By denaturing gradient gel electrophoresis, DNA sequencing and restriction fragment length polymorphism analysis, a G{r_arrow}A splice donor mutation in intron 3 of the proband`s low density lipoprotein receptor gene was identified as the underlying molecular defect. This mutation was described previously as a receptor-negative founder mutation in Norway (FH-Elverum) and subsequently in 6 unrelated heterozygous English patients, creating a severe phenotype of familial hypercholesterolemia. Type III HLP was confirmed by homozygosity for apolipoprotein (apo) E2 and an elevated ratio of very low density lipoprotein cholesterol to serum triglycerides (0.40; normal ratio about 0.20). The patient has unusual flat xanthomas in the interdigital webs of the hands which are normally not found in either disease. These dermatological findings might therefore be indicative of the rare combination of both disorders of lipoprotein metabolism in one individual. 29 refs., 5 figs., 1 tab.

  9. Heterozygous and homozygous JAK2(V617F states modeled by induced pluripotent stem cells from myeloproliferative neoplasm patients.

    Directory of Open Access Journals (Sweden)

    Joseph Saliba

    Full Text Available JAK2(V617F is the predominant mutation in myeloproliferative neoplasms (MPN. Modeling MPN in a human context might be helpful for the screening of molecules targeting JAK2 and its intracellular signaling. We describe here the derivation of induced pluripotent stem (iPS cell lines from 2 polycythemia vera patients carrying a heterozygous and a homozygous mutated JAK2(V617F, respectively. In the patient with homozygous JAK2(V617F, additional ASXL1 mutation and chromosome 20 allowed partial delineation of the clonal architecture and assignation of the cellular origin of the derived iPS cell lines. The marked difference in the response to erythropoietin (EPO between homozygous and heterozygous cell lines correlated with the constitutive activation level of signaling pathways. Strikingly, heterozygous iPS cells showed thrombopoietin (TPO-independent formation of megakaryocytic colonies, but not EPO-independent erythroid colony formation. JAK2, PI3K and HSP90 inhibitors were able to block spontaneous and EPO-induced growth of erythroid colonies from GPA(+CD41(+ cells derived from iPS cells. Altogether, this study brings the proof of concept that iPS can be used for studying MPN pathogenesis, clonal architecture, and drug efficacy.

  10. Detection of compound heterozygous of hb constant spring and hb q-Thailand by capillary electrophoresis and high performance liquid chromatography.

    Science.gov (United States)

    Pornprasert, Sakorn; Punyamung, Manoo

    2015-06-01

    A capillary electrophoresis (CE) has proven to be superior to a high performance liquid chromatography (HPLC) in the detection of hemoglobin Constant Spring (Hb CS). Thus the aim of this study was to analyze the efficacy of CE and HPLC for the detection of Hb CS in samples with compound heterozygous of Hb CS and Hb Q-Thailand. Hemoglobin analysis was performed in blood samples of 2 patients with compound heterozygous of Hb CS and Hb Q-Thailand by using HPLC and CE. The HPLC chromatogram and CE electrophoregram of the two techniques were compared. Hb CS was not found on HPLC chromatogram while Hb QA2 (α2 (QT)δ2), a derivative of Hb Q-Thailand, was presented at the retention time of 4.70-4.80 min and it was close to the retention time of Hb CS. On CE electrophoregram, Hb CS was presented at zone 2 (Z2) and it was distinctly separated from Hb QA2 which was presented at Z1. Therefore, CE was more efficient to the HPLC for diagnosis of compound heterozygous of Hb CS and Hb Q-Thailand.

  11. Compound heterozygous TYK2 mutations underlie primary immunodeficiency with T-cell lymphopenia.

    Science.gov (United States)

    Nemoto, Michiko; Hattori, Hiroyoshi; Maeda, Naoko; Akita, Nobuhiro; Muramatsu, Hideki; Moritani, Suzuko; Kawasaki, Tomonori; Maejima, Masami; Ode, Hirotaka; Hachiya, Atsuko; Sugiura, Wataru; Yokomaku, Yoshiyuki; Horibe, Keizo; Iwatani, Yasumasa

    2018-05-03

    Complete tyrosine kinase 2 (TYK2) deficiency has been previously described in patients with primary immunodeficiency diseases. The patients were infected with various pathogens, including mycobacteria and/or viruses, and one of the patients developed hyper-IgE syndrome. A detailed immunological investigation of these patients revealed impaired responses to type I IFN, IL-10, IL-12 and IL-23, which are associated with increased susceptibility to mycobacterial and/or viral infections. Herein, we report a recessive partial TYK2 deficiency in two siblings who presented with T-cell lymphopenia characterized by low naïve CD4 + T-cell counts and who developed Epstein-Barr virus (EBV)-associated B-cell lymphoma. Targeted exome-sequencing of the siblings' genomes demonstrated that both patients carried novel compound heterozygous mutations (c.209_212delGCTT/c.691C > T, p.Cys70Serfs*21/p.Arg231Trp) in the TYK2. The TYK2 protein levels were reduced by 35% in the T cells of the patient. Unlike the response under complete TYK2 deficiency, the patient's T cells responded normally to type I IFN, IL-6, IL-10 and IL-12, whereas the cells displayed an impaired response to IL-23. Furthermore, the level of STAT1 was low in the cells of the patient. These studies reveal a new clinical entity of a primary immunodeficiency with T-cell lymphopenia that is associated with compound heterozygous TYK2 mutations in the patients.

  12. Personalized Stem Cell Therapy to Correct Corneal Defects Due to a Unique Homozygous-Heterozygous Mosaicism of Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome.

    Science.gov (United States)

    Barbaro, Vanessa; Nasti, Annamaria Assunta; Raffa, Paolo; Migliorati, Angelo; Nespeca, Patrizia; Ferrari, Stefano; Palumbo, Elisa; Bertolin, Marina; Breda, Claudia; Miceli, Francesco; Russo, Antonella; Caenazzo, Luciana; Ponzin, Diego; Palù, Giorgio; Parolin, Cristina; Di Iorio, Enzo

    2016-08-01

    : Ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome is a rare autosomal dominant disease caused by mutations in the p63 gene. To date, approximately 40 different p63 mutations have been identified, all heterozygous. No definitive treatments are available to counteract and resolve the progressive corneal degeneration due to a premature aging of limbal epithelial stem cells. Here, we describe a unique case of a young female patient, aged 18 years, with EEC and corneal dysfunction, who was, surprisingly, homozygous for a novel and de novo R311K missense mutation in the p63 gene. A detailed analysis of the degree of somatic mosaicism in leukocytes from peripheral blood and oral mucosal epithelial stem cells (OMESCs) from biopsies of buccal mucosa showed that approximately 80% were homozygous mutant cells and 20% were heterozygous. Cytogenetic and molecular analyses excluded genomic alterations, thus suggesting a de novo mutation followed by an allelic gene conversion of the wild-type allele by de novo mutant allele as a possible mechanism to explain the homozygous condition. R311K-p63 OMESCs were expanded in vitro and heterozygous holoclones selected following clonal analysis. These R311K-p63 OMESCs were able to generate well-organized and stratified epithelia in vitro, resembling the features of healthy tissues. This study supports the rationale for the development of cultured autologous oral mucosal epithelial stem cell sheets obtained by selected heterozygous R311K-p63 stem cells, as an effective and personalized therapy for reconstructing the ocular surface of this unique case of EEC syndrome, thus bypassing gene therapy approaches. This case demonstrates that in a somatic mosaicism context, a novel homozygous mutation in the p63 gene can arise as a consequence of an allelic gene conversion event, subsequent to a de novo mutation. The heterozygous mutant R311K-p63 stem cells can be isolated by means of clonal analysis and given their good regenerative

  13. Delayed Recovery of Skeletal Muscle Mass following Hindlimb Immobilization in mTOR Heterozygous Mice

    OpenAIRE

    Lang, Susan M.; Kazi, Abid A.; Hong-Brown, Ly; Lang, Charles H.

    2012-01-01

    The present study addressed the hypothesis that reducing mTOR, as seen in mTOR heterozygous (+/-) mice, would exaggerate the changes in protein synthesis and degradation observed during hindlimb immobilization as well as impair normal muscle regrowth during the recovery period. Atrophy was produced by unilateral hindlimb immobilization and data compared to the contralateral gastrocnemius. In wild-type (WT) mice, the gradual loss of muscle mass plateaued by day 7. This response was associated ...

  14. Heterozygous Lmna(delK32) mice develop dilated cardiomyopathy through a combined pathomechanism of haploinsufficiency and peptide toxicity

    DEFF Research Database (Denmark)

    Cattin, M. E.; Bertrand, A. T.; Schlossarek, S.

    2013-01-01

    itself has a clear deleterious effect on engineered heart tissues force of contraction, it also leads to the nuclear aggregation of viral-mediated expression of K32-lamin. In conclusion, Het mice are the first knock-in Lmna model with cardiac-specific phenotype at the heterozygous state. Altogether, our....... The pathomechanisms linking mutations to DCM remain to be elucidated. We investigated the phenotype and associated pathomechanisms of heterozygous Lmna(K32/) (Het) knock-in mice, which carry a human mutation. Het mice developed a cardiac-specific phenotype. Two phases, with two different pathomechanisms, could...... be observed that lead to the development of cardiac dysfunction, DCM and death between 35 and 70 weeks of age. In young Het hearts, there was a clear reduction in lamin A/C level, mainly due to the degradation of toxic K32-lamin. As a side effect, lamin A/C haploinsufficiency probably triggers the cardiac...

  15. Chronic Toxoplasma gondii in Nurr1-Null Heterozygous Mice Exacerbates Elevated Open Field Activity

    OpenAIRE

    Eells, Jeffrey B.; Varela-Stokes, Andrea; Guo-Ross, Shirley X.; Kummari, Evangel; Smith, Holly M.; Cox, Erin; Lindsay, David S.

    2015-01-01

    Latent infection with Toxoplasma gondii is common in humans (approximately 30% of the global population) and is a significant risk factor for schizophrenia. Since prevalence of T. gondii infection is far greater than prevalence of schizophrenia (0.5-1%), genetic risk factors are likely also necessary to contribute to schizophrenia. To test this concept in an animal model, Nurr1-null heterozygous (+/-) mice and wild-type (+/+) mice were evaluate using an emergence test, activity in an open fie...

  16. Generalized pustular psoriasis in infant with heterozygous mutation in the IL36RN gene successfully treated with infliximab

    DEFF Research Database (Denmark)

    Glerup, Mia; Herlin, Troels; Veirum, Jens Erik

    , but to our knowledge heterozygous IL36RN mutation related to severe generalized pustular psoriasis in early childhood has not been described. Case presentation: First child of non-consanguineous caucasian (Danish) parents prenatally diagnosed with tetralogy of Fallot. Array CGH revealed normal karyotype...

  17. High-resolution melting (HRM) re-analysis of a polyposis patients cohort reveals previously undetected heterozygous and mosaic APC gene mutations.

    Science.gov (United States)

    Out, Astrid A; van Minderhout, Ivonne J H M; van der Stoep, Nienke; van Bommel, Lysette S R; Kluijt, Irma; Aalfs, Cora; Voorendt, Marsha; Vossen, Rolf H A M; Nielsen, Maartje; Vasen, Hans F A; Morreau, Hans; Devilee, Peter; Tops, Carli M J; Hes, Frederik J

    2015-06-01

    Familial adenomatous polyposis is most frequently caused by pathogenic variants in either the APC gene or the MUTYH gene. The detection rate of pathogenic variants depends on the severity of the phenotype and sensitivity of the screening method, including sensitivity for mosaic variants. For 171 patients with multiple colorectal polyps without previously detectable pathogenic variant, APC was reanalyzed in leukocyte DNA by one uniform technique: high-resolution melting (HRM) analysis. Serial dilution of heterozygous DNA resulted in a lowest detectable allelic fraction of 6% for the majority of variants. HRM analysis and subsequent sequencing detected pathogenic fully heterozygous APC variants in 10 (6%) of the patients and pathogenic mosaic variants in 2 (1%). All these variants were previously missed by various conventional scanning methods. In parallel, HRM APC scanning was applied to DNA isolated from polyp tissue of two additional patients with apparently sporadic polyposis and without detectable pathogenic APC variant in leukocyte DNA. In both patients a pathogenic mosaic APC variant was present in multiple polyps. The detection of pathogenic APC variants in 7% of the patients, including mosaics, illustrates the usefulness of a complete APC gene reanalysis of previously tested patients, by a supplementary scanning method. HRM is a sensitive and fast pre-screening method for reliable detection of heterozygous and mosaic variants, which can be applied to leukocyte and polyp derived DNA.

  18. Friendship and love story portrayed in haruki murakami’s novel “norwegian wood”

    OpenAIRE

    Simatupang, Anggi Rosalina

    2016-01-01

    Literature is a kind of imaginative writing. It reflects a problem of life by human being. Kertas karya ini berjudul: FRIENDSHIP AND LOVE STORY PORTRAYED IN HARUKI MURAKAMI’S NOVEL “NORWEGIAN WOOD.” The main character of that novel is Toru Watanabe. In writing this paper describe the silence hides friendship and love story of Watanabe. Watanabe, Kizuki of his classmate, Naoko is Kizuki girlfriend walk out the friendship. Watanabe dan Naoko miss the death of Kizuki who takes his own life. The ...

  19. Nonhomologous Synapsis and Reduced Crossing over in a Heterozygous Paracentric Inversion in Saccharomyces Cerevisiae

    Science.gov (United States)

    Dresser, M. E.; Ewing, D. J.; Harwell, S. N.; Coody, D.; Conrad, M. N.

    1994-01-01

    Homologous chromosome synapsis (``homosynapsis'') and crossing over are well-conserved aspects of meiotic chromosome behavior. The long-standing assumption that these two processes are causally related has been challenged recently by observations in Saccharomyces cerevisiae of significant levels of crossing over (1) between small sequences at nonhomologous locations and (2) in mutants where synapsis is abnormal or absent. In order to avoid problems of local sequence effects and of mutation pleiotropy, we have perturbed synapsis by making a set of isogenic strains that are heterozygous and homozygous for a large chromosomal paracentric inversion covering a well marked genetic interval and then measured recombination. We find that reciprocal recombination in the marked interval in heterozygotes is reduced variably across the interval, on average to ~55% of that in the homozygotes, and that positive interference still modulates crossing over. Cytologically, stable synapsis across the interval is apparently heterologous rather than homologous, consistent with the interpretation that stable homosynapsis is required to initiate or consummate a large fraction of the crossing over observed in wild-type strains. When crossing over does occur in heterozygotes, dicentric and acentric chromosomes are formed and can be visualized and quantitated on blots though not demonstrated in viable spores. We find that there is no loss of dicentric chromosomes during the two meiotic divisions and that the acentric chromosome is recovered at only 1/3 to 1/2 of the expected level. PMID:7851761

  20. Novel compound heterozygous mutations in MYO7A Associated with Usher syndrome 1 in a Chinese family.

    Science.gov (United States)

    Gao, Xue; Wang, Guo-Jian; Yuan, Yong-Yi; Xin, Feng; Han, Ming-Yu; Lu, Jing-Qiao; Zhao, Hui; Yu, Fei; Xu, Jin-Cao; Zhang, Mei-Guang; Dong, Jiang; Lin, Xi; Dai, Pu

    2014-01-01

    Usher syndrome is an autosomal recessive disease characterized by sensorineural hearing loss, age-dependent retinitis pigmentosa (RP), and occasionally vestibular dysfunction. The most severe form is Usher syndrome type 1 (USH1). Mutations in the MYO7A gene are responsible for USH1 and account for 29-55% of USH1 cases. Here, we characterized a Chinese family (no. 7162) with USH1. Combining the targeted capture of 131 known deafness genes, next-generation sequencing, and bioinformatic analysis, we identified two deleterious compound heterozygous mutations in the MYO7A gene: a reported missense mutation c.73G>A (p.G25R) and a novel nonsense mutation c.462C>A (p.C154X). The two compound variants are absent in 219 ethnicity-matched controls, co-segregates with the USH clinical phenotypes, including hearing loss, vestibular dysfunction, and age-dependent penetrance of progressive RP, in family 7162. Therefore, we concluded that the USH1 in this family was caused by compound heterozygous mutations in MYO7A.

  1. Novel compound heterozygous mutations in MYO7A Associated with Usher syndrome 1 in a Chinese family.

    Directory of Open Access Journals (Sweden)

    Xue Gao

    Full Text Available Usher syndrome is an autosomal recessive disease characterized by sensorineural hearing loss, age-dependent retinitis pigmentosa (RP, and occasionally vestibular dysfunction. The most severe form is Usher syndrome type 1 (USH1. Mutations in the MYO7A gene are responsible for USH1 and account for 29-55% of USH1 cases. Here, we characterized a Chinese family (no. 7162 with USH1. Combining the targeted capture of 131 known deafness genes, next-generation sequencing, and bioinformatic analysis, we identified two deleterious compound heterozygous mutations in the MYO7A gene: a reported missense mutation c.73G>A (p.G25R and a novel nonsense mutation c.462C>A (p.C154X. The two compound variants are absent in 219 ethnicity-matched controls, co-segregates with the USH clinical phenotypes, including hearing loss, vestibular dysfunction, and age-dependent penetrance of progressive RP, in family 7162. Therefore, we concluded that the USH1 in this family was caused by compound heterozygous mutations in MYO7A.

  2. Genetic Resistance to Scrapie Infection in Experimentally Challenged Goats

    Science.gov (United States)

    Lacroux, Caroline; Perrin-Chauvineau, Cécile; Corbière, Fabien; Aron, Naima; Aguilar-Calvo, Patricia; Torres, Juan Maria; Costes, Pierrette; Brémaud, Isabelle; Lugan, Séverine; Schelcher, François; Barillet, Francis

    2014-01-01

    In goats, several field studies have identified coding mutations of the gene encoding the prion protein (I/M142, N/D146, S/D146, R/Q211, and Q/K222) that are associated with a lower risk of developing classical scrapie. However, the data related to the levels of resistance to transmissible spongiform encephalopathies (TSEs) of these different PRNP gene mutations are still considered insufficient for developing large-scale genetic selection against scrapie in this species. In this study, we inoculated wild-type (WT) PRNP (I142R154R211Q222) goats and homozygous and/or heterozygous I/M142, R/H154, R/Q211, and Q/K222 goats with a goat natural scrapie isolate by either the oral or the intracerebral (i.c.) route. Our results indicate that the I/M142 PRNP polymorphism does not provide substantial resistance to scrapie infection following intracerebral or oral inoculation. They also demonstrate that H154, Q211, and K222 PRNP allele carriers are all resistant to scrapie infection following oral exposure. However, in comparison to WT animals, the H154 and Q211 allele carriers displayed only moderate increases in the incubation period following i.c. challenge. After i.c. challenge, heterozygous K222 and a small proportion of homozygous K222 goats also developed the disease, but with incubation periods that were 4 to 5 times longer than those in WT animals. These results support the contention that the K222 goat prion protein variant provides a strong but not absolutely protective effect against classical scrapie. PMID:24284317

  3. Improved motor performance in Dyt1 ΔGAG heterozygous knock-in mice by cerebellar Purkinje-cell specific Dyt1 conditional knocking-out.

    Science.gov (United States)

    Yokoi, Fumiaki; Dang, Mai Tu; Li, Yuqing

    2012-05-01

    Early-onset generalized torsion dystonia (dystonia 1) is an inherited movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Most patients have a 3-base pair deletion (ΔGAG) in one allele of DYT1, corresponding to a loss of a glutamic acid residue (ΔE) in the C-terminal region of the protein. Functional alterations in basal ganglia circuits and the cerebellum have been reported in dystonia. Pharmacological manipulations or mutations in genes that result in functional alterations of the cerebellum have been reported to have dystonic symptoms and have been used as phenotypic rodent models. Additionally, structural lesions in the abnormal cerebellar circuits, such as cerebellectomy, have therapeutic effects in these models. A previous study has shown that the Dyt1 ΔGAG heterozygous knock-in (KI) mice exhibit motor deficits in the beam-walking test. Both Dyt1 ΔGAG heterozygous knock-in (KI) and Dyt1 Purkinje cell-specific knockout (Dyt1 pKO) mice exhibit dendritic alterations of cerebellar Purkinje cells. Here, Dyt1 pKO mice exhibited significantly less slip numbers in the beam-walking test, suggesting better motor performance than control littermates, and normal gait. Furthermore, Dyt1 ΔGAG KI/Dyt1 pKO double mutant mice exhibited significantly lower numbers of slips than Dyt1 ΔGAG heterozygous KI mice, suggesting Purkinje-cell specific knockout of Dyt1 wild-type (WT) allele in Dyt1 ΔGAG heterozygous KI mice rescued the motor deficits. The results suggest that molecular lesions of torsinA in Purkinje cells by gene therapy or intervening in the signaling pathway downstream of the cerebellar Purkinje cells may rescue motor symptoms in dystonia 1. Copyright © 2012 Elsevier B.V. All rights reserved.

  4. Diagnosis of Compound Heterozygous Hb Tak/β-Thalassemia and HbD-Punjab/β-Thalassemia by HbA2 Levels on Capillary Electrophoresis.

    Science.gov (United States)

    Panyasai, Sitthichai; Sakkhachornphop, Supachai; Pornprasert, Sakorn

    2018-01-01

    A misdiagnosis of β-thalassemia carrier in samples with Hb Tak and HbD-Punjab, the β-variants, can be a cause of inappropriate genetic counseling thus having a new case of β-thalassemia major. A capillary electrophoresis (CE) is very efficient in separating and quantifying HbA 2 . In this study, HbA 2 levels of samples which were doubted for compound heterozygous Hb Tak/β-thalassemia or heterozygous HbD-Punjab/β-thalassemia were measured and compared between CE and high performance liquid chromatography (HPLC). The molecular confirmation for Hb Tak, HbD-Punjab and β-thalassemia codons 17 (A > T), 41/42 (-TCTT), 71/72 (+A) and IVSI-nt1 (G > T) mutations and 3.4 kb deletion were also performed. Based on DNA analysis, 3 cases were diagnosed as compound heterozygous Hb Tak/β-thalassemia and one for HbD-Punjab/β-thalassemia. The elevated HbA 2 levels were found in all 4 samples with rages of 4.6-7.3% on CE while those were not found on HPLC. Thus, the elevated HbA 2 measured by CE can be used as a screening parameter for differentiating the homozygote of Hb Tak and HbD-Punjab from the compound heterozygote of these hemoglobinopathies and β-thalassemia.

  5. Implications of compound heterozygous insulin receptor mutations in congenital muscle fibre type disproportion myopathy for the receptor kinase activation

    DEFF Research Database (Denmark)

    Klein, H H; Müller, R; Vestergaard, H

    1999-01-01

    We studied insulin receptor kinase activation in two brothers with congenital muscle fibre type disproportion myopathy and compound heterozygous mutations of the insulin receptor gene, their parents, and their unaffected brother. In the father who has a heterozygote Arg1174-->Gln mutation, in sit...

  6. Disruption of NBS1 gene leads to early embryonic lethality in homozygous null mice and induces specific cancer in heterozygous mice

    Energy Technology Data Exchange (ETDEWEB)

    Kurimasa, Akihiro; Burma, Sandeep; Henrie, Melinda; Ouyang, Honghai; Osaki, Mitsuhiko; Ito, Hisao; Nagasawa, Hatsumi; Little, John B.; Oshimura, Mitsuo; Li, Gloria C.; Chen, David J.

    2002-04-15

    Nijmegen breakage syndrome (NBS) is a rare autosomal recessive chromosome instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition, with cellular features similar to that of ataxia telangiectasia (AT). NBS results from mutations in the mammalian gene Nbs1 that codes for a 95-kDa protein called nibrin, NBS1, or p95. To establish an animal model for NBS, we attempted to generate NBS1 knockout mice. However, NBS1 gene knockouts were lethal at an early embryonic stage. NBS1 homozygous(-/-) blastocyst cells cultured in vitro showed retarded growth and subsequently underwent growth arrest within 5 days of culture. Apoptosis, assayed by TUNEL staining, was observed in NBSI homozygous(-/-) blastocyst cells cultured for four days. NBSI heterozygous(+/-) mice were normal, and exhibited no specific phenotype for at least one year. However, fibroblast cells from NBSI heterozygous(+/-) mice displayed an enhanced frequency of spontaneous transformation to anchorage-independent growth as compared to NBS1 wild-type(+/+) cells. Furthermore, heterozygous(+/-) mice exhibited a high incidence of hepatocellular carcinoma after one year compared to wild-type mice, even though no significant differences in the incidence of other tumors such as lung adenocarcinoma and lymphoma were observed. Taken together, these results strongly suggest that NBS1 heterozygosity and reduced NBSI expression induces formation of specific tumors in mice.

  7. A novel heterozygous SOX2 mutation causing anophthalmia/microphthalmia with genital anomalies.

    Science.gov (United States)

    Pedace, Lucia; Castori, Marco; Binni, Francesco; Pingi, Alberto; Grammatico, Barbara; Scommegna, Salvatore; Majore, Silvia; Grammatico, Paola

    2009-01-01

    Anophthalmia/microphthalmia is a rare developmental craniofacial defect, which recognizes a wide range of causes, including chromosomal abnormalities, single-gene mutations as well as environmental factors. Heterozygous mutations in the SOX2 gene are the most common monogenic form of anophthalmia/microphthalmia, as they are reported in up to 10-15% cases. Here, we describe a sporadic patient showing bilateral anophthalmia/microphthalmia and micropenis caused by a novel mutation (c.59_60insGG) in the SOX2 gene. Morphological and endocrinological evaluations excluded any anomaly of the hypothalamus-pituitary axis. Our finding supports the hypothesis that SOX2 is particularly prone to slipped-strand mispairing, which results in a high frequency of point deletions/insertions.

  8. Mutations in the gene for lipoprotein lipase. A cause for low HDL cholesterol levels in individuals heterozygous for familial hypercholesterolemia

    NARCIS (Netherlands)

    Pimstone, S. N.; Gagné, S. E.; Gagné, C.; Lupien, P. J.; Gaudet, D.; Williams, R. R.; Kotze, M.; Reymer, P. W.; Defesche, J. C.; Kastelein, J. J.

    1995-01-01

    Familial hypercholesterolemia (FH) is characterized by elevated plasma concentrations of LDL cholesterol resulting from mutations in the gene for the LDL receptor. Low HDL cholesterol levels are seen frequently in patients both heterozygous and homozygous for mutations in this gene. Suggested

  9. Disruption of hippocampus-regulated behavioural and cognitive processes by heterozygous constitutive deletion of SynGAP.

    Science.gov (United States)

    Muhia, Mary; Yee, Benjamin K; Feldon, Joram; Markopoulos, Foivos; Knuesel, Irene

    2010-02-01

    The brain-specific Ras/Rap-GTPase activating protein (SynGAP) is a prime candidate linking N-methyl-d-aspartate receptors to the regulation of the ERK/MAP kinase signalling cascade, suggested to be essential for experience-dependent synaptic plasticity. Here, we evaluated the behavioural phenotype of SynGAP heterozygous knockout mice (SG(+/-)), expressing roughly half the normal levels of SynGAP. In the cognitive domain, SG(+/-) mice demonstrated severe working and reference memory deficits in the radial arm maze task, a mild impairment early in the transfer test of the water maze task, and a deficiency in spontaneous alternation in an elevated T-maze. In the non-cognitive domain, SG(+/-) mice were hyperactive in the open field and appeared less anxious in the elevated plus maze test. In contrast, object recognition memory performance was not impaired in SG(+/-) mice. The reduction in SynGAP thus resulted in multiple behavioural traits suggestive of aberrant cognitive and non-cognitive processes normally mediated by the hippocampus. Immunohistochemical evaluation further revealed a significant reduction in calbindin-positive interneurons in the hippocampus and doublecortin-positive neurons in the dentate gyrus of adult SG(+/-) mice. Heterozygous constitutive deletion of SynGAP is therefore associated with notable behavioural as well as morphological phenotypes indicative of hippocampal dysfunction. Any suggestion of a possible causal link between them however remains a matter for further investigation.

  10. Double heterozygous mutations of MITF and PAX3 result in Waardenburg syndrome with increased penetrance in pigmentary defects.

    Science.gov (United States)

    Yang, T; Li, X; Huang, Q; Li, L; Chai, Y; Sun, L; Wang, X; Zhu, Y; Wang, Z; Huang, Z; Li, Y; Wu, H

    2013-01-01

    Waardenburg syndrome (WS) is characterized by sensorineural hearing loss and pigmentary defects of the hair, skin, and iris. Heterozygous mutations of MITF and its transactivator gene PAX3 are associated with Waardenburg syndrome type II (WS2) and type I (WS1), respectively. Most patients with MITF or PAX3 mutations, however, show variable penetrance of WS-associated phenotypes even within families segregating the same mutation, possibly mediated by genetic background or specific modifiers. In this study, we reported a rare Waardenburg syndrome simplex family in which a pair of WS parents gave birth to a child with double heterozygous mutations of MITF and PAX3. Compared to his parents who carried a single mutation in either MITF or PAX3, this child showed increased penetrance of pigmentary defects including white forelock, white eyebrows and eyelashes, and patchy facial depigmentation. This observation suggested that the expression level of MITF is closely correlated to the penetrance of WS, and variants in transcription regulator genes of MITF may modify the relevant clinical phenotypes. © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

  11. Molecular characterization of a genetic variant of the steroid hormone-binding globulin gene in heterozygous subjects

    Energy Technology Data Exchange (ETDEWEB)

    Hardy, D.O.; Catterall, J.F. [Population Council, New York, NY (United States); Carino, C. [Instituto National de la Nutricion, Mexico City, MX (United States)] [and others

    1995-04-01

    Steroid hormone-binding globulin in human serum displays different isoelectric focusing (IEF) patterns among individuals, suggesting genetic variation in the gene for this extracellular steroid carrier protein. Analysis of allele frequencies and family studies suggested the existence of two codominant alleles of the gene. Subsequent determination of the molecular basis of a variant of the gene was carried out using DNA from homozygous individuals from a single Belgian family. It was of interest to characterize other variant individuals to determine whether all variants identified by IEF phenotyping were caused by the same mutation or whether other mutations occurred in the gene in different populations. Previous studies identified Mexican subjects who were heterozygous for the variant IEF phenotype. Denaturing gradient gel electrophoresis was used to localize the mutation in these subjects and to purify the variant allele for DNA sequence analysis. The results show that the mutation in this population is identical to that identified in the Belgian family, and no other mutations were detected in the gene. These data represent the first analysis of steroid hormone-binding globulin gene variation in heterozygous subjects and further support the conclusion of biallelism of the gene worldwide. 11 refs., 2 figs., 1 tab.

  12. Sector Retinitis Pigmentosa Associated With Novel Compound Heterozygous Mutations of CDH23.

    Science.gov (United States)

    Branson, Sara V; McClintic, Jedediah I; Stamper, Tara H; Haldeman-Englert, Chad R; John, Vishak J

    2016-02-01

    Usher syndrome is an autosomal recessive condition characterized by retinitis pigmentosa (RP) and congenital hearing loss, with or without vestibular dysfunction. Allelic variants of CDH23 cause both Usher syndrome type 1D (USH1D) and a form of nonsyndromic hearing loss (DFNB12). The authors describe here a 34-year-old patient with congenital hearing loss and a new diagnosis of sector RP who was found to have two novel compound heterozygous mutations in CDH23, including one missense (c.8530C > A; p.Pro2844Thr) and one splice-site (c.5820 + 5G > A) mutation. This is the first report of sector RP associated with these types of mutations in CDH23. Copyright 2016, SLACK Incorporated.

  13. Identification of Heterozygous Single- and Multi-exon Deletions in IL7R by Whole Exome Sequencing.

    OpenAIRE

    Engelhardt, Karin R; Xu, Yaobo; Grainger, Angela; Germani Batacchi, Mila G C; Swan, David J; Willet, Joseph D P; Abd Hamid, Intan J; Agyeman, Philipp; Barge, Dawn; Bibi, Shahnaz; Jenkins, Lucy; Flood, Terence J; Abinun, Mario; Slatter, Mary A; Gennery, Andrew R

    2017-01-01

    Purpose We aimed to achieve a retrospective molecular diagnosis by applying state-of-the-art genomic sequencing methods to past patients with T-B+NK+ severe combined immunodeficiency (SCID). We included identification of copy number variations (CNVs) by whole exome sequencing (WES) using the CNV calling method ExomeDepth to detect gene alterations for which routine Sanger sequencing analysis is not suitable, such as large heterozygous deletions. Methods Of a total of 12 undiagnosed patients w...

  14. Lifetime exercise intolerance with lactic acidosis as key manifestation of novel compound heterozygous ACAD9 mutations causing complex I deficiency.

    Science.gov (United States)

    Schrank, Bertold; Schoser, Benedikt; Klopstock, Thomas; Schneiderat, Peter; Horvath, Rita; Abicht, Angela; Holinski-Feder, Elke; Augustis, Sarunas

    2017-05-01

    We report a 36-year-old female having lifetime exercise intolerance and lactic acidosis with nausea associated with novel compound heterozygous Acyl-CoA dehydrogenase 9 gene (ACAD9) mutations (p.Ala390Thr and p.Arg518Cys). ACAD9 is an assembly factor for the mitochondrial respiratory chain complex I. ACAD9 mutations are recognized as frequent causes of complex I deficiency. Our patient presented with exercise intolerance, rapid fatigue, and nausea since early childhood. Mild physical workload provoked the occurrence of nausea and vomiting repeatedly. Her neurological examination, laboratory findings and muscle biopsy demonstrated no abnormalities. A bicycle spiroergometry provoked significant lactic acidosis during and following exercise pointing towards a mitochondrial disorder. Subsequently, the analysis of respiratory chain enzyme activities in muscle revealed severe isolated complex I deficiency. Candidate gene sequencing revealed two novel heterozygous ACAD9 mutations. This patient report expands the mutational and phenotypic spectrum of diseases associated with mutations in ACAD9. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Comprehensive behavioral analysis of RNG105 (Caprin1) heterozygous mice: Reduced social interaction and attenuated response to novelty

    Science.gov (United States)

    Ohashi, Rie; Takao, Keizo; Miyakawa, Tsuyoshi; Shiina, Nobuyuki

    2016-01-01

    RNG105 (also known as Caprin1) is a major RNA-binding protein in neuronal RNA granules, and is responsible for mRNA transport to dendrites and neuronal network formation. A recent study reported that a heterozygous mutation in the Rng105 gene was found in an autism spectrum disorder (ASD) patient, but it remains unclear whether there is a causal relation between RNG105 deficiency and ASD. Here, we subjected Rng105+/− mice to a comprehensive behavioral test battery, and revealed the influence of RNG105 deficiency on mouse behavior. Rng105+/− mice exhibited a reduced sociality in a home cage and a weak preference for social novelty. Consistently, the Rng105+/− mice also showed a weak preference for novel objects and novel place patterns. Furthermore, although the Rng105+/− mice exhibited normal memory acquisition, they tended to have relative difficulty in reversal learning in the spatial reference tasks. These findings suggest that the RNG105 heterozygous knockout leads to a reduction in sociality, response to novelty and flexibility in learning, which are implicated in ASD-like behavior. PMID:26865403

  16. Heterozygous inactivation of tsc2 enhances tumorigenesis in p53 mutant zebrafish

    Directory of Open Access Journals (Sweden)

    Seok-Hyung Kim

    2013-07-01

    Tuberous sclerosis complex (TSC is a multi-organ disorder caused by mutations of the TSC1 or TSC2 genes. A key function of these genes is to inhibit mTORC1 (mechanistic target of rapamycin complex 1 kinase signaling. Cells deficient for TSC1 or TSC2 have increased mTORC1 signaling and give rise to benign tumors, although, as a rule, true malignancies are rarely seen. In contrast, other disorders with increased mTOR signaling typically have overt malignancies. A better understanding of genetic mechanisms that govern the transformation of benign cells to malignant ones is crucial to understand cancer pathogenesis. We generated a zebrafish model of TSC and cancer progression by placing a heterozygous mutation of the tsc2 gene in a p53 mutant background. Unlike tsc2 heterozygous mutant zebrafish, which never exhibited cancers, compound tsc2;p53 mutants had malignant tumors in multiple organs. Tumorigenesis was enhanced compared with p53 mutant zebrafish. p53 mutants also had increased mTORC1 signaling that was further enhanced in tsc2;p53 compound mutants. We found increased expression of Hif1-α, Hif2-α and Vegf-c in tsc2;p53 compound mutant zebrafish compared with p53 mutant zebrafish. Expression of these proteins probably underlies the increased angiogenesis seen in compound mutant zebrafish compared with p53 mutants and might further drive cancer progression. Treatment of p53 and compound mutant zebrafish with the mTORC1 inhibitor rapamycin caused rapid shrinkage of tumor size and decreased caliber of tumor-associated blood vessels. This is the first report using an animal model to show interactions between tsc2, mTORC1 and p53 during tumorigenesis. These results might explain why individuals with TSC rarely have malignant tumors, but also suggest that cancer arising in individuals without TSC might be influenced by the status of TSC1 and/or TSC2 mutations and be potentially treatable with mTORC1 inhibitors.

  17. Metabonomic study of the biochemical profiles of heterozygous myostatin knockout swine

    Directory of Open Access Journals (Sweden)

    Jianxiang XU,Dengke PAN,Jie ZHAO,Jianwu WANG,Xiaohong HE,Yuehui MA,Ning LI

    2015-03-01

    Full Text Available Myostatin is a transforming growth factor-β family member that normally acts to limit skeletal muscle growth. Myostatin gene (MSTN knockout (KO mice show possible effects for the prevention or treatment of metabolic disorders such as obesity and type 2 diabetes. We applied chromatography and mass spectrometry based metabonomics to assess system-wide metabolic response of heterozygous MSTN KO (MSTN+/- swine. Most of the metabolic data for MSTN+/- swine were similar to the data for wild type (WT control swine. There were, however, metabolic changes related to fatty acid metabolism, glucose utilization, lipid metabolism, as well as BCAA catabolism caused by monoallelic MSTN depletion.The statistical analyses suggested that: (1 most metabolic changes were not significant in MSTN+/- swine compared to WT swine; (2 only a few metabolic properties were significantly different between KO and WT swine, especially for lipid metabolism. Significantly, these minor changes were most evident in female KO swine and suggested differences in gender sensitivity to myostatin.

  18. Prickly pear induces upregulation of liver LDL binding in familial heterozygous hypercholesterolemia

    International Nuclear Information System (INIS)

    Palumbo, B.; Palumbo, R.; Efthimiou, Y.; Stamatopoulos, J.; Sinzinger, H.; Oguogho, A.; Budinsky, A.; Sinzinger, H.

    2003-01-01

    The hypoglycemic effect of prickly pear is well known by native local Indian population since a long time. Beside the beneficial effects on lipid metabolism, oxidation injury and platelet function has been claimed in experimental animals. We recently found an upregulation of apo-B/E receptor. We therefore examined 10 patients with isolated heterozygous familial hypercholesterolemia (FH) being enrolled in a dietary run-in phase of 6 weeks after dietary counselling and a further 6 weeks of prickly pear addition. Uptake of autologous 123 I-radiolabeled LDL was determined at entry as well as after 6 weeks of daily prickly pear ingestion. We found a significant (p 176.4 mg/dl; p 123 I-LDL binding by prickly pear in FH-patients in vivo and indicate that prickly pear exerts a significant hypolipidemic action via receptor upregulation. (author)

  19. A novel heterozygous mutation in the STAT1 SH2 domain causes chronic mucocutaneous candidiasis, atypically diverse infections, autoimmunity, and impaired cytokine regulation

    NARCIS (Netherlands)

    K. Meesilpavikkai (Kornvalee); W.A. Dik (Willem); B. Schrijver (Benjamin); N.M. Nagtzaam (Nicole); A.L. Rijswijk (Angelique); G.J.A. Driessen (Gertjan); P.J. van der Spek (Peter); P.M. van Hagen (Martin); V.A.S.H. Dalm (Virgil)

    2017-01-01

    textabstractChronic mucocutaneous candidiasis (CMC) is a primary immunodeficiency characterized by persistent or recurrent skin and mucosal surface infections with Candida species. Different gene mutations leading to CMC have been identified. These include various heterozygous gain-of-function (GOF)

  20. Waardenburg syndrome type 3 (Klein-Waardenburg syndrome) segregating with a heterozygous deletion in the paired box domain of PAX3: a simple variant or a true syndrome?

    Science.gov (United States)

    Tekin, M; Bodurtha, J N; Nance, W E; Pandya, A

    2001-10-01

    Klein-Waardenburg syndrome or Waardenburg syndrome type 3 (WS-III; MIM 148820) is characterized by the presence of musculoskeletal abnormalities in association with clinical features of Waardenburg syndrome type 1 (WS-I). Since the description of the first patient in 1947 (D. Klein, Arch Klaus Stift Vererb Forsch 1947: 22: 336-342), a few cases have been reported. Only occasional families have demonstrated autosomal-dominant inheritance of WS-III. In a previous report, a missense mutation in the paired domain of the PAX3 gene has been described in a family with dominant segregation of WS-III. In this report, we present a second family (mother and son) with typical clinical findings of WS-III segregating with a heterozygous 13-bp deletion in the paired domain of the PAX3 gene. Although homozygosity or compound heterozygosity has also been documented in patients with severe limb involvement, a consistent genotype-phenotype correlation for limb abnormalities associated with heterozygous PAX3 mutations has not previously been apparent. Heterozygous mutations could either reflect a unique dominant-negative effect or possibly the contribution of other unlinked genetic modifiers in determining the phenotype.

  1. A novel compound heterozygous mutation in an adolescent with insulin-dependent diabetes: The challenge of characterizing Wolfram syndrome.

    Science.gov (United States)

    Maltoni, Giulio; Minardi, Raffaella; Cristalli, Carlotta Pia; Nardi, Laura; D'Alberton, Franco; Mantovani, Vilma; Zucchini, Stefano

    2016-11-01

    WS diagnosis is often delayed since misdiagnosed as autoimmune diabetes. The rarity of the condition and the absence of other diseases at diabetes diagnosis might make extremely challenging the recognition of WS. However the novel compound heterozygosity for the here reported mutations, seems to confer a mild phenotype among the spectrum of WS manifestations. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  2. A novel heterozygous RIT1 mutation in a patient with Noonan syndrome, leukopenia, and transient myeloproliferation-a review of the literature.

    Science.gov (United States)

    Nemcikova, Michaela; Vejvalkova, Sarka; Fencl, Filip; Sukova, Martina; Krepelova, Anna

    2016-04-01

    Noonan syndrome (NS) is a genetic condition presenting with typical facies, cardiac defects, short stature, variable developmental deficit, cryptorchidism, skeletal, and other abnormalities. Germline mutations in genes involved in the RAS/MAPK signaling have been discovered to underlie NS. Recently, missense mutations in RIT1 have been reported as causative for individuals with clinical signs of NS. We report on a 2.5-year-old boy with NS phenotype with a novel heterozygous change in the RIT1 gene. The patient was born prematurely from pregnancy monitored for polyhydramnios. At 7 months of age, non-immune neutropenia and splenomegaly have been observed. During the severe pneumonia at 10 months, significant progression of hepatosplenomegaly, leukopenia with monocytosis (15-29 %), and thrombocytopenia occurred. Bone marrow evaluation showed myeloid hyperplasia and monocytosis, suggestive of myeloproliferative syndrome. Clinical phenotype (facial dysmorphism, soft hair, short neck, broad chest, widely spaced nipples, mild pectus carinatum, deep palmar creases, unilateral cryptorchidism), and moderate pulmonary valve stenosis with mild psychomotor delay were indicative of NS. DNA analysis identified a de novo heterozygous variant c.69A >T, p.(Lys23Asn) in exon 2 of the RIT1 gene, presumed to be causative. We present a patient with a clinical suspicion of NS carrying a novel substitution in RIT1 and hematologic findings not being observed in RIT1 positive patients to date. Thus, the case broadens variability of hematologic symptoms in RIT1 positive NS individuals. • Noonan syndrome is a common genetically heterogeneous disorder of autosomal dominant inheritance characterized by craniofacial dysmorphism, short stature, congenital heart defects, variable cognitive deficit, and other anomalies. What is new: • We report on a 2.5-year-old male patient with clinical signs of NS and hematologic abnormalities, in whom a novel heterozygous substitution in RIT1 with probable

  3. Role of heterozygous APC mutation in niche succession and initiation of colorectal cancer--a computational study.

    Directory of Open Access Journals (Sweden)

    Roschen Sasikumar

    Full Text Available Mutations in the adenomatous polyposis coli (APC gene are found in most colorectal cancers. They cause constitutive activation of proliferative pathways when both alleles of the gene are mutated. However studies on individuals with familial adenomatous polyposis (FAP have shown that a single mutated APC allele can also create changes in the precancerous colon crypt, like increased number of stem cells, increased crypt fission, greater variability of DNA methylation patterns, and higher somatic mutation rates. In this paper, using a computational model of colon crypt dynamics, we evolve and investigate a hypothesis on the effect of heterozygous APC mutation that explains these different observations. Based on previous reports and the results from the computational model we propose the hypothesis that heterozygous APC mutation has the effect of increasing the chances for a stem cell to divide symmetrically, producing two stem cell daughters. We incorporate this hypothesis into the model and perform simulation experiments to investigate the consequences of the hypothesis. Simulations show that this hypothesis links together the changes in FAP crypts observed in previous studies. The simulations also show that an APC(+/- stem cell gets selective advantages for dominating the crypt and progressing to cancer. This explains why most colon cancers are initiated by APC mutation. The results could have implications for preventing or retarding the onset of colon cancer in people with inherited or acquired mutation of one APC allele. Experimental validation of the hypothesis as well as investigation into the molecular mechanisms of this effect may therefore be worth undertaking.

  4. Heterozygous congenital Factor VII deficiency with the 9729del4 mutation, associated with severe spontaneous intracranial bleeding in an adolescent male.

    Science.gov (United States)

    Cramer, Thomas J; Anderson, Kristin; Navaz, Karanjia; Brown, Justin M; Mosnier, Laurent O; von Drygalski, Annette

    2016-03-01

    In congenital Factor (F) VII deficiency bleeding phenotype and intrinsic FVII activity levels don't always correlate. Patients with FVII activity levels <30% appear to have a higher bleeding propensity, but bleeding can also occur at higher FVII activity levels. Reasons for bleeding at higher FVII activity levels are unknown, and it remains challenging to manage such patients clinically. A 19year old male with spontaneous intracranial hemorrhage and FVII activity levels of 44%, requiring emergent surgical intervention and a strategy for FVII replacement. Genotyping showed the rare heterozygous FVII 9729del4 mutation. Bleed evacuation was complicated by epidural abscess requiring craniectomy, bone graft procedures, and prolonged administration of recombinant human (rh) activated FVII (FVIIa). The patient recovered without neurological deficits, and remains on prophylactic low dose treatment with rhFVIIa in relation to risky athletic activities. For clinicians, it is important to recognize that effects of rhFVIIa within these pathways are independent of its contribution to blood clot formation and cannot be assessed by clotting assays. Reduced FVII levels should therefore not be dismissed, as even a mild reduction may result in spontaneous bleeding. Treatment of mild FVII deficiency requires a careful case-by-case approach, based on the clinical scenario. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Reference: 691 [Arabidopsis Phenome Database[Archive

    Lifescience Database Archive (English)

    Full Text Available 691 http://metadb.riken.jp/db/SciNetS_ria224i/cria224u4ria224u18024555i Watanabe Mutsu...ogy Fukushima Atsushi|Kusano Miyako|Noji Masaaki|Oikawa Akira|Saito Kazuki|Watanabe Mutsumi

  6. Novel USH2A compound heterozygous mutations cause RP/USH2 in a Chinese family.

    Science.gov (United States)

    Liu, Xiaowen; Tang, Zhaohui; Li, Chang; Yang, Kangjuan; Gan, Guanqi; Zhang, Zibo; Liu, Jingyu; Jiang, Fagang; Wang, Qing; Liu, Mugen

    2010-03-17

    To identify the disease-causing gene in a four-generation Chinese family affected with retinitis pigmentosa (RP). Linkage analysis was performed with a panel of microsatellite markers flanking the candidate genetic loci of RP. These loci included 38 known RP genes. The complete coding region and exon-intron boundaries of Usher syndrome 2A (USH2A) were sequenced with the proband DNA to screen the disease-causing gene mutation. Restriction fragment length polymorphism (RFLP) analysis and direct DNA sequence analysis were done to demonstrate co-segregation of the USH2A mutations with the family disease. One hundred normal controls were used without the mutations. The disease-causing gene in this Chinese family was linked to the USH2A locus on chromosome 1q41. Direct DNA sequence analysis of USH2A identified two novel mutations in the patients: one missense mutation p.G1734R in exon 26 and a splice site mutation, IVS32+1G>A, which was found in the donor site of intron 32 of USH2A. Neither the p.G1734R nor the IVS32+1G>A mutation was found in the unaffected family members or the 100 normal controls. One patient with a homozygous mutation displayed only RP symptoms until now, while three patients with compound heterozygous mutations in the family of study showed both RP and hearing impairment. This study identified two novel mutations: p.G1734R and IVS32+1G>A of USH2A in a four-generation Chinese RP family. In this study, the heterozygous mutation and the homozygous mutation in USH2A may cause Usher syndrome Type II or RP, respectively. These two mutations expand the mutant spectrum of USH2A.

  7. Age-Related Hearing Loss in Mn-SOD Heterozygous Knockout Mice

    Directory of Open Access Journals (Sweden)

    Makoto Kinoshita

    2013-01-01

    Full Text Available Age-related hearing loss (AHL reduces the quality of life for many elderly individuals. Manganese superoxide dismutase (Mn-SOD, one of the antioxidant enzymes acting within the mitochondria, plays a crucial role in scavenging reactive oxygen species (ROS. To determine whether reduction in Mn-SOD accelerates AHL, we evaluated auditory function in Mn-SOD heterozygous knockout (HET mice and their littermate wild-type (WT C57BL/6 mice by means of auditory brainstem response (ABR. Mean ABR thresholds were significantly increased at 16 months when compared to those at 4 months in both WT and HET mice, but they did not significantly differ between them at either age. The extent of hair cell loss, spiral ganglion cell density, and thickness of the stria vascularis also did not differ between WT and HET mice at either age. At 16 months, immunoreactivity of 8-hydroxydeoxyguanosine was significantly greater in the SGC and SV in HET mice compared to WT mice, but that of 4-hydroxynonenal did not differ between them. These findings suggest that, although decrease of Mn-SOD by half may increase oxidative stress in the cochlea to some extent, it may not be sufficient to accelerate age-related cochlear damage under physiological aging process.

  8. Heterozygous carriers of a Parkin or PINK1 mutation share a common functional endophenotype

    DEFF Research Database (Denmark)

    van Nuenen, BF; Siebner, Hartwig; Weiss, MM

    2008-01-01

    inherited Parkinson disease alters the cortical control of sequential finger movements. METHODS: Nonmanifesting individuals carrying a single heterozygous Parkin (n = 13) or PINK1 (n = 9) mutation and 23 healthy controls without these mutations were studied with functional MRI (fMRI). During f...... rostral dorsal premotor cortex in mutation carriers but not in controls. Task-related activation of these premotor areas was similar in carriers of a Parkin or PINK1 mutation. CONCLUSION: Mutations in different genes linked to recessively inherited Parkinson disease are associated with an additional...... recruitment of rostral supplementary motor area and rostral dorsal premotor cortex during a simple motor sequence task. These premotor areas were recruited independently of the underlying genotype. The observed activation most likely reflects a "generic" compensatory mechanism to maintain motor function...

  9. Heterozygous de novo and inherited mutations in the smooth muscle actin (ACTG2 gene underlie megacystis-microcolon-intestinal hypoperistalsis syndrome.

    Directory of Open Access Journals (Sweden)

    Michael F Wangler

    2014-03-01

    Full Text Available Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS is a rare disorder of enteric smooth muscle function affecting the intestine and bladder. Patients with this severe phenotype are dependent on total parenteral nutrition and urinary catheterization. The cause of this syndrome has remained a mystery since Berdon's initial description in 1976. No genes have been clearly linked to MMIHS. We used whole-exome sequencing for gene discovery followed by targeted Sanger sequencing in a cohort of patients with MMIHS and intestinal pseudo-obstruction. We identified heterozygous ACTG2 missense variants in 15 unrelated subjects, ten being apparent de novo mutations. Ten unique variants were detected, of which six affected CpG dinucleotides and resulted in missense mutations at arginine residues, perhaps related to biased usage of CpG containing codons within actin genes. We also found some of the same heterozygous mutations that we observed as apparent de novo mutations in MMIHS segregating in families with intestinal pseudo-obstruction, suggesting that ACTG2 is responsible for a spectrum of smooth muscle disease. ACTG2 encodes γ2 enteric actin and is the first gene to be clearly associated with MMIHS, suggesting an important role for contractile proteins in enteric smooth muscle disease.

  10. Induced mutations in highly heterozygous vegetatively propagated grasses

    International Nuclear Information System (INIS)

    Powell, J.B.

    1976-01-01

    Experience with mutation induction of turf and forage grasses indicates that much progress can be achieved by this method. More than 300 mutations have been produced in our laboratory in the cultivars Tifgreen and Tifdwarf bermudagrass (Cynodon sp.). In the Tifway and Tifcote bermudagrasses we have demonstrated similar mutation responses. The first three clones are triploids and Tifcote is a probable tetraploid. No seeds are set on these clones. Two clones of bermudagrass, Coastal and Coastcross-1, occupy millions of hectares in the USA. Both are mutable and are known to be hybrids with 36 chromosomes. Biotypes of dallisgrass (Paspalum dilatatum Poir.) exist with 40 and 50 chromosomes and reproduce as sexual and obligate apomictic forms. Gamma-ray and thermal-neutron treatment of seed of these biotypes produced mutants that maintained the maternal characteristics in subsequent generations. Bahiagrass (Paspalum notatum Fluegge) also has sexual and apomictic biotypes. Some success was indicated for increased seed set by mutagen treatment. Kentucky bluegrass (Poa pratensis L.) is a facultative apomict with varying numbers of chromosomes in different cultivars. Gamma-ray mutagen treatment of rhizomes produced numerous mutations for plant type and disease reaction. Most mutations perpetuate themselves through the seed. The characteristic in common with all these grasses is their heterozygosity, which is maintained by the vegetative propagation or apomictic mode of reproduction. The experience in using ionizing radiation to induce heritable changes in these vegetatively propagated grasses is one of considerable success. Mutation rates in some of these irradiated grasses exceeded 65% and aberrant plants with characteristics previously never observed were found. Numerous hemizygous and heterozygous loci seem to be a sensitive target for mutagens. (author)

  11. Heterozygous M1V variant of ELA-2 gene mutation associated with G-CSF refractory severe congenital neutropenia.

    Science.gov (United States)

    Setty, Bhuvana A; Yeager, Nicholas D; Bajwa, Rajinder P

    2011-09-01

    Severe congenital neutropenia is an autosomal recessive disorder characterized by maturation arrest at the promyelocyte/myelocyte phase in the bone marrow, absolute neutrophil count ELA-2 have been described. We report the case of a premature male infant with congenital neutropenia, associated with multiple infections, refractory to treatment with granulocyte colony stimulating factor who subsequently underwent matched sibling donor stem-cell transplant. He was found to be heterozygous for the M1V variant of the ELA-2 gene that we postulate to be causative for his severe neutropenia Copyright © 2011 Wiley-Liss, Inc.

  12. Expression of embryonic hemoglobin genes in mice heterozygous for α-thalassemia or β-duplication traits and in mice heterozygous for both traits

    International Nuclear Information System (INIS)

    Popp, R.A.; Marsh, C.L.; Skow, L.C.

    1981-01-01

    Hemoglobins of mouse embryos at 11.5 through 16.5 days of gestation were separated by electrophoresis on cellulose acetate and quantitated by a scanning densitometer to study the effects of two radiation-induced mutations on the expression of embryonic hemoglobin genes in mice. Normal mice produce three kinds of embryonic hemoglobins. In heterozygous α-thalassemic embryos, expression of EI (x 2 y 2 ) and EII (α 2 y 2 ) is deficient because the x- and α-globin genes of one of the allelic pairs of Hba on chromosome 11 was deleted or otherwise inactivated by X irradiation. Simultaneous inactivation of the x- and α-globin genes indicates that these genes must be closely linked. Reduced x- and α-chain synthesis results in an excess of y chains that associate as homotetramers. This unique y 4 hemoglobin also appears in β-duplication embryos where excess y chains are produced by the presence of three rather than two functional alleles of y- and β-globin genes. In double heterozygotes, which have a single functional allele of x- and α-globin genes and three functional alleles of y- and β-globin genes, synthesis of α and non-α chains is severely imbalanced and half of the total hemoglobin is y 4 . Mouse y 4 has a high affinity for oxygen, P 50 of less than 10 mm Hg, but it lacks cooperativity so is inefficient for oxygen transport. The death of double heterozygotes in late fetal or neonatal life may be in large part to oxygen deprivation to the tissues

  13. A heterozygous mutation in RPGR associated with X-linked retinitis pigmentosa in a patient with Turner syndrome mosaicism (45,X/46,XX).

    Science.gov (United States)

    Zhou, Qi; Yao, Fengxia; Wang, Feng; Li, Hui; Chen, Rui; Sui, Ruifang

    2018-01-01

    Turner syndrome with retinitis pigmentosa (RP) is rare, with only three cases reported based on clinical examination alone. We summarized the 4-year follow-up and molecular findings in a 28-year-old patient with Turner syndrome and the typical features of short stature and neck webbing, who also had X-linked RP. Her main complaints were night blindness and progressive loss of vision since the age of 9 years. Ophthalmologic examination, optical coherent tomographic imaging, and visual electrophysiology tests showed classic manifestations of RP. The karyotype of peripheral blood showed mosaicism (45,X [72%]/46,XX[28%]). A novel heterozygous frameshift mutation (c.2403_2406delAGAG, p.T801fsX812) in the RP GTPase regulator (RPGR) gene was detected using next generation sequencing and validated by Sanger sequencing. We believe that this is the first report of X-linked RP in a patient with Turner syndrome associated with mosaicism, and an RPGR heterozygous mutation. We hypothesize that X-linked RP in this woman is not related to Turner syndrome, but may be a manifestation of the lack of a normal paternal X chromosome with intact but mutated RPGR. © 2017 Wiley Periodicals, Inc.

  14. Identification of a Novel De Novo Heterozygous Deletion in the SOX10 Gene in Waardenburg Syndrome Type II Using Next-Generation Sequencing.

    Science.gov (United States)

    Li, Haonan; Jin, Peng; Hao, Qian; Zhu, Wei; Chen, Xia; Wang, Ping

    2017-11-01

    Waardenburg syndrome (WS) is a rare autosomal dominant disorder associated with pigmentation abnormalities and sensorineural hearing loss. In this study, we investigated the genetic cause of WSII in a patient and evaluated the reliability of the targeted next-generation exome sequencing method for the genetic diagnosis of WS. Clinical evaluations were conducted on the patient and targeted next-generation sequencing (NGS) was used to identify the candidate genes responsible for WSII. Multiplex ligation-dependent probe amplification (MLPA) and real-time quantitative polymerase chain reaction (qPCR) were performed to confirm the targeted NGS results. Targeted NGS detected the entire deletion of the coding sequence (CDS) of the SOX10 gene in the WSII patient. MLPA results indicated that all exons of the SOX10 heterozygous deletion were detected; no aberrant copy number in the PAX3 and microphthalmia-associated transcription factor (MITF) genes was found. Real-time qPCR results identified the mutation as a de novo heterozygous deletion. This is the first report of using a targeted NGS method for WS candidate gene sequencing; its accuracy was verified by using the MLPA and qPCR methods. Our research provides a valuable method for the genetic diagnosis of WS.

  15. Draft Sequencing of the Heterozygous Diploid Genome of Satsuma (Citrus unshiu Marc. Using a Hybrid Assembly Approach

    Directory of Open Access Journals (Sweden)

    Tokurou Shimizu

    2017-12-01

    Full Text Available Satsuma (Citrus unshiu Marc. is one of the most abundantly produced mandarin varieties of citrus, known for its seedless fruit production and as a breeding parent of citrus. De novo assembly of the heterozygous diploid genome of Satsuma (“Miyagawa Wase” was conducted by a hybrid assembly approach using short-read sequences, three mate-pair libraries, and a long-read sequence of PacBio by the PLATANUS assembler. The assembled sequence, with a total size of 359.7 Mb at the N50 length of 386,404 bp, consisted of 20,876 scaffolds. Pseudomolecules of Satsuma constructed by aligning the scaffolds to three genetic maps showed genome-wide synteny to the genomes of Clementine, pummelo, and sweet orange. Gene prediction by modeling with MAKER-P proposed 29,024 genes and 37,970 mRNA; additionally, gene prediction analysis found candidates for novel genes in several biosynthesis pathways for gibberellin and violaxanthin catabolism. BUSCO scores for the assembled scaffold and predicted transcripts, and another analysis by BAC end sequence mapping indicated the assembled genome consistency was close to those of the haploid Clementine, pummel, and sweet orange genomes. The number of repeat elements and long terminal repeat retrotransposon were comparable to those of the seven citrus genomes; this suggested no significant failure in the assembly at the repeat region. A resequencing application using the assembled sequence confirmed that both kunenbo-A and Satsuma are offsprings of Kishu, and Satsuma is a back-crossed offspring of Kishu. These results illustrated the performance of the hybrid assembly approach and its ability to construct an accurate heterozygous diploid genome.

  16. Stimulation of cholesteryl ester synthesis in mouse peritoneal macrophages by cholesterol-rich very low density lipoproteins from the Watanabe heritable hyperlipidemic rabbit, an animal model of familial hypercholesterolemia

    International Nuclear Information System (INIS)

    Kita, T.; Yokode, M.; Watanabe, Y.; Narumiya, S.; Kawai, C.

    1986-01-01

    Cholesterol-rich very low density lipoproteins (VLDL) from the homozygous Watanabe heritable hyperlipidemic (WHHL) rabbit induced marked cholesteryl ester accumulation in mouse peritoneal macrophages. This WHHL rabbit, an animal model of human familial hypercholesterolemia, has severe hypercholesterolemia, cutaneous xanthomas, and fulminant atherosclerosis due to the deficiency of the low density lipoprotein (LDL) receptor. When incubated with mouse peritoneal macrophages, the VLDL from WHHL rabbit (WHHL-VLDL) stimulated cholesteryl [ 14 C]oleate synthesis 124-fold more than did VLDL from the normal Japanese White rabbit (control-VLDL). The enhancement in cholesteryl ester synthesis and accumulation of WHHL-VLDL was due to the presence of a high affinity binding receptor site on the macrophage cell surface that mediated the uptake and lysosomal degradation of WHHL-VLDL. Competition studies showed that the uptake and degradation of 125 I-WHHL-VLDL was inhibited by unlabeled excess WHHL-VLDL and beta-migrating VLDL (beta-VLDL), but not LDL. Furthermore, the degradation of WHHL-VLDL was not blocked by either fucoidin, polyinosinic acid, or polyguanylic acid, potent inhibitors of the acetylated (acetyl)-LDL binding site, or by acetyl-LDL. These results suggest that macrophages possess a high affinity receptor that recognizes the cholesterol-rich VLDL present in the plasma of the WHHL rabbit and that the receptor which mediates ingestion of WHHL-VLDL seems to be the same as that for beta-VLDL and leads to cholesteryl ester deposition within macrophages. Thus, the uptake of the cholesterol-rich VLDL from the WHHL rabbit by macrophages in vivo may play a significant role in the pathogenesis of atherosclerosis in the WHHL rabbit

  17. No evidence for association of autism with rare heterozygous point mutations in Contactin-Associated Protein-Like 2 (CNTNAP2, or in Other Contactin-Associated Proteins or Contactins.

    Directory of Open Access Journals (Sweden)

    John D Murdoch

    2015-01-01

    Full Text Available Contactins and Contactin-Associated Proteins, and Contactin-Associated Protein-Like 2 (CNTNAP2 in particular, have been widely cited as autism risk genes based on findings from homozygosity mapping, molecular cytogenetics, copy number variation analyses, and both common and rare single nucleotide association studies. However, data specifically with regard to the contribution of heterozygous single nucleotide variants (SNVs have been inconsistent. In an effort to clarify the role of rare point mutations in CNTNAP2 and related gene families, we have conducted targeted next-generation sequencing and evaluated existing sequence data in cohorts totaling 2704 cases and 2747 controls. We find no evidence for statistically significant association of rare heterozygous mutations in any of the CNTN or CNTNAP genes, including CNTNAP2, placing marked limits on the scale of their plausible contribution to risk.

  18. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene.

    Directory of Open Access Journals (Sweden)

    Ewan R Pearson

    2007-04-01

    Full Text Available Macrosomia is associated with considerable neonatal and maternal morbidity. Factors that predict macrosomia are poorly understood. The increased rate of macrosomia in the offspring of pregnant women with diabetes and in congenital hyperinsulinaemia is mediated by increased foetal insulin secretion. We assessed the in utero and neonatal role of two key regulators of pancreatic insulin secretion by studying birthweight and the incidence of neonatal hypoglycaemia in patients with heterozygous mutations in the maturity-onset diabetes of the young (MODY genes HNF4A (encoding HNF-4alpha and HNF1A/TCF1 (encoding HNF-1alpha, and the effect of pancreatic deletion of Hnf4a on foetal and neonatal insulin secretion in mice.We examined birthweight and hypoglycaemia in 108 patients from families with diabetes due to HNF4A mutations, and 134 patients from families with HNF1A mutations. Birthweight was increased by a median of 790 g in HNF4A-mutation carriers compared to non-mutation family members (p < 0.001; 56% (30/54 of HNF4A-mutation carriers were macrosomic compared with 13% (7/54 of non-mutation family members (p < 0.001. Transient hypoglycaemia was reported in 8/54 infants with heterozygous HNF4A mutations, but was reported in none of 54 non-mutation carriers (p = 0.003. There was documented hyperinsulinaemia in three cases. Birthweight and prevalence of neonatal hypoglycaemia were not increased in HNF1A-mutation carriers. Mice with pancreatic beta-cell deletion of Hnf4a had hyperinsulinaemia in utero and hyperinsulinaemic hypoglycaemia at birth.HNF4A mutations are associated with a considerable increase in birthweight and macrosomia, and are a novel cause of neonatal hypoglycaemia. This study establishes a key role for HNF4A in determining foetal birthweight, and uncovers an unanticipated feature of the natural history of HNF4A-deficient diabetes, with hyperinsulinaemia at birth evolving to decreased insulin secretion and diabetes later in life.

  19. The Intersection of Identity, Culture and Science Engagement

    Science.gov (United States)

    Strong, LaToya

    2016-01-01

    Ivã Gurgel, Mauricio Pietrocola, and Graciella Watanabe expand upon the existing literature, which links identity and science engagement. Specifically, the authors focus on ways in which the cultural identities of students relate to their engagement in physics. In doing so, Gurgel, Pietrocola, and Watanabe further build upon the idea that one's…

  20. Partial rescue of in vivo insulin signalling in skeletal muscle by impaired insulin clearance in heterozygous carriers of a mutation in the insulin receptor gene

    DEFF Research Database (Denmark)

    Højlund, K.; Wojtaszewski, Jørgen; Birk, Jesper Bratz

    2006-01-01

    AIMS/HYPOTHESIS: Recently we reported the coexistence of postprandial hypoglycaemia and moderate insulin resistance in heterozygous carriers of the Arg1174Gln mutation in the insulin receptor gene (INSR). Controlled studies of in vivo insulin signalling in humans with mutant INSR are unavailable,...

  1. Clinical Features and Long-Term Outcome of Nephrotic Syndrome Associated with Heterozygous NPHS1 and NPHS2 Mutations

    Science.gov (United States)

    Caridi, Gianluca; Gigante, Maddalena; Ravani, Pietro; Trivelli, Antonella; Barbano, Giancarlo; Scolari, Francesco; Dagnino, Monica; Murer, Luisa; Murtas, Corrado; Edefonti, Alberto; Allegri, Landino; Amore, Alessandro; Coppo, Rosanna; Emma, Francesco; De Palo, Tommaso; Penza, Rosa; Gesualdo, Loreto; Ghiggeri, Gian Marco

    2009-01-01

    Background and objectives: Mutations in nephrin (NPHS1) and podocin (NPHS2) genes represent a major cause of idiopathic nephrotic syndrome (NS) in children. It is not yet clear whether the presence of a single mutation acts as a modifier of the clinical course of NS. Design, setting, participants, & measurements: We reviewed the clinical features of 40 patients with NS associated with heterozygous mutations or variants in NPHS1 (n = 7) or NPHS2 (n = 33). Long-term renal survival probabilities were compared with those of a concurrent cohort with idiopathic NS. Results: Patients with a single mutation in NPHS1 received a diagnosis before those with potentially nongenetic NS and had a good response to therapies. Renal function was normal in all cases. For NPHS2, six patients had single heterozygous mutations, six had a p.P20L variant, and 21 had a p.R229Q variant. Age at diagnosis and the response to drugs were comparable in all NS subgroups. Overall, they had similar renal survival probabilities as non-NPHS1/NPHS2 cases (log-rank χ2 0.84, P = 0.656) that decreased in presence of resistance to therapy (P < 0.001) and in cases with renal lesions of glomerulosclerosis and IgM deposition (P < 0.001). Cox regression confirmed that the only significant predictor of dialysis was resistance to therapy. Conclusions: Our data indicate that single mutation or variant in NPHS1 and NPHS2 does not modify the outcome of primary NS. These patients should be treated following consolidated schemes and have good chances for a good long-term outcome. PMID:19406966

  2. Nature vs. nurture: can enrichment rescue the behavioural phenotype of BDNF heterozygous mice?

    Science.gov (United States)

    Chourbaji, Sabine; Brandwein, Christiane; Vogt, Miriam A; Dormann, Christof; Hellweg, Rainer; Gass, Peter

    2008-10-10

    In earlier experiments we have demonstrated that group-housing in a rather impoverished "standard" environment can be a crucial stress factor in male C57Bl/6 mice. The present study aimed at investigating the effect of combining a probable genetic vulnerability--postulated by the "Neurotrophin Hypothesis of Depression"--with the potentially modulating influence of a stressful environment such as "impoverished" standard housing conditions. For that purpose mice with a partial deletion of brain-derived neurotrophic factor (BDNF) were group-housed under standard and enriched housing conditions and analysed in a well-established test battery for emotional behaviours. Standard group-housing affected emotional behaviour in male and female BDNF heterozygous mice, causing an increase in anxiety, changes in exploration as well as nociception. Providing the animals' cages with supplementary enrichment, however, led to a rescue of emotional alterations, which emphasises the significance of external factors and their relevance for a valid investigation of genetic aspects in these mutants as well as others, which may be examined in terms of stress-responsiveness or emotionality.

  3. Generation of an ASS1 heterozygous knockout human embryonic stem cell line, WAe001-A-13, using CRISPR/Cas9

    Directory of Open Access Journals (Sweden)

    Fang Yuan

    2018-01-01

    Full Text Available The ASS1 gene encodes argininosuccinate synthetase-1, a cytosolic enzyme with a critical role in the urea cycle. Mutations are found in all ASS1 exons and cause the autosomal recessive disorder citrullinemia. Using CRISPR/Cas9-editing, we established the WAe001-A-13 cell line, which was heterozygous for an ASS1 mutation, from the human embryonic stem cell line H1. The WAe001-A-13 cell line maintained the pluripotent phenotype, the ability to differentiate into all three germ layers and a normal karyotype.

  4. Autosomal-dominant Leber Congenital Amaurosis Caused by a Heterozygous CRX Mutation in a Father and Son.

    Science.gov (United States)

    Arcot Sadagopan, Karthikeyan; Battista, Robert; Keep, Rosanne B; Capasso, Jenina E; Levin, Alex V

    2015-06-01

    Leber congenital amaurosis (LCA) is most often an autosomal recessive disorder. We report a father and son with autosomal dominant LCA due to a mutation in the CRX gene. DNA screening using an allele specific assay of 90 of the most common LCA-causing variations in the coding sequences of AIPL1, CEP290, CRB1, CRX, GUCY2D, RDH12 and RPE65 was performed on the father. Automated DNA sequencing of his son examining exon 3 of the CRX gene was subsequently performed. Both father and son have a heterozygous single base pair deletion of an adenine at codon 153 in the coding sequence of the CRX gene resulting in a frameshift mutation. Mutations involving the CRX gene may demonstrate an autosomal dominant inheritance pattern for LCA.

  5. The detection of heterozygous familial hypercholesterolemia in Ireland.

    LENUS (Irish Health Repository)

    O'Kane, Maurice J

    2012-05-01

    Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant condition with a population prevalence of 1 in 500, and is associated with significant cardiovascular morbidity and mortality. It may be caused by mutations in the low-density lipoprotein (LDL) receptor, apolipoprotein B100 (Apo B100), or proprotein convertase subtilisin\\/kexin type 9 (PCSK9) genes, with over 1,000 causative mutations described. Statin therapy in HeFH is considered effective and safe. Audit data suggest that approximately 80% of the putative HeFH population remains unidentified and, therefore, there is a need to develop a strategy for the identification of affected individuals so that early lipid-lowering treatment may be offered. There is good evidence showing the effectiveness and acceptability of HeFH screening programs in Europe. The authors describe a protocol for an all island approach to HeFH detection in the Republic of Ireland\\/Northern Ireland. Index cases will be identified by opportunistic screening using the Simon Broome, or Make Early Diagnosis to Prevent Early Death (MedPed) and World Health Organization (WHO) criteria. Patients identified as "definite," "probable," or "possible" HeFH criteria will be offered genetic testing. The authors expect causative mutations to be identified in approximately 80% of patients with "definite" HeFH but in only approximately 20% of patients with "possible" HeFH. Cascade screening will be undertaken in first-degree relatives of the index case using genetic testing (where a causative mutation has been identified), or otherwise using LDL cholesterol concentration. The establishment of a HeFH screening program on an all-island basis will require: expansion of the existing molecular genetics diagnostic services, the establishment of a cohort of nurses\\/genetic counselors, a HeFH database to support cascade testing, the development of a network of lipid clinics (in a primary or secondary care setting), and an educational

  6. DMPD: Activation of lymphokine genes in T cells: role of cis-acting DNA elements thatrespond to T cell activation signals. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available thatrespond to T cell activation signals. Arai N, Naito Y, Watanabe M, Masuda ES, Yamaguchi-Iwai Y, Tsuboi A, Heike T,Matsud... in T cells: role of cis-acting DNA elements thatrespond to T cell activation signals. Authors Arai N, Naito Y, Watanabe M, Masud...a ES, Yamaguchi-Iwai Y, Tsuboi A, Heike T,Matsuda I, Yokota

  7. On the validity of cosmic no-hair conjecture in an anisotropic inationary model

    Science.gov (United States)

    Do, Tuan Q.

    2018-05-01

    We will present main results of our recent investigations on the validity of cosmic no-hair conjecture proposed by Hawking and his colleagues long time ago in the framework of an anisotropic inflationary model proposed by Kanno, Soda, and Watanabe. As a result, we will show that the cosmic no-hair conjecture seems to be generally violated in the Kanno-Soda- Watanabe model for both canonical and non-canonical scalar fields due to the existence of a non-trivial coupling term between scalar and electromagnetic fields. However, we will also show that the validity of the cosmic no-hair conjecture will be ensured once a unusual scalar field called the phantom field, whose kinetic energy term is negative definite, is introduced into the Kanno-Soda-Watanabe model.

  8. Altered hippocampal replay is associated with memory impairment in mice heterozygous for the Scn2a gene.

    Science.gov (United States)

    Middleton, Steven J; Kneller, Emily M; Chen, Shuo; Ogiwara, Ikuo; Montal, Mauricio; Yamakawa, Kazuhiro; McHugh, Thomas J

    2018-06-04

    An accumulating body of experimental evidence has implicated hippocampal replay occurring within sharp wave ripples (SPW-Rs) as crucial for learning and memory in healthy subjects. This raises speculation that neurological disorders impairing memory disrupt either SPW-Rs or their underlying neuronal activity. We report that mice heterozygous for the gene Scn2a, a site of frequent de novo mutations in humans with intellectual disability, displayed impaired spatial memory. While we observed no changes during encoding, to either single place cells or cell assemblies, we identified abnormalities restricted to SPW-R episodes that manifest as decreased cell assembly reactivation strengths and truncated hippocampal replay sequences. Our results suggest that alterations to hippocampal replay content may underlie disease-associated memory deficits.

  9. Selection on viability of individuals heterozygous for the temperature-sensitive lethal mutation l(2)M167DTS in experimental populations of Drosophila melanogaster

    Czech Academy of Sciences Publication Activity Database

    Kulikov, A. M.; Marec, František; Mitrofanov, V. G.

    2005-01-01

    Roč. 41, č. 6 (2005), s. 613-619 ISSN 1022-7954 Grant - others:Russian Foundation for Basic Research(RU) 02-04-50021; Program of the Presidium of the Russian Academy of Sciences "Dynamics of Gene Pools in Plants, Animals, and Humans"(RU) 10002-251/P-24/154-150/2004-04-111 Institutional research plan: CEZ:AV0Z50070508 Keywords : heterozygous Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.240, year: 2005

  10. Wilson's disease: Rapid diagnosis and differentiation of heterozygous and homozygous carriers with 64CuCl2

    International Nuclear Information System (INIS)

    Wesch, H.; Przuntek, H.; Feist, D.; Wuerzburg Univ.; Heidelberg Univ.

    1980-01-01

    In the modified radiocopper test, a constant amount of copper and not of radioactivity is injected, a difference being made between males and females. The rate of incorporation of 64 Cu into caeruloplasmin and urinary excretion of nuclides is measured. It is a method with low radiation exposure, providing a definite diagnosis after 30 hours. This was demonstrated in 27 homozygous patients, 30 parents and 33 siblings, and 25 controls: a clear-cut diagnosis was made in all untreated homozygous patients. In five of eight patients treated with D-penicillamine for several years, the values were in the range of heterozygotes, so that the test makes treatment control possible. The recognition of heterozygous carriers is interfered with by contraceptives and infections. The results in control subjects were all widely outside the range for patients with Wilson's disease. (orig.) [de

  11. Novel compound heterozygous mutations in MYO7A in a Chinese family with Usher syndrome type 1.

    Science.gov (United States)

    Liu, Fei; Li, Pengcheng; Liu, Ying; Li, Weirong; Wong, Fulton; Du, Rong; Wang, Lei; Li, Chang; Jiang, Fagang; Tang, Zhaohui; Liu, Mugen

    2013-01-01

    To identify the disease-causing mutation(s) in a Chinese family with autosomal recessive Usher syndrome type 1 (USH1). An ophthalmic examination and an audiometric test were conducted to ascertain the phenotype of two affected siblings. The microsatellite marker D11S937, which is close to the candidate gene MYO7A (USH1B locus), was selected for genotyping. From the DNA of the proband, all coding exons and exon-intron boundaries of MYO7A were sequenced to identify the disease-causing mutation(s). Restriction fragment length polymorphism (RFLP) analysis was performed to exclude the alternative conclusion that the mutations are non-pathogenic rare polymorphisms. Based on severe hearing impairment, unintelligible speech, and retinitis pigmentosa, a clinical diagnosis of Usher syndrome type 1 was made. The genotyping results did not exclude the USH1B locus, which suggested that the MYO7A gene was likely the gene associated with the disease-causing mutation(s) in the family. With direct DNA sequencing of MYO7A, two novel compound heterozygous mutations (c.3742G>A and c.6051+1G>A) of MYO7A were identified in the proband. DNA sequence analysis and RFLP analysis of other family members showed that the mutations cosegregated with the disease. Unaffected members, including the parents, uncle, and sister of the proband, carry only one of the two mutations. The mutations were not present in the controls (100 normal Chinese subjects=200 chromosomes) according to the RFLP analysis. In this study, we identified two novel mutations, c.3742G>A (p.E1248K) and c.6051+1G>A (donor splice site mutation in intron 44), of MYO7A in a Chinese non-consanguineous family with USH1. The mutations cosegregated with the disease and most likely cause the phenotype in the two affected siblings who carry these mutations compound heterozygously. Our finding expands the mutational spectrum of MYO7A.

  12. Novel heterozygous nonsense mutation of the OPTN gene segregating in a Danish family with ALS

    DEFF Research Database (Denmark)

    Tümer, Zeynep; Bertelsen, Birgitte; Gredal, Ole

    2012-01-01

    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. About 10% of ALS cases are familial (FALS) and the genetic defect is known only in approximately 20%-30% of these cases. The most common genetic cause of ALS is SOD1 (superoxide dismutase 1) mutation. Very recently......, mutations of the optineurin gene (OPTN), which is involved in open-angle glaucoma, were identified in 3 Japanese patients/families with ALS, and subsequently in a few FALS patients of European descent. We found a heterozygous nonsense mutation (c.493C>T, p.Gln165X, exon 6) in the OPTN gene in a Danish...... patient with ALS, and the mutation segregated from his affected father. The p.Gln165X mutation could not be detected in 1070 healthy Danish controls, in 1000 Danish individuals with metabolic phenotypes or in 64 sporadic ALS (SALS) cases. The p.Gln165X mutation described in this study is the first...

  13. Generation of a heterozygous knockout human embryonic stem cell line for the OCIAD1 locus using CRISPR/CAS9 mediated targeting: BJNhem20-OCIAD1-CRISPR-20

    Directory of Open Access Journals (Sweden)

    Deeti K. Shetty

    2016-03-01

    Full Text Available Ovarian carcinoma immuno-reactive antigen domain containing 1(OCIAD1 single copy was knocked out generating an OCIAD1 heterozygous knockout human embryonic stem line named BJNhem20-OCIAD1-CRISPR-20. The line was generated using CRISPR-Cas9D10A double nickase knockout strategy (Mali et al., 2013.

  14. Low oxygen saturation and severe anemia in compound heterozygous Hb Louisville [β42(CD1)Phe→Leu] and Hb La Desirade [β129(H7)Ala→Val].

    Science.gov (United States)

    Kamseng, Parin; Trakulsrichai, Satariya; Trachoo, Objoon; Yimniam, Walaiporn; Panthan, Bhakbhoom; Jittorntam, Paisan; Niparuck, Pimjai; Sanguanwit, Pitsucha; Wananukul, Winai; Jindadamrongwech, Sumalee

    2017-03-01

    To investigate the cause(s) of a Thai male proband presenting low oxygen saturation by pulse oximetry (SpO 2 ) and severe anemia. As Hb variant was suspected, Hb typing was determined by high-performance liquid chromatography and capillary electrophoresis, and subsequently Hb variant was identified by DNA sequencing. Complete blood counts were performed using automated blood cell counter and oxygen saturation was measured by pulse oximetry. Proband was compound heterozygous for Hb Louisville [β42(CD1)Phe→Leu] and Hb La Desirade [β129(H7)Ala→Val]. Of the proband's two sons, one was compound heterozygous for Hb Louisville and Hb E and the other for Hb La Desirade and Hb E. The former son had similar clinical features and laboratory findings with those of the proband while the latter showed had no abnormal clinical manifestations. This the first report of compound heterozygosity of Hb Louisville and Hb La Desirade in an individual of Southeast Asian ethnicity. Hb variant identification is crucial for genetic counseling and appropriate treatment in regions where hemoglobinopathies are common.

  15. Identification of a Novel Heterozygous Missense Mutation in the CACNA1F Gene in a Chinese Family with Retinitis Pigmentosa by Next Generation Sequencing

    Directory of Open Access Journals (Sweden)

    Qi Zhou

    2015-01-01

    Full Text Available Background. Retinitis pigmentosa (RP is an inherited retinal degenerative disease, which is clinically and genetically heterogeneous, and the inheritance pattern is complex. In this study, we have intended to study the possible association of certain genes with X-linked RP (XLRP in a Chinese family. Methods. A Chinese family with RP was recruited, and a total of seven individuals were enrolled in this genetic study. Genomic DNA was isolated from peripheral leukocytes, and used for the next generation sequencing (NGS. Results. The affected individual presented the clinical signs of XLRP. A heterozygous missense mutation (c.1555C>T, p.R519W was identified by NGS in exon 13 of the CACNA1F gene on X chromosome, and was confirmed by Sanger sequencing. It showed perfect cosegregation with the disease in the family. The mutation at this position in the CACNA1F gene of RP was found novel by database searching. Conclusion. By using NGS, we have found a novel heterozygous missense mutation (c.1555C>T, p.R519W in CACNA1F gene, which is probably associated with XLRP. The findings might provide new insights into the cause and diagnosis of RP, and have implications for genetic counseling and clinical management in this family.

  16. [Haplotype Analysis of Coagulation Factor VII Gene in a Patient with Congenital Coagulation Factor VII Deficiency with Heterozygous p.Arg337Cys Mutation and o.Aro413Gin Polymorphism..

    Science.gov (United States)

    Suzuki, Keijiro; Yoshioka, Tomoko; Obara, Takehiro; Suwabe, Akira

    2016-05-01

    Congenital coagulation factor VII (FVII) deficiency is a rare hemorrhagic disease with an autosomal reces- sive inheritance pattern. We analyzed coagulation factor VII gene (F7) of a patient with FVII deficiency and used expression studies to investigate the effect of a missense mutation on FVII secretion. The proband, a 69-year-old Japanese woman, had a history of postpartum bleeding and excessive bleeding after dental extrac- tion. She was found to have mildly increased PT-INR (1.17) before an ophthalmic operation. FVII activity and antigen were reduced (29.0% and 32.8%). Suspecting that the proband was FVII deficient, we analyzed F7 of the patient. Sequence analysis revealed that the patient was heterozygous for a point mutation (p.Arg337Cys) in the catalytic domain and polymorphisms: the decanucleotide insertion at the promoter re- gion, dimorphism (c.525C >T) in exon 5, and p.Arg413Gln in exon 8. Haplotype analysis clarified that p.Arg337Cys was located on the p.Arg413 allele (Ml allele). The other allele had the p.Arg413Gln polymor- phism(M2 allele) which is known to produce less FVII. Expression studies revealed that p.Arg337Cys causes impairment of FVII secretion. Insufficient secretion of FVII arising from both the p.Arg337Cys/M1 allele and the p.Arg337/M2 allele might lower the FVII level of this patient(<50%). The FVII level in a heterozygous FVII deficient patient might be influenced by F7 polymorphisms on the normal allele. There- fore, genetic analyses are important for the diagnosis of heterozygous FVII deficiency.

  17. Compound heterozygous loss-of-function mutations in KIF20A are associated with a novel lethal congenital cardiomyopathy in two siblings.

    Directory of Open Access Journals (Sweden)

    Jacoba J Louw

    2018-01-01

    Full Text Available Congenital or neonatal cardiomyopathies are commonly associated with a poor prognosis and have multiple etiologies. In two siblings, a male and female, we identified an undescribed type of lethal congenital restrictive cardiomyopathy affecting the right ventricle. We hypothesized a novel autosomal recessive condition. To identify the cause, we performed genetic, in vitro and in vivo studies. Genome-wide SNP typing and parametric linkage analysis was done in a recessive model to identify candidate regions. Exome sequencing analysis was done in unaffected and affected siblings. In the linkage regions, we selected candidate genes that harbor two rare variants with predicted functional effects in the patients and for which the unaffected sibling is either heterozygous or homozygous reference. We identified two compound heterozygous variants in KIF20A; a maternal missense variant (c.544C>T: p.R182W and a paternal frameshift mutation (c.1905delT: p.S635Tfs*15. Functional studies confirmed that the R182W mutation creates an ATPase defective form of KIF20A which is not able to support efficient transport of Aurora B as part of the chromosomal passenger complex. Due to this, Aurora B remains trapped on chromatin in dividing cells and fails to translocate to the spindle midzone during cytokinesis. Translational blocking of KIF20A in a zebrafish model resulted in a cardiomyopathy phenotype. We identified a novel autosomal recessive congenital restrictive cardiomyopathy, caused by a near complete loss-of-function of KIF20A. This finding further illustrates the relationship of cytokinesis and congenital cardiomyopathy.

  18. Command and Control of the U.S. Tenth Army During the Battle of Okinawa

    Science.gov (United States)

    2009-06-12

    Army‘s XXIV Corps, commanded by Major General John R . Hodge, and the U.S. Marine Corps‘ III Amphibious Corps, commanded by Major General Roy S. Geiger...Watanabe, was activated in April 1944. Ushijima assumed command in August 1944, after Watanabe was bedridden and sent back to Japan due to chronic...great success and combat experience during the war in the Pacific. Army Major General John R . Hodge commanded the XXIV Corps. Hodge was commissioned

  19. [Hereditary heterozygous factor VII deficiency in patients undergoing surgery : Clinical relevance].

    Science.gov (United States)

    Woehrle, D; Martinez, M; Bolliger, D

    2016-10-01

    A hereditary deficiency in coagulation factor VII (FVII) may affect the international normalized ratio (INR) value. However, FVII deficiency is occasionally associated with a tendency to bleed spontaneously. We hypothesized that perioperative substitution with coagulation factor concentrates might not be indicated in most patients. In this retrospective data analysis, we included all patients with hereditary heterozygous FVII deficiency who underwent surgical procedures at the University Hospital Basel between December 2010 and November 2015. In addition, by searching the literature, we identified publications reporting patients with FVII deficiency undergoing surgical procedures without perioperative substitution. We identified 22 patients undergoing 46 surgical procedures, resulting in a prevalence of 1:1500-2000. Coagulation factor concentrates were administered during the perioperative period in 15 procedures (33 %), whereas in the other 31 procedures (66 %), FVII deficiency was not substituted. No postoperative bleeding or thromboembolic events were reported. In addition, we found no differences in pre- and postoperative hemoglobin and coagulation parameters, with the exception of an improved postoperative INR value in the substituted group. In the literature review, we identified five publications, including 125 patients with FVII deficiency, undergoing 213 surgical procedures with no perioperative substitution. Preoperative substitution using coagulation factor concentrates does not seem to be mandatory in patients with an FVII level ≥15 %. For decision-making on preoperative substitution, patient history of an increased tendency to bleed may be more important than the FVII level or increased INR value.

  20. Cognitive assessment of mice strains heterozygous for cell-adhesion genes reveals strain-specific alterations in timing.

    Science.gov (United States)

    Gallistel, C R; Tucci, Valter; Nolan, Patrick M; Schachner, Melitta; Jakovcevski, Igor; Kheifets, Aaron; Barboza, Luendro

    2014-03-05

    We used a fully automated system for the behavioural measurement of physiologically meaningful properties of basic mechanisms of cognition to test two strains of heterozygous mutant mice, Bfc (batface) and L1, and their wild-type littermate controls. Both of the target genes are involved in the establishment and maintenance of synapses. We find that the Bfc heterozygotes show reduced precision in their representation of interval duration, whereas the L1 heterozygotes show increased precision. These effects are functionally specific, because many other measures made on the same mice are unaffected, namely: the accuracy of matching temporal investment ratios to income ratios in a matching protocol, the rate of instrumental and classical conditioning, the latency to initiate a cued instrumental response, the trials on task and the impulsivity in a switch paradigm, the accuracy with which mice adjust timed switches to changes in the temporal constraints, the days to acquisition, and mean onset time and onset variability in the circadian anticipation of food availability.

  1. Generalized pustular psoriasis in infant with heterozygous mutation in the IL36RN gene successfully treated with infliximab

    DEFF Research Database (Denmark)

    Glerup, Mia; Veirum, Jens Erik; Iversen, L

    2014-01-01

    started on intravenous antibiotics and topical corticosteroids. During the following week the dermal changes presented with scaly sharply demarcated psoriasiform plaques. Infection was cleared and treatment with topical betamethasone gave a partial improvement. Cardiac surgery was performed at the age...... during the cardiac procedures, but the extracorporeal membrane oxygenation (ECMO) system had been primed with methyl-prednisolone and a rebound effect of steroid was suspected. Methotrexate treatment was initiated and topical corticosteroids and parenteral antibiotics were added. On suspection for DIRA......L IL36Ra mutation along with heterozygous Q705K NLRP3 mutation, phenotypically expressed as DITRA with severe generalized pustular psoriasis. Reduction of the IL36Ra function will lead to excessive activity of cytokines belonging to the IL-1 family, furthermore the gain-of-function mutation in NLRP3...

  2. Aberrant methylation of Polo-like kinase CpG islands in Plk4 heterozygous mice

    International Nuclear Information System (INIS)

    Ward, Alejandra; Morettin, Alan; Shum, David; Hudson, John W

    2011-01-01

    Hepatocellular carcinoma (HCC), one of the most common cancers world-wide occurs twice as often in men compared to women. Predisposing conditions such as alcoholism, chronic viral hepatitis, aflatoxin B1 ingestion, and cirrhosis all contribute to the development of HCC. We used a combination of methylation specific PCR and bisulfite sequencing, qReal-Time PCR (qPCR), and Western blot analysis to examine epigenetic changes for the Polo-like kinases (Plks) during the development of hepatocellular carcinoma (HCC) in Plk4 heterozygous mice and murine embryonic fibroblasts (MEFs). Here we report that the promoter methylation of Plk4 CpG islands increases with age, was more prevalent in males and that Plk4 epigenetic modification and subsequent downregulation of expression was associated with the development of HCC in Plk4 mutant mice. Interestingly, the opposite occurs with another Plk family member, Plk1 which was typically hypermethylated in normal liver tissue but became hypomethylated and upregulated in liver tumours. Furthermore, upon alcohol exposure murine embryonic fibroblasts exhibited increased Plk4 hypermethylation and downregulation along with increased centrosome numbers and multinucleation. These results suggest that aberrant Plk methylation is correlated with the development of HCC in mice

  3. R353Q polymorphism in the factor VII gene and cardiovascular risk in Heterozygous Familial Hypercholesterolemia: a case-control study.

    Science.gov (United States)

    Criado-García, Juan; Fuentes, Francisco; Cruz-Teno, Cristina; García-Rios, Antonio; Jiménez-Morales, Anabel; Delgado-Lista, Javier; Mata, Pedro; Alonso, Rodrigo; López-Miranda, José; Pérez-Jiménez, Francisco

    2011-04-09

    Heterozygous Familial Hypercholesterolemia (FH) is a genetic disorder characterized by a high risk of cardiovascular disease. Certain polymorphisms of the factor VII gene have been associated with the development of coronary artery disease and there is a known association between factor VII levels and polymorphic variants in this gene. To date, no study has evaluated the association between factor VII and coronary artery disease in patients with FH. This case-control study comprised 720 patients (546 with FH and 174 controls). We determined the prevalence and allele frequencies of the R353Q polymorphism of factor VII, the plasma levels of factor VII antigen (FVII Ag) and whether they could be predictive factors for cardiovascular risk. 75% (410) of the patients with FH were RR, 23% (127) RQ and 1.6% (9) QQ; in the control group 75.3% (131) were RR, 21.3% (37) RQ and 3.4% (6) QQ (p = 0.32). No statistically significant associations were observed in the distribution of genotypes and allele frequencies between case (FH) and control groups. Nor did we find differences when we evaluated the relationship between the R353Q polymorphism and cardiovascular risk (including coronary disease, ischemic stroke and peripheral arterial disease), either in the univariate analysis or after adjustment for sex, age, arterial hypertension, body mass index, xanthomas, diabetes, smoking, HDLc and LDLc and lipid-lowering treatment. The FVII Ag concentrations behaved in a similar fashion, with no differences for the interaction between controls and those with FH (RR vs. RQ/QQ; p = 0.96). In the subgroup of patients with FH no association was found among cardiovascular disease, genotype and FVII Ag levels (RR vs. RQ/QQ; p = 0.97). Our study did not find a direct relationship between cardiovascular risk in patients with Heterozygous Familial Hypercholesterolemia, the R353Q polymorphism of factor VII and FVII Ag levels.

  4. Poly(ADP-ribose) synthesis following DNA damage in cells heterozygous or homozygous for the xeroderma pigmentosum genotype

    International Nuclear Information System (INIS)

    McCurry, L.S.; Jacobson, M.K.

    1981-01-01

    Treatment of normal human cells with DNA-damaging agents such as uv light or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) stimulates the conversion of NAD to the chromosomal polymer poly(ADP-ribose) which in turn results in a rapid depletion of the cellular NAD pool. The effect of uv light or MNNG on the NAD pools of seven cell lines of human fibroblasts either homozygous or heterozygous for the xeroderma pigmentosum genotype has been studied. Xeroderma pigmentosum cells of genetic complementation groups A, C, and D are deficient in the excision repair of DNA damage caused by uv light. Following uv treatment, the NAD content of these cells was unchanged or only slightly reduced. All of the cell lines are able to excise DNA damage caused by MNNG and all of the cell lines had a greatly reduced content of NAD following MNNG treatment. The results demonstrate a close relationship between the conversion of NAD to poly(ADP-ribose) and DNA excision repair in human cells

  5. Novel compound heterozygous MYO7A mutations in Moroccan families with autosomal recessive non-syndromic hearing loss.

    Directory of Open Access Journals (Sweden)

    Amina Bakhchane

    Full Text Available The MYO7A gene encodes a protein belonging to the unconventional myosin super family. Mutations within MYO7A can lead to either non syndromic hearing loss or to the Usher syndrome type 1B (USH1B. Here, we report the results of genetic analyses performed on Moroccan families with autosomal recessive non syndromic hearing loss that identified two families with compound heterozygous MYO7A mutations. Five mutations (c.6025delG, c.6229T>A, c.3500T>A, c.5617C>T and c.4487C>A were identified in these families, the latter presenting two differently affected branches. Multiple bioinformatics programs and molecular modelling predicted the pathogenic effect of these mutations. In conclusion, the absence of vestibular and retinal symptom in the affected patients suggests that these families have the isolated non-syndromic hearing loss DFNB2 (nonsyndromic autosomal recessive hearing loss presentation, instead of USH1B.

  6. Normal X-inactivation mosaicism in corneas of heterozygous FlnaDilp2/+ female mice--a model of human Filamin A (FLNA diseases

    Directory of Open Access Journals (Sweden)

    Douvaras Panagiotis

    2012-02-01

    Full Text Available Abstract Background Some abnormalities of mouse corneal epithelial maintenance can be identified by the atypical mosaic patterns they produce in X-chromosome inactivation mosaics and chimeras. Human FLNA/+ females, heterozygous for X-linked, filamin A gene (FLNA mutations, display a range of disorders and X-inactivation mosaicism is sometimes quantitatively unbalanced. FlnaDilp2/+ mice, heterozygous for an X-linked filamin A (Flna nonsense mutation have variable eye, skeletal and other abnormalities, but X-inactivation mosaicism has not been investigated. The aim of this study was to determine whether X-inactivation mosaicism in the corneal epithelia of FlnaDilp2/+ mice was affected in any way that might predict abnormal corneal epithelial maintenance. Results X-chromosome inactivation mosaicism was studied in the corneal epithelium and a control tissue (liver of FlnaDilp2/+ and wild-type (WT female X-inactivation mosaics, hemizygous for the X-linked, LacZ reporter H253 transgene, using β-galactosidase histochemical staining. The corneal epithelia of FlnaDilp2/+ and WT X-inactivation mosaics showed similar radial, striped patterns, implying epithelial cell movement was not disrupted in FlnaDilp2/+ corneas. Corrected stripe numbers declined with age overall (but not significantly for either genotype individually, consistent with previous reports suggesting an age-related reduction in stem cell function. Corrected stripe numbers were not reduced in FlnaDilp2/+ compared with WT X-inactivation mosaics and mosaicism was not significantly more unbalanced in the corneal epithelia or livers of FlnaDilp2/+ than wild-type Flna+/+ X-inactivation mosaics. Conclusions Mosaic analysis identified no major effect of the mouse FlnaDilp2 mutation on corneal epithelial maintenance or the balance of X-inactivation mosaicism in the corneal epithelium or liver.

  7. A novel heterozygous mutation of the WFS1 gene leading to constitutive endoplasmic reticulum stress is the cause of Wolfram syndrome.

    Science.gov (United States)

    Morikawa, Shuntaro; Tajima, Toshihiro; Nakamura, Akie; Ishizu, Katsura; Ariga, Tadashi

    2017-12-01

    Wolfram syndrome (WS) is a disorder characterized by the association of insulin-dependent diabetes mellitus (DM), diabetes insipidus, deafness, and optic nerve atrophy. WS is caused by WFS1 mutations encoding WFS1 protein expressed in endoplasmic reticulum (ER). During ER protein synthesis, misfolded and unfolded proteins accumulate, known as "ER stress". This is attenuated by the unfolded protein response (UPR), which recovers and maintains ER functions. Because WFS1 is a UPR component, mutant WFS1 might cause unresolvable ER stress conditions and cell apoptosis, the major causes underlying WS symptoms. We encountered an 11-month-old Japanese female WS patient with insulin-dependent DM, congenital cataract and severe bilateral hearing loss. Analyze the WFS1 and functional consequence of the patient WFS1 in vitro. The patient WFS1 contained a heterozygous 4 amino acid in-frame deletion (p.N325_I328del). Her mutant WFS1 increased GRP78 and ATF6α promoter activities in the absence of thapsigargin, indicating constitutive ER stress and nuclear factor of activated T-cell reporter activity, reflecting elevated cytosolic Ca 2+ signals. Mutant transfection into cells reduced mRNA expression levels of sarcoplasmic/endoplasmic reticulum Ca 2+ transport ATPase 2b (SERCA2b) compared with wild type. Because SERCA2b is required for ER and cytoplasmic Ca 2+ homeostasis, decreased SERCA2b expression might affect ER Ca 2+ efflux, causing cell apoptosis. A novel heterozygous mutation of WFS1 induced constitutive ER stress through ATF6α activation and ER Ca 2+ efflux, resulting in cell apoptosis. These results provide new insights into the roles of WFS1 in UPR and mechanism of monogenic DM. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Heterozygous Disruption of Autism susceptibility candidate 2 Causes Impaired Emotional Control and Cognitive Memory.

    Directory of Open Access Journals (Sweden)

    Kei Hori

    Full Text Available Mutations in the Autism susceptibility candidate 2 gene (AUTS2 have been associated with a broad range of psychiatric illnesses including autism spectrum disorders, intellectual disability and schizophrenia. We previously demonstrated that the cytoplasmic AUTS2 acts as an upstream factor for the Rho family small GTPase Rac1 and Cdc42 that regulate the cytoskeletal rearrangements in neural cells. Moreover, genetic ablation of the Auts2 gene in mice has resulted in defects in neuronal migration and neuritogenesis in the developing cerebral cortex caused by inactivation of Rac1-signaling pathway, suggesting that AUTS2 is required for neural development. In this study, we conducted a battery of behavioral analyses on Auts2 heterozygous mutant mice to examine the involvement of Auts2 in adult cognitive brain functions. Auts2-deficient mice displayed a decrease in exploratory behavior as well as lower anxiety-like behaviors in the absence of any motor dysfunction. Furthermore, the capability for novel object recognition and cued associative memory were impaired in Auts2 mutant mice. Social behavior and sensory motor gating functions were, however, normal in the mutant mice as assessed by the three-chamber test and prepulse inhibition test, respectively. Together, our findings indicate that AUTS2 is critical for the acquisition of neurocognitive function.

  9. Recombination and synaptic adjustment in oocytes of mice heterozygous for a large paracentric inversion.

    Science.gov (United States)

    Torgasheva, Anna A; Rubtsov, Nikolai B; Borodin, Pavel M

    2013-03-01

    Homologous chromosome synapsis in inversion heterozygotes results in the formation of inversion loops. These loops might be transformed into straight, non-homologously paired bivalents via synaptic adjustment. Synaptic adjustment was discovered 30 years ago; however, its relationship with recombination has remained unclear. We analysed this relationship in female mouse embryos heterozygous for large paracentric inversion In(1)1Rk using immunolocalisation of the synaptonemal complex (SYCP3) and mature recombination nodules (MLH1) proteins. The frequency of cells containing bivalents with inversion loops decreased from 69 % to 28 % during pachytene. If an MLH1 focus was present in the non-homologously paired inverted region of the straight bivalent, it was always located in the middle of the inversion. Most of the small, incompletely adjusted loops contained MLH1 foci near the points at which pairing partners were switched. This observation indicates that the degree of synaptic adjustment depended on the crossover position. Complete synaptic adjustment was only possible if a crossover (CO) was located exactly in the middle of the inversion. If a CO was located at any other site, this interrupted synaptic adjustment and resulted in inversion loops of different sizes with an MLH1 focus at or near the edge of the remaining loop.

  10. High-throughput SNP genotyping in the highly heterozygous genome of Eucalyptus: assay success, polymorphism and transferability across species

    Science.gov (United States)

    2011-01-01

    Background High-throughput SNP genotyping has become an essential requirement for molecular breeding and population genomics studies in plant species. Large scale SNP developments have been reported for several mainstream crops. A growing interest now exists to expand the speed and resolution of genetic analysis to outbred species with highly heterozygous genomes. When nucleotide diversity is high, a refined diagnosis of the target SNP sequence context is needed to convert queried SNPs into high-quality genotypes using the Golden Gate Genotyping Technology (GGGT). This issue becomes exacerbated when attempting to transfer SNPs across species, a scarcely explored topic in plants, and likely to become significant for population genomics and inter specific breeding applications in less domesticated and less funded plant genera. Results We have successfully developed the first set of 768 SNPs assayed by the GGGT for the highly heterozygous genome of Eucalyptus from a mixed Sanger/454 database with 1,164,695 ESTs and the preliminary 4.5X draft genome sequence for E. grandis. A systematic assessment of in silico SNP filtering requirements showed that stringent constraints on the SNP surrounding sequences have a significant impact on SNP genotyping performance and polymorphism. SNP assay success was high for the 288 SNPs selected with more rigorous in silico constraints; 93% of them provided high quality genotype calls and 71% of them were polymorphic in a diverse panel of 96 individuals of five different species. SNP reliability was high across nine Eucalyptus species belonging to three sections within subgenus Symphomyrtus and still satisfactory across species of two additional subgenera, although polymorphism declined as phylogenetic distance increased. Conclusions This study indicates that the GGGT performs well both within and across species of Eucalyptus notwithstanding its nucleotide diversity ≥2%. The development of a much larger array of informative SNPs across

  11. Functional recovery of regenerating motor axons is delayed in mice heterozygously deficient for the myelin protein P(0) gene

    DEFF Research Database (Denmark)

    Rosberg, Mette Romer; Alvarez, Susana; Krarup, Christian

    2013-01-01

    Mice with a heterozygous knock-out of the myelin protein P0 gene (P0+/-) develop a neuropathy similar to human Charcot-Marie-Tooth disease. They are indistinguishable from wild-types (WT) at birth and develop a slowly progressing demyelinating neuropathy. The aim of this study was to investigate...... whether the regeneration capacity of early symptomatic P0+/- is impaired as compared to age matched WT. Right sciatic nerves were lesioned at the thigh in 7-8 months old mice. Tibial motor axons at ankle were investigated by conventional motor conduction studies and axon excitability studies using...... threshold tracking. To evaluate regeneration we monitored the recovery of motor function after crush, and then compared the fiber distribution by histology. The overall motor performance was investigated using Rotor-Rod. P0+/- had reduced compound motor action potential amplitudes and thinner myelinated...

  12. Changes in 5-HT4 receptor and 5-HT transporter binding in olfactory bulbectomized and glucocorticoid receptor heterozygous mice

    DEFF Research Database (Denmark)

    Licht, Cecilie L; Kirkegaard, Lisbeth; Zueger, Maha

    2010-01-01

    . The olfactory bulbectomized mice displayed increased activity in the open field test, a characteristic depression-like feature of this model. After bulbectomy, 5-HT(4) receptor binding was increased in the ventral hippocampus (12%) but unchanged in the dorsal hippocampus, frontal and caudal caudate putamen......]citalopram in two murine models of depression-related states, olfactory bulbectomy and glucocorticoid receptor heterozygous (GR(+/-)) mice. The olfactory bulbectomy model is characterized by 5-HT system changes, while the GR(+/-) mice have a deficit in hypothalamic-pituitary-adrenal (HPA) system control....... Among post hoc analyzed regions, there was a 14% decrease in 5-HT(4) receptor binding in the olfactory tubercles. The 5-HTT binding was unchanged in the hippocampus and caudate putamen of bulbectomized mice but post hoc analysis showed small decreases in lateral septum and lateral globus pallidus...

  13. R353Q polymorphism in the factor VII gene and cardiovascular risk in Heterozygous Familial Hypercholesterolemia: a case-control study

    Directory of Open Access Journals (Sweden)

    Pérez-Jiménez Francisco

    2011-04-01

    Full Text Available Abstract Background Heterozygous Familial Hypercholesterolemia (FH is a genetic disorder characterized by a high risk of cardiovascular disease. Certain polymorphisms of the factor VII gene have been associated with the development of coronary artery disease and there is a known association between factor VII levels and polymorphic variants in this gene. To date, no study has evaluated the association between factor VII and coronary artery disease in patients with FH. Results This case-control study comprised 720 patients (546 with FH and 174 controls. We determined the prevalence and allele frequencies of the R353Q polymorphism of factor VII, the plasma levels of factor VII antigen (FVII Ag and whether they could be predictive factors for cardiovascular risk. 75% (410 of the patients with FH were RR, 23% (127 RQ and 1.6% (9 QQ; in the control group 75.3% (131 were RR, 21.3% (37 RQ and 3.4% (6 QQ (p = 0.32. No statistically significant associations were observed in the distribution of genotypes and allele frequencies between case (FH and control groups. Nor did we find differences when we evaluated the relationship between the R353Q polymorphism and cardiovascular risk (including coronary disease, ischemic stroke and peripheral arterial disease, either in the univariate analysis or after adjustment for sex, age, arterial hypertension, body mass index, xanthomas, diabetes, smoking, HDLc and LDLc and lipid-lowering treatment. The FVII Ag concentrations behaved in a similar fashion, with no differences for the interaction between controls and those with FH (RR vs. RQ/QQ; p = 0.96. In the subgroup of patients with FH no association was found among cardiovascular disease, genotype and FVII Ag levels (RR vs. RQ/QQ; p = 0.97. Conclusions Our study did not find a direct relationship between cardiovascular risk in patients with Heterozygous Familial Hypercholesterolemia, the R353Q polymorphism of factor VII and FVII Ag levels.

  14. Commission 22: Meters, Meteorites and Interplanetary Dust

    Science.gov (United States)

    Watanabe, Junichi; Jenniskens, Peter; Spurný, Pavel; Borovička, Jiří; Campbell-Brown, Margaret; Consolmagno, Guy; Jopek, Tadeusz; Vaubaillon, Jeremie; Williams, Iwan P.; Zhu, Jin

    2010-05-01

    The business meeting of commission 22 was held at the room 5 in the SulAmerica Convention Center in Rio de Janeiro(14:00-15:30). Fifteen people attended at this meeting:J.Borovička, E.Bowell, G.Consolmagno, D.Green, P. Jenniskens, A. Pellinen-Wannberg, R. Rudawska, J. Watanabe, J. Zhu, P. H. A. Hasselmann, F. Ostroviski, D. A. Oszkiewicz, W. Thuillot, P. Mahajani, and A. Sule. This meeting was managed by Junichi Watanabe, the current C22 Vice-President. The summary of the meeting is described.

  15. Explosive mutation accumulation triggered by heterozygous human Pol ε proofreading-deficiency is driven by suppression of mismatch repair

    Science.gov (United States)

    Campbell, Brittany B; Ungerleider, Nathan; Light, Nicholas; Wu, Tong; LeCompte, Kimberly G; Goksenin, A Yasemin; Bunnell, Bruce A; Tabori, Uri; Shlien, Adam

    2018-01-01

    Tumors defective for DNA polymerase (Pol) ε proofreading have the highest tumor mutation burden identified. A major unanswered question is whether loss of Pol ε proofreading by itself is sufficient to drive this mutagenesis, or whether additional factors are necessary. To address this, we used a combination of next generation sequencing and in vitro biochemistry on human cell lines engineered to have defects in Pol ε proofreading and mismatch repair. Absent mismatch repair, monoallelic Pol ε proofreading deficiency caused a rapid increase in a unique mutation signature, similar to that observed in tumors from patients with biallelic mismatch repair deficiency and heterozygous Pol ε mutations. Restoring mismatch repair was sufficient to suppress the explosive mutation accumulation. These results strongly suggest that concomitant suppression of mismatch repair, a hallmark of colorectal and other aggressive cancers, is a critical force for driving the explosive mutagenesis seen in tumors expressing exonuclease-deficient Pol ε. PMID:29488881

  16. Effects of LSD on grooming behavior in serotonin transporter heterozygous (Sert⁺/⁻) mice.

    Science.gov (United States)

    Kyzar, Evan J; Stewart, Adam Michael; Kalueff, Allan V

    2016-01-01

    Serotonin (5-HT) plays a crucial role in the brain, modulating mood, cognition and reward. The serotonin transporter (SERT) is responsible for the reuptake of 5-HT from the synaptic cleft and regulates serotonin signaling in the brain. In humans, SERT genetic variance is linked to the pathogenesis of various psychiatric disorders, including anxiety, autism spectrum disorders (ASD) and obsessive-compulsive disorder (OCD). Rodent self-grooming is a complex, evolutionarily conserved patterned behavior relevant to stress, ASD and OCD. Genetic ablation of mouse Sert causes various behavioral deficits, including increased anxiety and grooming behavior. The hallucinogenic drug lysergic acid diethylamide (LSD) is a potent serotonergic agonist known to modulate human and animal behavior. Here, we examined heterozygous Sert(+/-) mouse behavior following acute administration of LSD (0.32 mg/kg). Overall, Sert(+/-) mice displayed a longer duration of self-grooming behavior regardless of LSD treatment. In contrast, LSD increased serotonin-sensitive behaviors, such as head twitching, tremors and backwards gait behaviors in both Sert(+/+) and Sert(+/-) mice. There were no significant interactions between LSD treatment and Sert gene dosage in any of the behavioral domains measured. These results suggest that Sert(+/-) mice may respond to the behavioral effects of LSD in a similar manner to wild-type mice. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. [Novel CHST6 compound heterozygous mutations cause macular corneal dystrophy in a Chinese family].

    Science.gov (United States)

    Qi, Yan-hua; Dang, Xiu-hong; Su, Hong; Zhou, Nan; Liang, Ting; Wang, Zheng; Huang, Shang-zhi

    2010-02-01

    The aim of this study was to identify mutations of CHST6 gene in a Chinese family with macular corneal dystrophy (MCD) and to investigate the histopathological changes of MCD. Corneal button of the proband was obtained from penetrating keratoplasty for the treatment of severe corneal dystrophy. The sections and ultrathin sections of this specimen were examined under light microscope and transmission electron microscope (TEM). Genomic DNA was extracted from leukocytes in peripheral blood from the family members. The coding region of CHST6 was amplified by polymerase chain reaction (PCR). The PCR products were analyzed by direct sequencing and restriction enzyme digestion. Histochemical study revealed positive results of colloidal iron stain. TEM revealed enlargement of smooth endoplasmic reticulum and the presence of intracytoplasmic vacuoles. Two mutations, Q298X Y358H, were identified in exon 3 of CHST6. Three patients were compound heterozygotes of these two mutations. The C892T transversion occurred at codon 298 turned the codon of glutamine to a stop codon; the T1072C transversion occurred at codon 358 caused a missense mutation, tyrosine to histidine. All six unaffected family members were heterozygotes. These two mutations were not detected in any of the 100 control subjects. The novel compound heterozygous mutation results in loss of CHST6 function and causes the occurrence of MCD. This is the first report of this gene mutation.

  18. A novel loss-of-function heterozygous BRCA2 c.8946_8947delAG mutation found in a Chinese woman with family history of breast cancer.

    Science.gov (United States)

    Ma, Jing; Yang, Jichun; Jian, Wenjing; Wang, Xianming; Xiao, Deyong; Xia, Wenjun; Xiong, Likuan; Ma, Duan

    2017-04-01

    Breast cancer is the most frequent female malignancy worldwide. Among them, some cases have hereditary susceptibility in two leading genes, BRCA1 and BRCA2. Heterozygous germ line mutations in them are related with increased risk of breast, ovarian and other cancer, following autosomal dominant inheritance mode. For purpose of early finding, early diagnosis and early treatment, mutation detecting of BRCA1/2 genes was performed in unselected 300 breast or ovarian patients and unaffected women using next-generation sequencing and then confirmed by Sanger sequencing. A non-previously reported heterozygous mutation c.8946_8947delAG (p.D2983FfsX34) of BRCA2 gene was identified in an unaffected Chinese woman with family history of breast cancer (her breast cancer mother, also carrying this mutation). The BRCA2-truncated protein resulted from the frame shift mutation was found to lose two putative nuclear localization signals and a Rad51-binding motif in the extreme C-terminal region by bioinformatic prediction. And then in vitro experiments showed that nearly all the mutant protein was unable to translocate to the nucleus to perform DNA repair activity. This novel mutant BRCA2 protein is dysfunction. We classify the mutation into disease causing and conclude that it is the risk factor for breast cancer in this family. So, conducting the same mutation test and providing genetic counseling for this family is practically meaningful and significant. Meanwhile, the identification of this new mutation enriches the Breast Cancer Information Core database, especially in China.

  19. Two novel mutations in exon 3 and 4 of low density lipoprotein (LDL) receptor gene in patients with heterozygous familial hypercholesterolemia

    International Nuclear Information System (INIS)

    Khan, S.P.

    2011-01-01

    Objective: To determine the common mutation of low density lipoprotein receptor in hypercholesterolemia patients requiring screening for heterozygous familial hypercholesterolemia (HeFH) in Karachi. Study Design: Case-series. Place and Duration of Study: Dr. Ziauddin Hospital Laboratory and Dr. Rubina Ghani's Pathological and Molecular Laboratories, Karachi, for the PCR bench work from June 2008 to October 2009. Methodology: All the patients selected for this study were from Dr. Ziauddin Hospital and National Institute of Cardiovascular Diseases. All the patients having high total cholesterol and LDL-cholesterol were included in this study with premature coronary artery diseases or a family history of hypercholesterolemia. Exclusion criteria included Diabetes mellitus, hypertension, renal disease, hypothyroidism and steroid therapy. After lipid profile with overnight fasting, DNA was extracted from whole blood collected in EDTA (ethylenediamine tetra acetic acid) tube and multiplex PCR (polymerase chain reaction) using forward and reverse primers of exons 3, 4, 9 and 14 of base pairs 162, 431, 550 and 496 respectively. Results: Out of total of 120 hypercholesterolemia cases, 42 patients were classical cases of HeFH (heterozygous familial hypercholesterolemia) with xanthomas, xanthelasmas and LDL-C > 160 mg/dl. The total cholesterol (260 +- 57 mg/dL) and LDL-C (192 +- 39 mg/dL ) of cases was significantly high as compared to, controls having total cholesterol (184 9 +- 27 mg/dL) and LDL-C (105 +- 22 mg/dL), p > 0.001. Two novel point mutations were noted in exon 3 and exon 4. The other 78 cases were probable with raised LDL-C (low density lipoprotein cholesterol) and family history of premature coronary heart diseases. Conclusion: The frequency of HeFH was 35% classical and 65% probable cases out of total 120 hypercholesterolemia patients from two tertiary care hospitals in Karachi. The point mutation on exon 3 and exon 4 of LDLR gene was the most common. PCR is

  20. A kinase-dead knock-in mutation in mTOR leads to early embryonic lethality and is dispensable for the immune system in heterozygous mice

    Directory of Open Access Journals (Sweden)

    Cavender Druie

    2009-05-01

    Full Text Available Abstract Background The mammalian target of rapamycin protein (mTOR is an evolutionarily conserved kinase that regulates protein synthesis, cell cycle progression and proliferation in response to various environmental cues. As a critical downstream mediator of PI3K signaling, mTOR is important for lymphocyte development and function of mature T and B-cells. Most studies of mTOR in immune responses have relied on the use of pharmacological inhibitors, such as rapamycin. Rapamycin-FKBP12 complex exerts its immunosuppressive and anti-proliferative effect by binding outside the kinase domain of mTOR, and subsequently inhibiting downstream mTOR signaling. Results To determine the requirement for mTOR kinase activity in the immune system function, we generated knock-in mice carrying a mutation (D2338 in the catalytic domain of mTOR. While homozygous mTOR kd/kd embryos died before embryonic day 6.5, heterozygous mTOR+/kd mice appeared entirely normal and are fertile. mTOR +/kd mice exhibited normal T and B cell development and unaltered proliferative responses of splenocytes to IL-2 and TCR/CD28. In addition, heterozygousity for the mTOR kinase-dead allele did not sensitize T cells to rapamycin in a CD3-mediated proliferation assay. Unexpectedly, mTOR kinase activity towards its substrate 4E-BP1 was not decreased in hearts and livers from heterozygous animals. Conclusion Altogether, our findings indicate that mTOR kinase activity is indispensable for the early development of mouse embryos. Moreover, a single wild type mTOR allele is sufficient to maintain normal postnatal growth and lymphocyte development and proliferation.

  1. Heterozygous Null Bone Morphogenetic Protein Receptor Type 2 Mutations Promote SRC Kinase-dependent Caveolar Trafficking Defects and Endothelial Dysfunction in Pulmonary Arterial Hypertension*

    Science.gov (United States)

    Prewitt, Allison R.; Ghose, Sampa; Frump, Andrea L.; Datta, Arumima; Austin, Eric D.; Kenworthy, Anne K.; de Caestecker, Mark P.

    2015-01-01

    Hereditary pulmonary arterial hypertension (HPAH) is a rare, fatal disease of the pulmonary vasculature. The majority of HPAH patients inherit mutations in the bone morphogenetic protein type 2 receptor gene (BMPR2), but how these promote pulmonary vascular disease is unclear. HPAH patients have features of pulmonary endothelial cell (PEC) dysfunction including increased vascular permeability and perivascular inflammation associated with decreased PEC barrier function. Recently, frameshift mutations in the caveolar structural protein gene Caveolin-1 (CAV-1) were identified in two patients with non-BMPR2-associated HPAH. Because caveolae regulate endothelial function and vascular permeability, we hypothesized that defects in caveolar function might be a common mechanism by which BMPR2 mutations promote pulmonary vascular disease. To explore this, we isolated PECs from mice carrying heterozygous null Bmpr2 mutations (Bmpr2+/−) similar to those found in the majority of HPAH patients. We show that Bmpr2+/− PECs have increased numbers and intracellular localization of caveolae and caveolar structural proteins CAV-1 and Cavin-1 and that these defects are reversed after blocking endocytosis with dynasore. SRC kinase is also constitutively activated in Bmpr2+/− PECs, and localization of CAV-1 to the plasma membrane is restored after treating Bmpr2+/− PECs with the SRC kinase inhibitor 3-(4-chlorophenyl)-1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (PP2). Late outgrowth endothelial progenitor cells isolated from HPAH patients show similar increased activation of SRC kinase. Moreover, Bmpr2+/− PECs have impaired endothelial barrier function, and barrier function is restored after treatment with PP2. These data suggest that heterozygous null BMPR2 mutations promote SRC-dependent caveolar trafficking defects in PECs and that this may contribute to pulmonary endothelial barrier dysfunction in HPAH patients. PMID:25411245

  2. Whole-exome sequencing identifies novel compound heterozygous mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa.

    Science.gov (United States)

    Méndez-Vidal, Cristina; González-Del Pozo, María; Vela-Boza, Alicia; Santoyo-López, Javier; López-Domingo, Francisco J; Vázquez-Marouschek, Carmen; Dopazo, Joaquin; Borrego, Salud; Antiñolo, Guillermo

    2013-01-01

    Retinitis pigmentosa (RP) is an inherited retinal dystrophy characterized by extreme genetic and clinical heterogeneity. Thus, the diagnosis is not always easily performed due to phenotypic and genetic overlap. Current clinical practices have focused on the systematic evaluation of a set of known genes for each phenotype, but this approach may fail in patients with inaccurate diagnosis or infrequent genetic cause. In the present study, we investigated the genetic cause of autosomal recessive RP (arRP) in a Spanish family in which the causal mutation has not yet been identified with primer extension technology and resequencing. We designed a whole-exome sequencing (WES)-based approach using NimbleGen SeqCap EZ Exome V3 sample preparation kit and the SOLiD 5500×l next-generation sequencing platform. We sequenced the exomes of both unaffected parents and two affected siblings. Exome analysis resulted in the identification of 43,204 variants in the index patient. All variants passing filter criteria were validated with Sanger sequencing to confirm familial segregation and absence in the control population. In silico prediction tools were used to determine mutational impact on protein function and the structure of the identified variants. Novel Usher syndrome type 2A (USH2A) compound heterozygous mutations, c.4325T>C (p.F1442S) and c.15188T>G (p.L5063R), located in exons 20 and 70, respectively, were identified as probable causative mutations for RP in this family. Family segregation of the variants showed the presence of both mutations in all affected members and in two siblings who were apparently asymptomatic at the time of family ascertainment. Clinical reassessment confirmed the diagnosis of RP in these patients. Using WES, we identified two heterozygous novel mutations in USH2A as the most likely disease-causing variants in a Spanish family diagnosed with arRP in which the cause of the disease had not yet been identified with commonly used techniques. Our data

  3. Hearing dysfunction in heterozygous Mitf(Mi-wh) /+ mice, a model for Waardenburg syndrome type 2 and Tietz syndrome.

    Science.gov (United States)

    Ni, Christina; Zhang, Deming; Beyer, Lisa A; Halsey, Karin E; Fukui, Hideto; Raphael, Yehoash; Dolan, David F; Hornyak, Thomas J

    2013-01-01

    The human deafness-pigmentation syndromes, Waardenburg syndrome (WS) type 2a, and Tietz syndrome are characterized by profound deafness but only partial cutaneous pigmentary abnormalities. Both syndromes are caused by mutations in MITF. To illuminate differences between cutaneous and otic melanocytes in these syndromes, their development and survival in heterozygous Microphthalmia-White (Mitf(Mi-wh) /+) mice were studied and hearing function of these mice characterized. Mitf(Mi-wh) /+ mice have a profound hearing deficit, characterized by elevated auditory brainstem response thresholds, reduced distortion product otoacoustic emissions, absent endocochlear potential, loss of outer hair cells, and stria vascularis abnormalities. Mitf(Mi-wh) /+ embryos have fewer melanoblasts during embryonic development than their wild-type littermates. Although cochlear melanocytes are present at birth, they disappear from the Mitf(Mi-wh) /+ cochlea between P1 and P7. These findings may provide insight into the mechanism of melanocyte and hearing loss in human deafness-pigmentation syndromes such as WS and Tietz syndrome and illustrate differences between otic and follicular melanocytes. © 2012 John Wiley & Sons A/S.

  4. Pregnancy-associated osteoporosis with a heterozygous deactivating LDL receptor-related protein 5 (LRP5) mutation and a homozygous methylenetetrahydrofolate reductase (MTHFR) polymorphism.

    Science.gov (United States)

    Cook, Fiona J; Mumm, Steven; Whyte, Michael P; Wenkert, Deborah

    2014-04-01

    Pregnancy-associated osteoporosis (PAO) is a rare, idiopathic disorder that usually presents with vertebral compression fractures (VCFs) within 6 months of a first pregnancy and delivery. Spontaneous improvement is typical. There is no known genetic basis for PAO. A 26-year-old primagravida with a neonatal history of unilateral blindness attributable to hyperplastic primary vitreous sustained postpartum VCFs consistent with PAO. Her low bone mineral density (BMD) seemed to respond to vitamin D and calcium therapy, with no fractures after her next successful pregnancy. Investigation of subsequent fetal losses revealed homozygosity for the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism associated both with fetal loss and with osteoporosis (OP). Because her neonatal unilateral blindness and OP were suggestive of loss-of-function mutation(s) in the gene that encodes LDL receptor-related protein 5 (LRP5), LRP5 exon and splice site sequencing was also performed. This revealed a unique heterozygous 12-bp deletion in exon 21 (c.4454_4465del, p.1485_1488del SSSS) in the patient, her mother and sons, but not her father or brother. Her mother had a normal BMD, no history of fractures, PAO, ophthalmopathy, or fetal loss. Her two sons had no ophthalmopathy and no skeletal issues. Her osteoporotic father (with a family history of blindness) and brother had low BMDs first documented at ages ∼40 and 32 years, respectively. Serum biochemical and bone turnover studies were unremarkable in all subjects. We postulate that our patient's heterozygous LRP5 mutation together with her homozygous MTHFR polymorphism likely predisposed her to low peak BMD. However, OP did not cosegregate in her family with the LRP5 mutation, the homozygous MTHFR polymorphism, or even the combination of the two, implicating additional genetic or nongenetic factors in her PAO. Nevertheless, exploration for potential genetic contributions to PAO may explain part of the pathogenesis of this

  5. Identification of FASTKD2 compound heterozygous mutations as the underlying cause of autosomal recessive MELAS-like syndrome.

    Science.gov (United States)

    Yoo, Da Hye; Choi, Young-Chul; Nam, Da Eun; Choi, Sun Seong; Kim, Ji Won; Choi, Byung-Ok; Chung, Ki Wha

    2017-07-01

    Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a condition that affects many parts of the body, particularly the brain and muscles. This study examined a Korean MELAS-like syndrome patient with seizure, stroke-like episode, and optic atrophy. Target sequencing of whole mtDNA and 73 nuclear genes identified compound heterozygous mutations p.R205X and p.L255P in the FASTKD2. Each of his unaffected parents has one of the two mutations, and both mutations were not found in 302 controls. FASTKD2 encodes a FAS-activated serine-threonine (FAST) kinase domain 2 which locates in the mitochondrial inner compartment. A FASTKD2 nonsense mutation was once reported as the cause of a recessive infantile mitochondrial encephalomyopathy. The present case showed relatively mild symptoms with a late onset age, compared to a previous patient with FASTKD2 mutation, implicating an inter-allelic clinical heterogeneity. Because this study is the second report of an autosomal recessive mitochondrial encephalomyopathy patient with a FASTKD2 mutation, it will extend the phenotypic spectrum of the FASTKD2 mutation. Copyright © 2017. Published by Elsevier B.V.

  6. Clonal evolution following chemotherapy-induced stem cell depletion in cats heterozygous for glucose-6-phosphate dehydrogenase

    International Nuclear Information System (INIS)

    Abkowitz, J.L.; Ott, R.M.; Holly, R.D.; Adamson, J.W.

    1988-01-01

    The number of hematopoietic stem cells necessary to support normal hematopoiesis is not known but may be small. If so, the depletion or damage of such cells could result in apparent clonal dominance. To test this hypothesis, dimethylbusulfan [2 to 4 mg/kg intravenously (IV) x 3] was given to cats heterozygous for the X-linked enzyme glucose-6-phosphate dehydrogenase (G-6-PD). These cats were the daughters of domestic X Geoffroy parents. After the initial drug-induced cytopenias (2 to 4 weeks), peripheral blood counts and the numbers of marrow progenitors detected in culture remained normal, although the percentages of erythroid burst-forming cells (BFU-E) and granulocyte/macrophage colony-forming cells (CFU-GM) in DNA synthesis increased, as determined by the tritiated thymidine suicide technique. In three of six cats treated, a dominance of Geoffroy-type G-6-PD emerged among the progenitor cells, granulocytes, and RBCs. These skewed ratios of domestic to Geoffroy-type G-6-PD have persisted greater than 3 years. No changes in cell cycle kinetics or G-6-PD phenotypes were noted in similar studies in six control cats. These data suggest that clonal evolution may reflect the depletion or damage of normal stem cells and not only the preferential growth and dominance of neoplastic cells

  7. Thiamine responsive megaloblastic anemia: a novel SLC19A2 compound heterozygous mutation in two siblings.

    Science.gov (United States)

    Mozzillo, Enza; Melis, Daniela; Falco, Mariateresa; Fattorusso, Valentina; Taurisano, Roberta; Flanagan, Sarah E; Ellard, Sian; Franzese, Adriana

    2013-08-01

    Thiamine responsive megaloblastic anemia (TRMA) is an autosomal recessive disease caused by loss of function mutations in the SLC19A2 gene. TRMA is characterized by anemia, deafness, and diabetes. In some cases, optic atrophy or more rarely retinitis pigmentosa is noted. We now report two sisters, the eldest of which presented to a different hospital during childhood with sensorineural deafness, which was treated with a hearing prosthesis, insulin requiring diabetes, retinitis pigmentosa, optic atrophy, and macrocytic anemia. These features initially suggested a clinical diagnosis of Wolfram syndrome (WS). Therapy with thiamine was initiated which resulted in the resolution of the anemia. The younger sister, who was affected with sensorineural deafness, was referred to our hospital for non-autoimmune diabetes. She was found to have macrocytosis and ocular abnormalities. Because a diagnosis of TRMA was suspected, therapy with insulin and thiamine was started. Sequencing analysis of the SLC19A2 gene identified a compound heterozygous mutation p.Y81X/p.L457X (c.242insA/c.1370delT) in both sisters. Non-autoimmune diabetes associated with deafness and macrocytosis, without anemia, suggests a diagnosis of TRMA. Patients clinically diagnosed with WS with anemia and/or macrocytosis should be reevaluated for TRMA. © 2012 John Wiley & Sons A/S.

  8. Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism.

    Science.gov (United States)

    Frazier, T W; Embacher, R; Tilot, A K; Koenig, K; Mester, J; Eng, C

    2015-09-01

    PTEN is a tumor suppressor associated with an inherited cancer syndrome and an important regulator of ongoing neural connectivity and plasticity. The present study examined molecular and phenotypic characteristics of individuals with germline heterozygous PTEN mutations and autism spectrum disorder (ASD) (PTEN-ASD), with the aim of identifying pathophysiologic markers that specifically associate with PTEN-ASD and that may serve as targets for future treatment trials. PTEN-ASD patients (n=17) were compared with idiopathic (non-PTEN) ASD patients with (macro-ASD, n=16) and without macrocephaly (normo-ASD, n=38) and healthy controls (n=14). Group differences were evaluated for PTEN pathway protein expression levels, global and regional structural brain volumes and cortical thickness measures, neurocognition and adaptive behavior. RNA expression patterns and brain characteristics of a murine model of Pten mislocalization were used to further evaluate abnormalities observed in human PTEN-ASD patients. PTEN-ASD had a high proportion of missense mutations and showed reduced PTEN protein levels. Compared with the other groups, prominent white-matter and cognitive abnormalities were specifically associated with PTEN-ASD patients, with strong reductions in processing speed and working memory. White-matter abnormalities mediated the relationship between PTEN protein reductions and reduced cognitive ability. The Pten(m3m4) murine model had differential expression of genes related to myelination and increased corpus callosum. Processing speed and working memory deficits and white-matter abnormalities may serve as useful features that signal clinicians that PTEN is etiologic and prompting referral to genetic professionals for gene testing, genetic counseling and cancer risk management; and could reveal treatment targets in trials of treatments for PTEN-ASD.

  9. Stanol esters attenuate the aggravating effect of dietary cholesterol on atherosclerosis in homozygous Watanabe rabbits

    DEFF Research Database (Denmark)

    Schrøder, Malene; Husche, Constanze; Pilegaard, Kirsten

    2009-01-01

    Plant stanols are marketed as natural means to lower blood cholesterol in humans; hence the effect on combined familial hyperlipidemia is not known. The objective was to investigate the effect of stanol esters on blood lipids and aortic atherosclerosis in homozygous WHHL rabbits challenged...... with dietary cholesterol. A total of 36 rabbits, 6 weeks of age, with initial plasma cholesterol of 22.5 mmol/L were assigned to two treatment groups fed a standard rabbit chow with 1 g/kg cholesterol or this diet added 34 g/kg stanol ester, respectively, for 16 weeks. Plasma cholesterol was measured initially...... and at termination, also in lipoproteins. Aortic atherosclerosis was evaluated as cholesterol content and area covered by plaque. Plasma cholesterol was not significantly different between the groups at termination (35.7 mmol/L vs. 35.5 mmol/L). A significant increase in LDL was seen (13.1 mmol/L vs. 16.5 mmol...

  10. A high incidence of meiotic silencing of unsynapsed chromatin is not associated with substantial pachytene loss in heterozygous male mice carrying multiple simple robertsonian translocations.

    Directory of Open Access Journals (Sweden)

    Marcia Manterola

    2009-08-01

    Full Text Available Meiosis is a complex type of cell division that involves homologous chromosome pairing, synapsis, recombination, and segregation. When any of these processes is altered, cellular checkpoints arrest meiosis progression and induce cell elimination. Meiotic impairment is particularly frequent in organisms bearing chromosomal translocations. When chromosomal translocations appear in heterozygosis, the chromosomes involved may not correctly complete synapsis, recombination, and/or segregation, thus promoting the activation of checkpoints that lead to the death of the meiocytes. In mammals and other organisms, the unsynapsed chromosomal regions are subject to a process called meiotic silencing of unsynapsed chromatin (MSUC. Different degrees of asynapsis could contribute to disturb the normal loading of MSUC proteins, interfering with autosome and sex chromosome gene expression and triggering a massive pachytene cell death. We report that in mice that are heterozygous for eight multiple simple Robertsonian translocations, most pachytene spermatocytes bear trivalents with unsynapsed regions that incorporate, in a stage-dependent manner, proteins involved in MSUC (e.g., gammaH2AX, ATR, ubiquitinated-H2A, SUMO-1, and XMR. These spermatocytes have a correct MSUC response and are not eliminated during pachytene and most of them proceed into diplotene. However, we found a high incidence of apoptotic spermatocytes at the metaphase stage. These results suggest that in Robertsonian heterozygous mice synapsis defects on most pachytene cells do not trigger a prophase-I checkpoint. Instead, meiotic impairment seems to mainly rely on the action of a checkpoint acting at the metaphase stage. We propose that a low stringency of the pachytene checkpoint could help to increase the chances that spermatocytes with synaptic defects will complete meiotic divisions and differentiate into viable gametes. This scenario, despite a reduction of fertility, allows the spreading

  11. A heterozygous microdeletion of 20p12.2-3 encompassing PROKR2 and BMP2 in a patient with congenital hypopituitarism and growth hormone deficiency.

    Science.gov (United States)

    Parsons, Samuel J H; Wright, Neville B; Burkitt-Wright, Emma; Skae, Mars S; Murray, Phillip G

    2017-08-01

    Congenital growth hormone deficiency is a rare disorder with an incidence of approximately 1 in 4,000 live births. Pituitary development is under the control of a multitude of spatiotemporally regulated signaling molecules and transcription factors. Mutations in the genes encoding these molecules can result in hypopituitarism but for the majority of children with congenital hypopituitarism, the aetiology of their disease remains unknown. The proband is a 5-year-old girl who presented with neonatal hypoglycaemia and prolonged jaundice. No definitive endocrine cause of hypoglycaemia was identified in the neonatal period. She was born of normal size at 42 weeks but demonstrated growth failure with a progressive reduction in height to -3.2 SD by age 4.5 years and failed a growth hormone stimulation test with a peak growth hormone of 4.2 mcg/L. MRI of the pituitary gland demonstrated a hypoplastic anterior lobe and ectopic posterior lobe. Array CGH demonstrated an inherited 0.2 Mb gain at 1q21.1 and a de novo 4.8 Mb heterozygous deletion at 20p12.2-3. The deletion contained 17 protein coding genes including PROKR2 and BMP2, both of which are expressed during embryological development of the pituitary gland. PROKR2 mutations have been associated with hypopituitarism but a heterozygous deletion of this gene with hypopituitarism is a novel observation. In conclusion, congenital hypopituitarism can be present in individuals with a 20p12.3 deletion, observed with incomplete penetrance. Array CGH may be a useful investigation in select cases of early onset growth hormone deficiency, and patients with deletions within this region should be evaluated for pituitary hormone deficiencies. © 2017 Wiley Periodicals, Inc.

  12. Non-alcoholic fatty liver disease in mice with heterozygous mutation in TMED2.

    Directory of Open Access Journals (Sweden)

    Wenyang Hou

    Full Text Available The transmembrane emp24 domain/p24 (TMED family are essential components of the vesicular transport machinery. Members of the TMED family serve as cargo receptors implicated in selection and packaging of endoplasmic reticulum (ER luminal proteins into coatomer (COP II coated vesicles for anterograde transport to the Golgi. Deletion or mutations of Tmed genes in yeast and Drosophila results in ER-stress and activation of the unfolded protein response (UPR. The UPR leads to expression of genes and proteins important for expanding the folding capacity of the ER, degrading misfolded proteins, and reducing the load of new proteins entering the ER. The UPR is activated in non-alcoholic fatty liver disease (NAFLD in human and mouse and may contribute to the development and the progression of NAFLD. Tmed2, the sole member of the vertebrate Tmed β subfamily, exhibits tissue and temporal specific patterns of expression in embryos and developing placenta but is ubiquitously expressed in all adult organs. We previously identified a single point mutation, the 99J mutation, in the signal sequence of Tmed2 in an N-ethyl-N-nitrosourea (ENU mutagenesis screen. Histological and molecular analysis of livers from heterozygous mice carrying the 99J mutation, Tmed299J/+, revealed a requirement for TMED2 in liver health. We show that Tmed299J/+ mice had decreased levels of TMED2 and TMED10, dilated endoplasmic reticulum membrane, and increased phosphorylation of eIF2α, indicating ER-stress and activation of the UPR. Increased expression of Srebp1a and 2 at the newborn stage and increased incidence of NAFLD were also found in Tmed299J/+ mice. Our data establishes Tmed299J/+ mice as a novel mouse model for NAFLD and supports a role for TMED2 in liver health.

  13. BDNF-Deficient Mice Show Reduced Psychosis-Related Behaviors Following Chronic Methamphetamine.

    Science.gov (United States)

    Manning, Elizabeth E; Halberstadt, Adam L; van den Buuse, Maarten

    2016-04-01

    One of the most devastating consequences of methamphetamine abuse is increased risk of psychosis. Brain-derived neurotrophic factor has been implicated in both psychosis and neuronal responses to methamphetamine. We therefore examined persistent psychosis-like behavioral effects of methamphetamine in brain-derived neurotrophic factor heterozygous mice. Mice were chronically treated with methamphetamine from 6 to 9 weeks of age, and locomotor hyperactivity to an acute D-amphetamine challenge was tested in photocell cages after a 2-week withdrawal period. Methamphetamine-treated wild-type mice, but not brain-derived neurotrophic factor heterozygous mice, showed locomotor sensitization to acute 3mg/kg D-amphetamine. Qualitative analysis of exploration revealed tolerance to D-amphetamine effects on entropy in methamphetamine-treated brain-derived neurotrophic factor heterozygous mice, but not wild-type mice. Chronic methamphetamine exposure induces contrasting profiles of behavioral changes in wild-type and brain-derived neurotrophic factor heterozygous mice, with attenuation of behaviors relevant to psychosis in methamphetamine-treated brain-derived neurotrophic factor heterozygous mice. This suggests that brain-derived neurotrophic factor signalling changes may contribute to development of psychosis in methamphetamine users. © The Author 2015. Published by Oxford University Press on behalf of CINP.

  14. Biallelic PMS2 Mutation and Heterozygous DICER1 Mutation Presenting as Constitutional Mismatch Repair Deficiency With Corpus Callosum Agenesis: Case Report and Review of Literature.

    Science.gov (United States)

    Cheyuo, Cletus; Radwan, Walid; Ahn, Janice; Gyure, Kymberly; Qaiser, Rabia; Tomboc, Patrick

    2017-10-01

    Constitutional mismatch repair deficiency syndrome is a cancer predisposition syndrome caused by autosomal recessive biallelic (homozygous) germline mutations in the mismatch repair genes (MLH1, MSH2, MSH6, and PMS2). The clinical spectrum includes neoplastic and non-neoplastic manifestations. We present the case of a 7-year-old boy who presented with T-lymphoblastic lymphoma and glioblastoma, together with non-neoplastic manifestations including corpus callosum agenesis, arachnoid cyst, developmental venous anomaly, and hydrocephalus. Gene mutation analysis revealed pathogenic biallelic mutations of PMS2 and heterozygous DICER1 variant predicted to be pathogenic. This report is the first to allude to a possible interaction of the mismatch repair system with DICER1 to cause corpus callosum agenesis.

  15. Compound heterozygous deletions in pseudoautosomal region 1 in an infant with mild manifestations of langer mesomelic dysplasia.

    Science.gov (United States)

    Tsuchiya, Takayoshi; Shibata, Minoru; Numabe, Hironao; Jinno, Tomoko; Nakabayashi, Kazuhiko; Nishimura, Gen; Nagai, Toshiro; Ogata, Tsutomu; Fukami, Maki

    2014-02-01

    Haploinsufficiency of SHOX on the short arm pseudoautosomal region (PAR1) leads to Leri-Weill dyschondrosteosis (LWD), and nullizygosity of SHOX results in Langer mesomelic dysplasia (LMD). Molecular defects of LWD/LMD include various microdeletions in PAR1 that involve exons and/or the putative upstream or downstream enhancer regions of SHOX, as well as several intragenic mutations. Here, we report on a Japanese male infant with mild manifestations of LMD and hitherto unreported microdeletions in PAR1. Clinical analysis revealed mesomelic short stature with various radiological findings indicative of LMD. Molecular analyses identified compound heterozygous deletions, that is, a maternally inherited ∼46 kb deletion involving the upstream region and exons 1-5 of SHOX, and a paternally inherited ∼500 kb deletion started from a position ∼300 kb downstream from SHOX. In silico analysis revealed that the downstream deletion did not affect the known putative enhancer regions of SHOX, although it encompassed several non-coding elements which were well conserved among various species with SHOX orthologs. These results provide the possibility of the presence of a novel enhancer for SHOX in the genomic region ∼300 to ∼800 kb downstream of the start codon. © 2013 Wiley Periodicals, Inc.

  16. The use of high resolution melting analysis to detect Fabry mutations in heterozygous females via dry bloodspots.

    Science.gov (United States)

    Tai, Chang-Long; Liu, Mei-Ying; Yu, Hsiao-Chi; Chiang, Chiang-Chuan; Chiang, Hung; Suen, Jeng-Hung; Kao, Shu-Min; Huang, Yu-Hsiu; Wu, Tina Jui-Ting; Yang, Chia-Feng; Tsai, Fang-Chih; Lin, Ching-Yuang; Chang, Jan-Gowth; Chen, Hong-Duo; Niu, Dau-Ming

    2012-02-18

    As an X-linked genetic disorder, Fabry disease was first thought to affect males only, and females were generally considered to be asymptomatic carriers. However, recent research suggests that female carriers of Fabry disease may still develop vital organ damage causing severe morbidity and mortality. In the previous newborn screening, from 299,007 newborns, we identified a total of 20 different Fabry mutations and 121 newborns with Fabry mutations. However, we found that most female carriers are not detected by enzyme assays. A streamlined method for high resolution melting (HRM) analysis was designed to screen for GLA gene mutations using a same PCR and melting program. Primer sets were designed to cover the 7 exons and the Chinese common intronic mutation, IVS4+919G>A of GLA gene. The HRM analysis was successful in identifying heterozygous and hemizygous patients with the 20 surveyed mutations. We were also successful in using this method to test dry blood spots of newborns afflicted with Fabry mutations without having to determine DNA concentration before PCR amplification. The results of this study show that HRM could be a reliable and sensitive method for use in the rapid screening of females for GLA mutations. Copyright © 2011 Elsevier B.V. All rights reserved.

  17. Myosin-binding Protein C Compound Heterozygous Variant Effect on the Phenotypic Expression of Hypertrophic Cardiomyopathy.

    Science.gov (United States)

    Rafael, Julianny Freitas; Cruz, Fernando Eugênio Dos Santos; Carvalho, Antônio Carlos Campos de; Gottlieb, Ilan; Cazelli, José Guilherme; Siciliano, Ana Paula; Dias, Glauber Monteiro

    2017-04-01

    Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disease caused by mutations in genes encoding sarcomere proteins. It is the major cause of sudden cardiac death in young high-level athletes. Studies have demonstrated a poorer prognosis when associated with specific mutations. The association between HCM genotype and phenotype has been the subject of several studies since the discovery of the genetic nature of the disease. This study shows the effect of a MYBPC3 compound variant on the phenotypic HCM expression. A family in which a young man had a clinical diagnosis of HCM underwent clinical and genetic investigations. The coding regions of the MYH7, MYBPC3 and TNNT2 genes were sequenced and analyzed. The proband present a malignant manifestation of the disease, and is the only one to express HCM in his family. The genetic analysis through direct sequencing of the three main genes related to this disease identified a compound heterozygous variant (p.E542Q and p.D610H) in MYBPC3. A family analysis indicated that the p.E542Q and p.D610H alleles have paternal and maternal origin, respectively. No family member carrier of one of the variant alleles manifested clinical signs of HCM. We suggest that the MYBPC3-biallelic heterozygous expression of p.E542Q and p.D610H may cause the severe disease phenotype seen in the proband. Resumo A cardiomiopatia hipertrófica (CMH) é uma doença autossômica dominante causada por mutações em genes que codificam as proteínas dos sarcômeros. É a principal causa de morte súbita cardíaca em atletas jovens de alto nível. Estudos têm demonstrado um pior prognóstico associado a mutações específicas. A associação entre genótipo e fenótipo em CMH tem sido objeto de diversos estudos desde a descoberta da origem genética dessa doença. Este trabalho apresenta o efeito de uma mutação composta em MYBPC3 na expressão fenotípica da CMH. Uma família na qual um jovem tem o diagnóstico clínico de CMH foi

  18. A 3-year study of atorvastatin in children and adolescents with heterozygous familial hypercholesterolemia.

    Science.gov (United States)

    Langslet, Gisle; Breazna, Andrei; Drogari, Euridiki

    2016-01-01

    The efficacy and safety of atorvastatin in children/adolescents aged 10-17 years with heterozygous familial hypercholesterolemia (HeFH) have been demonstrated in trials of up to 1 year in duration. However, the efficacy/safety of >1 year use of atorvastatin in children/adolescents with HeFH, including children from 6 years of age, has not been assessed. To characterize the efficacy and safety of atorvastatin over 3 years and to assess the impact on growth and development in children aged 6-15 years with HeFH. A total of 272 subjects aged 6-15 years with HeFH and low-density lipoprotein cholesterol (LDL-C) ≥4.0 mmol/L (154 mg/dL) were enrolled in a 3-year study (NCT00827606). Subjects were initiated on atorvastatin (5 mg or 10 mg) with doses increased to up to 80 mg based on LDL-C levels. Mean percentage reductions from baseline in LDL-C at 36 months/early termination were 43.8% for subjects at Tanner stage (TS) 1 and 39.9% for TS ≥2. There was no evidence of variations in the lipid-lowering efficacy of atorvastatin between the TS groups analyzed (1 vs ≥2) or in subjects aged Atorvastatin had a favorable safety and tolerability profile, and only 6 (2.2%) subjects discontinued because of adverse events. Atorvastatin over 3 years was efficacious, had no impact on growth/maturation, and was well tolerated in children and adolescents with HeFH aged 6-15 years. Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.

  19. Long-Term Effects of Prenatal Hypoxia on Schizophrenia-Like Phenotype in Heterozygous Reeler Mice.

    Science.gov (United States)

    Howell, Kristy R; Pillai, Anilkumar

    2016-07-01

    Prenatal hypoxia (PHX) is a well-known environmental factor implicated in the pathophysiology of schizophrenia. However, the long-term effects of PHX on schizophrenia-related neuroplasticity are poorly understood. Using behavioral tasks, MRI imaging, and biochemical studies, we examined the long-term effects of PHX in heterozygous reeler mice (HRM; mice deficient for reelin, a candidate gene for schizophrenia). PHX at E17 failed to induce any significant deficits in prepulse inhibition, spatial memory, anxiety-like behavior, or blood flow in wild type (WT) and HRM at 6 months of age. However, PHX induced a significant increase in frontal cortex volume in WT whereas the higher frontal cortical volume found in HRM was significantly reduced by PHX. A significant decrease in reelin levels was observed in frontal cortex of WT and HRM and hippocampus of HRM following PHX. In addition, PHX induced significant reductions in hypoxia inducible factor-1α (HIF-1α) levels in frontal cortex and hippocampus of HRM. Although no significant effect of PHX was observed in vascular endothelial growth factor (VEGF) protein levels in frontal cortex and hippocampus of WT and HRM, serum VEGF levels were found higher in HRM following PHX. Moreover, glucocorticoid receptor (GR) protein levels were significantly lower in frontal cortex of WT and HRM and hippocampus of HRM following PHX. We found a significant reduction in serum corticosterone levels of PHX-treated WT mice. These findings suggest that future experiments addressing gene-environment interaction in schizophrenia should consider age-dependent effects of the environmental factor, in addition to the specificity of the gene of interest.

  20. A novel heterozygous mutation in the Indian hedgehog gene (IHH) is associated with brachydactyly type A1 in a Chinese family.

    Science.gov (United States)

    Liu, Mugen; Wang, Xu; Cai, Zhou; Tang, Zhaohui; Cao, Kangsheng; Liang, Bo; Ren, Xiang; Liu, Jing Yu; Wang, Qing K

    2006-01-01

    Brachydactyly type A1 (BDA1) is caused by mutations in the Indian hedgehog gene, IHH, on chromosome 2q35-36. In this study, a large five-generation Chinese family with BDA1 was identified and characterized. All affected family members demonstrated significant homogeneous phenotype and some unique clinical features different from those associated with the reported BDA1 mutations in IHH. Linkage analysis showed that the BDA1 gene in the family was linked to marker D2S126 close to IHH with a LOD score of 4.74 at a recombination fraction of 0. DNA sequence analysis revealed a heterozygous C to T transition at nucleotide 461 of IHH, resulting in a novel T154I substitution. The T154I mutation co-segregated with all affected individuals in the family, and was not present in normal family members or 200 normal controls. These results expand the spectrum of clinical phenotype associated with IHH mutations.

  1. Elastic scattering of 7Li projectiles in the energy range of 20 to 34 MeV

    International Nuclear Information System (INIS)

    Khallaf, S.A.E.

    1983-01-01

    As far as it is known, the Watanabe folding model has not been used to analyse the elastic scattering of 7 Li projectiles. The main purpose of the present work is to calculate the differential cross sections for 7 Li elastic scattering von 90 Zr, 48 , 40 Ca, 16 O and 12 C at incident energies of 20 to 34 MeV using the Watanabe folding model and to study the applicability of this model for 7 Li elastic scattering. The potentials of 7 Li ions are revealed by Taylor expansions of alpha and triton cluster potentials. The resulting differential cross sections are compared with the predicted cross sections using phenomenological potentials of 7 Li ions. (orig./WL)

  2. Heterozygous Germline Mutations in the CBL Tumor-Suppressor Gene Cause a Noonan Syndrome-like Phenotype

    Science.gov (United States)

    Martinelli, Simone; De Luca, Alessandro; Stellacci, Emilia; Rossi, Cesare; Checquolo, Saula; Lepri, Francesca; Caputo, Viviana; Silvano, Marianna; Buscherini, Francesco; Consoli, Federica; Ferrara, Grazia; Digilio, Maria C.; Cavaliere, Maria L.; van Hagen, Johanna M.; Zampino, Giuseppe; van der Burgt, Ineke; Ferrero, Giovanni B.; Mazzanti, Laura; Screpanti, Isabella; Yntema, Helger G.; Nillesen, Willy M.; Savarirayan, Ravi; Zenker, Martin; Dallapiccola, Bruno; Gelb, Bruce D.; Tartaglia, Marco

    2010-01-01

    RAS signaling plays a key role in controlling appropriate cell responses to extracellular stimuli and participates in early and late developmental processes. Although enhanced flow through this pathway has been established as a major contributor to oncogenesis, recent discoveries have revealed that aberrant RAS activation causes a group of clinically related developmental disorders characterized by facial dysmorphism, a wide spectrum of cardiac disease, reduced growth, variable cognitive deficits, ectodermal and musculoskeletal anomalies, and increased risk for certain malignancies. Here, we report that heterozygous germline mutations in CBL, a tumor-suppressor gene that is mutated in myeloid malignancies and encodes a multivalent adaptor protein with E3 ubiquitin ligase activity, can underlie a phenotype with clinical features fitting or partially overlapping Noonan syndrome (NS), the most common condition of this disease family. Independent CBL mutations were identified in two sporadic cases and two families from among 365 unrelated subjects who had NS or suggestive features and were negative for mutations in previously identified disease genes. Phenotypic heterogeneity and variable expressivity were documented. Mutations were missense changes altering evolutionarily conserved residues located in the RING finger domain or the linker connecting this domain to the N-terminal tyrosine kinase binding domain, a known mutational hot spot in myeloid malignancies. Mutations were shown to affect CBL-mediated receptor ubiquitylation and dysregulate signal flow through RAS. These findings document that germline mutations in CBL alter development to cause a clinically variable condition that resembles NS and that possibly predisposes to malignancies. PMID:20619386

  3. Deep vein thrombosis, ecythyma gangrenosum and heparin-induced thrombocytopenia occurring in a man with a heterozygous Factor V Leiden mutation

    Directory of Open Access Journals (Sweden)

    Mariya Apostolova

    2012-11-01

    Full Text Available Skin necrosis and limb gangrene are occasional thrombotic manifestations of anticoagulation therapy. We report a man heterozygous for the Factor V Leiden (FVL mutation, and with a history of recurrent deep venous thrombosis, who initially presented with a necrotic skin lesion of the right flank while on warfarin therapy with a therapeutic international normalized ratio. Warfarin was discontinued and he received intravenous heparin. Thereafter he developed thrombocytopenia and pedal erythema and was diagnosed with heparin-induced thrombocytopenia (HIT. Heparin was replaced with argatroban. He ultimately underwent bilateral below-knee amputations for the thrombotic complications of the HIT. The initial necrotic lesion healed with antibiotics and wound care. Pathologic examination of multiple biopsy specimens revealed two separate lesions. One was necrotic tissue infiltrated with methicillin resistant Staphylococcus aureus having features of ecthyma gangrenosum. The second showed thrombotic changes consistent with HIT. The case illustrates the differential diagnosis of skin necrosis and limb gangrene in patients on warfarin and heparin, and also the clinical complexities that can occur in a FVL heterozygote.

  4. [Identification of novel compound heterozygous mutations of USH2A gene in a family with Usher syndrome type II].

    Science.gov (United States)

    Jiang, Haiou; Ge, Chuanqin; Wang, Yiwang; Tang, Genyun; Quan, Qingli

    2015-06-01

    To identify potential mutations in a Chinese family with Usher syndrome type II. Genomic DNA was obtained from two affected and four unaffected members of the family and subjected to amplification of the entire coding sequence and splicing sites of USH2A gene. Mutation detection was conducted by direct sequencing of the PCR products. A total of 100 normal unrelated individuals were used as controls. The patients were identified to be a compound heterozygote for two mutations: c.8272G>T (p.E2758X) in exon 42 from his mother and c.12376-12378ACT>TAA(p.T4126X) in exon 63 of the USH2A gene from his father. Both mutations were not found in either of the two unaffected family members or 100 unrelated controls, and had completely co-segregated with the disease phenotype in the family. Neither mutation has been reported in the HGMD database. The novel compound heterozygous mutations c.8272G>T and c.12376-12378ACT>TAA within the USH2A gene may be responsible for the disease. This result may provide new clues for molecular diagnosis of this disease.

  5. Exome sequencing identifies compound heterozygous mutations in CYP4V2 in a pedigree with retinitis pigmentosa.

    Directory of Open Access Journals (Sweden)

    Yun Wang

    Full Text Available Retinitis pigmentosa (RP is a heterogeneous group of progressive retinal degenerations characterized by pigmentation and atrophy in the mid-periphery of the retina. Twenty two subjects from a four-generation Chinese family with RP and thin cornea, congenital cataract and high myopia is reported in this study. All family members underwent complete ophthalmologic examinations. Patients of the family presented with bone spicule-shaped pigment deposits in retina, retinal vascular attenuation, retinal and choroidal dystrophy, as well as punctate opacity of the lens, reduced cornea thickness and high myopia. Peripheral venous blood was obtained from all patients and their family members for genetic analysis. After mutation analysis in a few known RP candidate genes, exome sequencing was used to analyze the exomes of 3 patients III2, III4, III6 and the unaffected mother II2. A total of 34,693 variations shared by 3 patients were subjected to several filtering steps against existing variation databases. Identified variations were verified in the rest family members by PCR and Sanger sequencing. Compound heterozygous c.802-8_810del17insGC and c.1091-2A>G mutations of the CYP4V2 gene, known as genetic defects for Bietti crystalline corneoretinal dystrophy, were identified as causative mutations for RP of this family.

  6. Heterozygous deletion of FOXA2 segregates with disease in a family with heterotaxy, panhypopituitarism, and biliary atresia.

    Science.gov (United States)

    Tsai, Ellen A; Grochowski, Christopher M; Falsey, Alexandra M; Rajagopalan, Ramakrishnan; Wendel, Danielle; Devoto, Marcella; Krantz, Ian D; Loomes, Kathleen M; Spinner, Nancy B

    2015-06-01

    Biliary atresia (BA) is a pediatric cholangiopathy with unknown etiology occurring in isolated and syndromic forms. Laterality defects affecting the cardiovascular and gastrointestinal systems are the most common features present in syndromic BA. Most cases are sporadic, although reports of familial cases have led to the hypothesis of genetic susceptibility in some patients. We identified a child with BA, malrotation, and interrupted inferior vena cava whose father presented with situs inversus, polysplenia, panhypopituitarism, and mildly dysmorphic facial features. Chromosomal microarray analysis demonstrated a 277 kb heterozygous deletion on chromosome 20, which included a single gene, FOXA2, in the proband and her father. This deletion was confirmed to be de novo in the father. The proband and her father share a common diagnosis of heterotaxy, but they also each presented with a variety of other issues. Further genetic screening revealed that the proband carried an additional protein-altering polymorphism (rs1904589; p.His165Arg) in the NODAL gene that is not present in the father, and this variant has been shown to decrease expression of the gene. As FOXA2 can be a regulator of NODAL expression, we propose that haploinsufficiency for FOXA2 combined with a decreased expression of NODAL is the likely cause for syndromic BA in this proband. © 2015 WILEY PERIODICALS, INC.

  7. Chronic Toxoplasma gondii in Nurr1-null heterozygous mice exacerbates elevated open field activity.

    Science.gov (United States)

    Eells, Jeffrey B; Varela-Stokes, Andrea; Guo-Ross, Shirley X; Kummari, Evangel; Smith, Holly M; Cox, Erin; Lindsay, David S

    2015-01-01

    Latent infection with Toxoplasma gondii is common in humans (approximately 30% of the global population) and is a significant risk factor for schizophrenia. Since prevalence of T. gondii infection is far greater than prevalence of schizophrenia (0.5-1%), genetic risk factors are likely also necessary to contribute to schizophrenia. To test this concept in an animal model, Nurr1-null heterozygous (+/-) mice and wild-type (+/+) mice were evaluate using an emergence test, activity in an open field and with a novel object, response to bobcat urine and prepulse inhibition of the acoustic startle response (PPI) prior to and 6 weeks after infection with T. gondii. In the emergence test, T. gondii infection significantly decreased the amount of time spent in the cylinder. Toxoplasma gondii infection significantly elevated open field activity in both +/+ and +/- mice but this increase was significantly exacerbated in +/- mice. T. gondii infection reduced PPI in male +/- mice but this was not statistically significant. Aversion to bobcat urine was abolished by T. gondii infection in +/+ mice. In female +/- mice, aversion to bobcat urine remained after T. gondii infection while the male +/- mice showed no aversion to bobcat urine. Antibody titers of infected mice were a critical variable associated with changes in open field activity, such that an inverted U shaped relationship existed between antibody titers and the percent change in open field activity with a significant increase in activity at low and medium antibody titers but no effect at high antibody titers. These data demonstrate that the Nurr1 +/- genotype predisposes mice to T. gondii-induced alterations in behaviors that involve dopamine neurotransmission and are associated with symptoms of schizophrenia. We propose that these alterations in murine behavior were due to further exacerbation of the altered dopamine neurotransmission in Nurr1 +/- mice.

  8. Chronic Toxoplasma gondii in Nurr1-null heterozygous mice exacerbates elevated open field activity.

    Directory of Open Access Journals (Sweden)

    Jeffrey B Eells

    Full Text Available Latent infection with Toxoplasma gondii is common in humans (approximately 30% of the global population and is a significant risk factor for schizophrenia. Since prevalence of T. gondii infection is far greater than prevalence of schizophrenia (0.5-1%, genetic risk factors are likely also necessary to contribute to schizophrenia. To test this concept in an animal model, Nurr1-null heterozygous (+/- mice and wild-type (+/+ mice were evaluate using an emergence test, activity in an open field and with a novel object, response to bobcat urine and prepulse inhibition of the acoustic startle response (PPI prior to and 6 weeks after infection with T. gondii. In the emergence test, T. gondii infection significantly decreased the amount of time spent in the cylinder. Toxoplasma gondii infection significantly elevated open field activity in both +/+ and +/- mice but this increase was significantly exacerbated in +/- mice. T. gondii infection reduced PPI in male +/- mice but this was not statistically significant. Aversion to bobcat urine was abolished by T. gondii infection in +/+ mice. In female +/- mice, aversion to bobcat urine remained after T. gondii infection while the male +/- mice showed no aversion to bobcat urine. Antibody titers of infected mice were a critical variable associated with changes in open field activity, such that an inverted U shaped relationship existed between antibody titers and the percent change in open field activity with a significant increase in activity at low and medium antibody titers but no effect at high antibody titers. These data demonstrate that the Nurr1 +/- genotype predisposes mice to T. gondii-induced alterations in behaviors that involve dopamine neurotransmission and are associated with symptoms of schizophrenia. We propose that these alterations in murine behavior were due to further exacerbation of the altered dopamine neurotransmission in Nurr1 +/- mice.

  9. A lower dose threshold for the in vivo protective adaptive response to radiation. Tumorigenesis in chronically exposed normal and Trp53 heterozygous C57BL/6 mice

    International Nuclear Information System (INIS)

    Mitchel, R.E.J.; Burchart, P.; Wyatt, H.

    2008-01-01

    Low doses of ionizing radiation to cells and animals may induce adaptive responses that reduce the risk of cancer. However, there are upper dose thresholds above which these protective adaptive responses do not occur. We have now tested the hypothesis that there are similar lower dose thresholds that must be exceeded in order to induce protective effects in vivo. We examined the effects of low dose/low dose rate fractionated exposures on cancer formation in Trp53 normal or cancer-prone Trp53 heterozygous female C57BL/6 mice. Beginning at 6 weeks of age, mice were exposed 5 days/week to single daily doses (0.33 mGy, 0.7 mGy/h) totaling 48, 97 or 146 mGy over 30, 60 or 90 weeks. The exposures for shorter times (up to 60 weeks) appeared to be below the level necessary to induce overall protective adaptive responses in Trp53 normal mice, and detrimental effects (shortened lifespan, increased frequency) evident for only specific tumor types (B- and T-cell lymphomas), were produced. Only when the exposures were continued for 90 weeks did the dose become sufficient to induce protective adaptive responses, balancing the detrimental effects for these specific cancers, and reducing the risk level back to that of the unexposed animals. Detrimental effects were not seen for other tumor types, and a protective effect was seen for sarcomas after 60 weeks of exposure, which was then lost when the exposure continued for 90 weeks. As previously shown for the upper dose threshold for protection by low doses, the lower dose boundary between protection and harm was influenced by Trp53 functionality. Neither protection nor harm was observed in exposed Trp53 heterozygous mice, indicating that reduced Trp53 function raises the lower dose/dose rate threshold for both detrimental and protective tumorigenic effects. (author)

  10. Augmentation of phenotype in a transgenic Parkinson mouse heterozygous for a Gaucher mutation.

    Science.gov (United States)

    Fishbein, Ianai; Kuo, Yien-Ming; Giasson, Benoit I; Nussbaum, Robert L

    2014-12-01

    The involvement of the protein α-synuclein (SNCA) in the pathogenesis of Parkinson's disease is strongly supported by the facts that (i) missense and copy number mutations in the SNCA gene can cause inherited Parkinson's disease; and (ii) Lewy bodies in sporadic Parkinson's disease are largely composed of aggregated SNCA. Unaffected heterozygous carriers of Gaucher disease mutations have an increased risk for Parkinson's disease. As mutations in the GBA gene encoding glucocerebrosidase (GBA) are known to interfere with lysosomal protein degradation, GBA heterozygotes may demonstrate reduced lysosomal SNCA degradation, leading to increased steady-state SNCA levels and promoting its aggregation. We have created mouse models to investigate the interaction between GBA mutations and synucleinopathies. We investigated the rate of SNCA degradation in cultured primary cortical neurons from mice expressing wild-type mouse SNCA, wild-type human SNCA, or mutant A53T SNCA, in a background of either wild-type Gba or heterozygosity for the L444P GBA mutation associated with Gaucher disease. We also tested the effect of this Gaucher mutation on motor and enteric nervous system function in these transgenic animals. We found that human SNCA is stable, with a half-life of 61 h, and that the A53T mutation did not significantly affect its half-life. Heterozygosity for a naturally occurring Gaucher mutation, L444P, reduced GBA activity by 40%, reduced SNCA degradation and triggered accumulation of the protein in culture. This mutation also resulted in the exacerbation of motor and gastrointestinal deficits found in the A53T mouse model of Parkinson's disease. This study demonstrates that heterozygosity for a Gaucher disease-associated mutation in Gba interferes with SNCA degradation and contributes to its accumulation, and exacerbates the phenotype in a mouse model of Parkinson's disease. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain

  11. Andermann syndrome can be a phenocopy of hereditary motor and sensory neuropathy--report of a discordant sibship with a compound heterozygous mutation of the KCC3 gene.

    Science.gov (United States)

    Rudnik-Schöneborn, S; Hehr, U; von Kalle, T; Bornemann, A; Winkler, J; Zerres, K

    2009-06-01

    Andermann syndrome is a rare autosomal recessive disorder characterized by agenesis of the corpus callosum (ACC), progressive motor-sensory neuropathy, mental retardation and facial features. We report on two siblings with the clinical picture of a demyelinating hereditary motor and sensory neuropathy (HMSN), where only the presence of ACC in the younger brother pointed to the diagnosis of Andermann syndrome. Mutation analysis of the KCC3 (SLC12A6) gene showed a compound heterozygous mutation; a maternal missense mutation c.1616G>A (p.G539D) and a paternal splice mutation c.1118+1G>A in both siblings. We hypothesize that mutations of the KCC3 gene may result in non-syndromic childhood onset HMSN.

  12. One year variability of peak heights, heterozygous balance and inter-locus balance for the DNA positive control of AmpFℓSTR© Identifiler© STR kit.

    Science.gov (United States)

    Debernardi, A; Suzanne, E; Formant, A; Pène, L; Dufour, A B; Lobry, J R

    2011-01-01

    Multivariate analyses of 205 positive control experiments in an AmpFℓSTR© Identifiler© STR kit were used to analyze the factors affecting peak heights at 16 loci. Peak heights were found to be highly correlated between loci and there was evidence for a difference in sensitivity of the two genetic analyzers in the blue channel. Heterozygous balance response at 10 loci was found to behave as a random variable following a beta-distribution with typical median values of 90%, without locus or genetic analyzer effect. Inter-locus balance at 16 loci was influenced by the blue channel effect and a temporal switch of unexplained origin. The implications of these results for the choice of minimum threshold values in quality control are discussed. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  13. Dynamics of multi-frequency oscillator ensembles with resonant coupling

    International Nuclear Information System (INIS)

    Lueck, S.; Pikovsky, A.

    2011-01-01

    We study dynamics of populations of resonantly coupled oscillators having different frequencies. Starting from the coupled van der Pol equations we derive the Kuramoto-type phase model for the situation, where the natural frequencies of two interacting subpopulations are in relation 2:1. Depending on the parameter of coupling, ensembles can demonstrate fully synchronous clusters, partial synchrony (only one subpopulation synchronizes), or asynchrony in both subpopulations. Theoretical description of the dynamics based on the Watanabe-Strogatz approach is developed. -- Highlights: → Kuramoto model is generalized on the case of resonantly interacting oscillators having frequency ratio 2:1. → Regimes of full and partial synchrony, as well as non-synchronous ones are reported. → Analytical description is developed on the basis of the Watanabe-Strogatz approach.

  14. Dynamics of multi-frequency oscillator ensembles with resonant coupling

    Energy Technology Data Exchange (ETDEWEB)

    Lueck, S. [Department of Physics and Astronomy, Potsdam University, Karl-Liebknecht-Str. 24-25, 14476 Potsdam (Germany); Pikovsky, A., E-mail: pikovsky@stat.physik.uni-potsdam.de [Department of Physics and Astronomy, Potsdam University, Karl-Liebknecht-Str. 24-25, 14476 Potsdam (Germany)

    2011-07-11

    We study dynamics of populations of resonantly coupled oscillators having different frequencies. Starting from the coupled van der Pol equations we derive the Kuramoto-type phase model for the situation, where the natural frequencies of two interacting subpopulations are in relation 2:1. Depending on the parameter of coupling, ensembles can demonstrate fully synchronous clusters, partial synchrony (only one subpopulation synchronizes), or asynchrony in both subpopulations. Theoretical description of the dynamics based on the Watanabe-Strogatz approach is developed. -- Highlights: → Kuramoto model is generalized on the case of resonantly interacting oscillators having frequency ratio 2:1. → Regimes of full and partial synchrony, as well as non-synchronous ones are reported. → Analytical description is developed on the basis of the Watanabe-Strogatz approach.

  15. DISKRIMINASI GENDER DALAM NOVEL GINKO KARYA JUNICHI WATANABE

    OpenAIRE

    Linda Unsriana

    2015-01-01

    Discrimination is an attitude and behavior that violates human rights. Discrimination can also be interpreted as a treatment for individuals differently based on race, religion, or gender. Any harassment, restriction, or exclusion to race, religion, or gender includes discriminatory actions. The theme of discrimination experienced by many women made the writer want to examine it from literature point of view, especially Japanese literature. The problem in this paper is gender discrimination e...

  16. (-)-anipamil retards atherosclerosis in Watanabe heritable hyperlipidemic rabbits

    DEFF Research Database (Denmark)

    Hansen, B F; Mortensen, A; Hansen, J F

    1995-01-01

    Calcium antagonists have been reported to limit atherosclerosis in cholesterol fed rabbits. The purpose of this study was to examine the effect of the calcium antagonist (-)-anipamil on the spontaneous development of atherosclerosis in homozygote WHHL rabbits. From the age of 7 weeks, three groups...... differences were found in serum lipids (i.e., VLDL, IDL, LDL, HDL) in the study period among the three groups. Plasma anipamil at the end of the study was 0.23 +/- 6, and 202 +/- 19 ng/ml, respectively, in the three treatment groups. The degree of atherosclerosis in the abdominal aorta was significantly lower...... (p atherosclerosis in the abdominal aorta in WHHL rabbits....

  17. Neural activity changes underlying the working memory deficit in alpha-CaMKII heterozygous knockout mice

    Directory of Open Access Journals (Sweden)

    Naoki Matsuo

    2009-09-01

    Full Text Available The alpha-isoform of calcium/calmodulin-dependent protein kinase II (α-CaMKII is expressed abundantly in the forebrain and is considered to have an essential role in synaptic plasticity and cognitive function. Previously, we reported that mice heterozygous for a null mutation of α-CaMKII (α-CaMKII+/- have profoundly dysregulated behaviors including a severe working memory deficit, which is an endophenotype of schizophrenia and other psychiatric disorders. In addition, we found that almost all the neurons in the dentate gyrus (DG of the mutant mice failed to mature at molecular, morphological and electrophysiological levels. In the present study, to identify the brain substrates of the working memory deficit in the mutant mice, we examined the expression of the immediate early genes (IEGs, c-Fos and Arc, in the brain after a working memory version of the eight-arm radial maze test. c-Fos expression was abolished almost completely in the DG and was reduced significantly in neurons in the CA1 and CA3 areas of the hippocampus, central amygdala, and medial prefrontal cortex (mPFC. However, c-Fos expression was intact in the entorhinal and visual cortices. Immunohistochemical studies using arc promoter driven dVenus transgenic mice demonstrated that arc gene activation after the working memory task occurred in mature, but not immature neurons in the DG of wild-type mice. These results suggest crucial insights for the neural circuits underlying spatial mnemonic processing during a working memory task and suggest the involvement of α-CaMKII in the proper maturation and integration of DG neurons into these circuits.

  18. Polymorphisms of the low-density lipoprotein receptor gene in Brazilian individuals with heterozygous familial hypercholesterolemia

    Directory of Open Access Journals (Sweden)

    L.A. Salazar

    2000-11-01

    Full Text Available Familial hypercholesterolemia (FH is a metabolic disorder inherited as an autosomal dominant trait characterized by an increased plasma low-density lipoprotein (LDL level. The disease is caused by several different mutations in the LDL receptor gene. Although early identification of individuals carrying the defective gene could be useful in reducing the risk of atherosclerosis and myocardial infarction, the techniques available for determining the number of the functional LDL receptor molecules are difficult to carry out and expensive. Polymorphisms associated with this gene may be used for unequivocal diagnosis of FH in several populations. The aim of our study was to evaluate the genotype distribution and relative allele frequencies of three polymorphisms of the LDL receptor gene, HincII1773 (exon 12, AvaII (exon 13 and PvuII (intron 15, in 50 unrelated Brazilian individuals with a diagnosis of heterozygous FH and in 130 normolipidemic controls. Genomic DNA was extracted from blood leukocytes by a modified salting-out method. The polymorphisms were detected by PCR-RFLP. The FH subjects showed a higher frequency of A+A+ (AvaII, H+H+ (HincII1773 and P1P1 (PvuII homozygous genotypes when compared to the control group (P<0.05. In addition, FH probands presented a high frequency of A+ (0.58, H+ (0.61 and P1 (0.78 alleles when compared to normolipidemic individuals (0.45, 0.45 and 0.64, respectively. The strong association observed between these alleles and FH suggests that AvaII, HincII1773 and PvuII polymorphisms could be useful to monitor the inheritance of FH in Brazilian families.

  19. Compound heterozygous mutations (p.Leu13Pro and p.Tyr294*) associated with factor VII deficiency cause impaired secretion through ineffective translocation and extensive intracellular degradation of factor VII.

    Science.gov (United States)

    Suzuki, Keijiro; Sugawara, Takeshi; Ishida, Yoji; Suwabe, Akira

    2013-02-01

    Congenital coagulation factor VII (FVII) deficiency is a rare coagulation disease. We investigated the molecular mechanisms of this FVII deficiency in a patient with compound heterozygous mutations. A 22-year-old Japanese female was diagnosed with asymptomatic FVII deficiency. The FVII activity and antigen were greatly reduced (activity, 13.0%; antigen, 10.8%). We analyzed the F7 gene of this patient and characterized mutant FVII proteins using in vitro expression studies. Sequence analysis revealed that the patient was compound heterozygous with a point mutation (p.Leu13Pro) in the central hydrophobic core of the signal peptides and a novel non-sense mutation (p.Tyr294*) in the catalytic domain. Expression studies revealed that mutant FVII with p.Leu13Pro (FVII13P) showed less accumulation in the cells (17.5%) and less secretion into the medium (64.8%) than wild type showed. Truncated FVII resulting from p.Tyr294* (FVII294X) was also decreased in the cells (32.0%), but was not secreted into the medium. Pulse-chase experiments revealed that both mutants were extensively degraded intracellularly compared to wild type. The majority of FVII13P cannot translocate into endoplasmic reticulum (ER). However, a small amount of FVII13P was processed normally with post-translational modifications and was secreted into the medium. The fact that FVII294X was observed only in ER suggests that it is retained in ER. Proteasome apparently plays a central role in these degradations. These findings demonstrate that both mutant FVIIs impaired secretion through ineffective translocation to and retention in ER with extensive intracellular degradation, resulting in an insufficient phenotype. Copyright © 2012 Elsevier Ltd. All rights reserved.

  20. A Novel Heterozygous Intronic Mutation in the FBN1 Gene Contributes to FBN1 RNA Missplicing Events in the Marfan Syndrome

    Directory of Open Access Journals (Sweden)

    Mario Torrado

    2018-01-01

    Full Text Available Marfan syndrome (MFS is an autosomal dominantly inherited connective tissue disorder, mostly caused by mutations in the fibrillin-1 (FBN1 gene. We, by using targeted next-generation sequence analysis, identified a novel intronic FBN1 mutation (the c.2678-15C>A variant in a MFS patient with aortic dilatation. The computational predictions showed that the heterozygous c.2678-15C>A intronic variant might influence the splicing process by differentially affecting canonical versus cryptic splice site utilization within intron 22 of the FBN1 gene. RT-PCR and Western blot analyses, using FBN1 minigenes transfected into HeLa and COS-7 cells, revealed that the c.2678-15C>A variant disrupts normal splicing of intron 22 leading to aberrant 13-nt intron 22 inclusion, frameshift, and premature termination codon. Collectively, the results strongly suggest that the c.2678-15C>A variant could lead to haploinsufficiency of the FBN1 functional protein and structural connective tissue fragility in MFS complicated by aorta dilation, a finding that further expands on the genetic basis of aortic pathology.

  1. Tropomyosin 2 heterozygous knockout in mice using CRISPR-Cas9 system displays the inhibition of injury-induced epithelial-mesenchymal transition, and lens opacity

    Science.gov (United States)

    Shibata, Teppei; Shibata, Shinsuke; Ishigaki, Yasuhito; Kiyokawa, Etsuko; Ikawa, Masahito; Singh, Dhirendra P.; Sasaki, Hiroshi; Kubo, Eri

    2018-01-01

    The process of epithelial–mesenchymal transition (EMT) of lens epithelial cells (LECs) after cataract surgery contributes to tissue fibrosis, wound healing and lens regeneration via a mechanism not yet fully understood. Here, we show that tropomyosin 2 (Tpm2) plays a critical role in wound healing and lens aging. Posterior capsular opacification (PCO) after lens extraction surgery was accompanied by elevated expression of Tpm2. Tpm2 heterozygous knockout mice, generated via the clustered regularly interspaced short palindromic repeat/ Cas9 (CRISPR/Cas9) system showed promoted progression of cataract with age. Further, injury-induced EMT of the mouse lens epithelium, as evaluated histologically and by the expression patterns of Tpm1 and Tpm2, was attenuated in the absence of Tpm2. In conclusion, Tpm2 may be important in maintaining lens physiology and morphology. However, Tpm2 is involved in the progression of EMT during the wound healing process of mouse LECs, suggesting that inhibition of Tpm2 may suppress PCO. PMID:29510160

  2. Review Cyclic AMP response element binding protein and brain ...

    Indian Academy of Sciences (India)

    Madhu

    Several types of adult-onset stressors, including physical and psychosocial stressors ... stress-induced atrophy with antidepressant therapy in animal models (Watanabe et ..... (Strauss et al 2005) and geriatric depression (Hwang et al. 2005).

  3. Identification of two novel compound heterozygous mutations of ADGRV1 in a Chinese family with Usher syndrome type IIC.

    Science.gov (United States)

    Zhang, Nian; Wang, Juan; Liu, Shuting; Liu, Mugen; Jiang, Fagang

    2018-06-08

    To describe the clinical and genetic findings in a Chinese family with three sibs diagnosed with Usher syndrome type IIC. Four members received ophthalmic and otologic tests to ascertain the clinical characteristics. According to the clinical phenotype, we focused attention on a total of 658 genes associated with them. We screened the possible pathogenic mutation sites, used Sanger to exclude the false positive and verified whether there were co-segregated among the family members. Typical fundus features found in the proband supported the diagnosis of retinitis pigmentosa (RP). Audiometric test indicated moderate to severe sensorineural hearing impairment while the vestibular function was normal. Whole-exome sequencing identified the presence of two novel compound heterozygous mutations in ADGRV1, a known gene responsible for Usher syndrome type IIC. Mutationc.15008delG/p.Gly5003AlafsTer13 was inherited from the mother while c.18383_18386dupACAG/p.His6130GlnfsTer84 was inherited from the father, and they were co-segregated with the disease phenotype in the family. The mutations found in our study not only broaden the mutation spectrum of ADGRV1, but also provide assistances for future genetic diagnosis and treatment for Usher syndrome patients.

  4. The Properties of Red Blood Cells from Patients Heterozygous for HbS and HbC (HbSC Genotype

    Directory of Open Access Journals (Sweden)

    A. Hannemann

    2011-01-01

    Full Text Available Sickle cell disease (SCD is one of the commonest severe inherited disorders, but specific treatments are lacking and the pathophysiology remains unclear. Affected individuals account for well over 250,000 births yearly, mostly in the Tropics, the USA, and the Caribbean, also in Northern Europe as well. Incidence in the UK amounts to around 12–15,000 individuals and is increasing, with approximately 300 SCD babies born each year as well as with arrival of new immigrants. About two thirds of SCD patients are homozygous HbSS individuals. Patients heterozygous for HbS and HbC (HbSC constitute about a third of SCD cases, making this the second most common form of SCD, with approximately 80,000 births per year worldwide. Disease in these patients shows differences from that in homozygous HbSS individuals. Their red blood cells (RBCs, containing approximately equal amounts of HbS and HbC, are also likely to show differences in properties which may contribute to disease outcome. Nevertheless, little is known about the behaviour of RBCs from HbSC heterozygotes. This paper reviews what is known about SCD in HbSC individuals and will compare the properties of their RBCs with those from homozygous HbSS patients. Important areas of similarity and potential differences will be emphasised.

  5. Heterozygous SSBP1 start loss mutation co-segregates with hearing loss and the m.1555A>G mtDNA variant in a large multigenerational family.

    Science.gov (United States)

    Kullar, Peter J; Gomez-Duran, Aurora; Gammage, Payam A; Garone, Caterina; Minczuk, Michal; Golder, Zoe; Wilson, Janet; Montoya, Julio; Häkli, Sanna; Kärppä, Mikko; Horvath, Rita; Majamaa, Kari; Chinnery, Patrick F

    2018-01-01

    The m.1555A>G mtDNA variant causes maternally inherited deafness, but the reasons for the highly variable clinical penetrance are not known. Exome sequencing identified a heterozygous start loss mutation in SSBP1, encoding the single stranded binding protein 1 (SSBP1), segregating with hearing loss in a multi-generational family transmitting m.1555A>G, associated with mtDNA depletion and multiple deletions in skeletal muscle. The SSBP1 mutation reduced steady state SSBP1 levels leading to a perturbation of mtDNA metabolism, likely compounding the intra-mitochondrial translation defect due to m.1555A>G in a tissue-specific manner. This family demonstrates the importance of rare trans-acting genetic nuclear modifiers in the clinical expression of mtDNA disease. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

  6. Generation, genome edition and characterization of iPSC lines from a patient with coenzyme Q10 deficiency harboring a heterozygous mutation in COQ4 gene

    Directory of Open Access Journals (Sweden)

    Damià Romero-Moya

    2017-10-01

    Full Text Available We report the generation, CRISPR/Cas9-edition and characterization of induced pluripotent stem cell (iPSC lines from a patient with coenzyme Q10 deficiency harboring the heterozygous mutation c.483G > C in the COQ4 gene. iPSCs were generated using non-integrative Sendai Viruses containing the reprogramming factors OCT4, SOX2, KLF4 and C-MYC. The iPSC lines carried the c.483G > C COQ4 mutation, silenced the OKSM expression and were mycoplasma-free. They were bona fide pluripotent cells as characterized by morphology, immunophenotype/gene expression for pluripotent-associated markers/genes, NANOG and OCT4 promoter demethylation, karyotype and teratoma formation. The COQ4 mutation was CRISPR/Cas9 edited resulting in isogenic, diploid and off-target free COQ4-corrected iPSCs.

  7. Genetics Home Reference: hypochondrogenesis

    Science.gov (United States)

    ... Achondrogenesis Health Topic: Connective Tissue Disorders Health Topic: Dwarfism Additional NIH Resources (1 link) National Institute of ... T, Nishimura G, Watanabe H, Arisaka O. Prenatal diagnosis of hypochondrogenesis using fetal MRI: a case report. ...

  8. Establishment of a Conditionally Immortalized Wilms Tumor Cell Line with a Homozygous WT1 Deletion within a Heterozygous 11p13 Deletion and UPD Limited to 11p15.

    Directory of Open Access Journals (Sweden)

    Artur Brandt

    Full Text Available We describe a stromal predominant Wilms tumor with focal anaplasia and a complex, tumor specific chromosome 11 aberration: a homozygous deletion of the entire WT1 gene within a heterozygous 11p13 deletion and an additional region of uniparental disomy (UPD limited to 11p15.5-p15.2 including the IGF2 gene. The tumor carried a heterozygous p.T41A mutation in CTNNB1. Cells established from the tumor carried the same chromosome 11 aberration, but a different, homozygous p.S45Δ CTNNB1 mutation. Uniparental disomy (UPD 3p21.3pter lead to the homozygous CTNNB1 mutation. The tumor cell line was immortalized using the catalytic subunit of human telomerase (hTERT in conjunction with a novel thermolabile mutant (U19dl89-97tsA58 of SV40 large T antigen (LT. This cell line is cytogenetically stable and can be grown indefinitely representing a valuable tool to study the effect of a complete lack of WT1 in tumor cells. The origin/fate of Wilms tumors with WT1 mutations is currently poorly defined. Here we studied the expression of several genes expressed in early kidney development, e.g. FOXD1, PAX3, SIX1, OSR1, OSR2 and MEIS1 and show that these are expressed at similar levels in the parental and the immortalized Wilms10 cells. In addition the limited potential for muscle/ osteogenic/ adipogenic differentiation similar to all other WT1 mutant cell lines is also observed in the Wilms10 tumor cell line and this is retained in the immortalized cells. In summary these Wilms10 cells are a valuable model system for functional studies of WT1 mutant cells.

  9. Establishment of a Conditionally Immortalized Wilms Tumor Cell Line with a Homozygous WT1 Deletion within a Heterozygous 11p13 Deletion and UPD Limited to 11p15

    Science.gov (United States)

    Brandt, Artur; Löhers, Katharina; Beier, Manfred; Leube, Barbara; de Torres, Carmen; Mora, Jaume; Arora, Parineeta; Jat, Parmjit S.; Royer-Pokora, Brigitte

    2016-01-01

    We describe a stromal predominant Wilms tumor with focal anaplasia and a complex, tumor specific chromosome 11 aberration: a homozygous deletion of the entire WT1 gene within a heterozygous 11p13 deletion and an additional region of uniparental disomy (UPD) limited to 11p15.5-p15.2 including the IGF2 gene. The tumor carried a heterozygous p.T41A mutation in CTNNB1. Cells established from the tumor carried the same chromosome 11 aberration, but a different, homozygous p.S45Δ CTNNB1 mutation. Uniparental disomy (UPD) 3p21.3pter lead to the homozygous CTNNB1 mutation. The tumor cell line was immortalized using the catalytic subunit of human telomerase (hTERT) in conjunction with a novel thermolabile mutant (U19dl89-97tsA58) of SV40 large T antigen (LT). This cell line is cytogenetically stable and can be grown indefinitely representing a valuable tool to study the effect of a complete lack of WT1 in tumor cells. The origin/fate of Wilms tumors with WT1 mutations is currently poorly defined. Here we studied the expression of several genes expressed in early kidney development, e.g. FOXD1, PAX3, SIX1, OSR1, OSR2 and MEIS1 and show that these are expressed at similar levels in the parental and the immortalized Wilms10 cells. In addition the limited potential for muscle/ osteogenic/ adipogenic differentiation similar to all other WT1 mutant cell lines is also observed in the Wilms10 tumor cell line and this is retained in the immortalized cells. In summary these Wilms10 cells are a valuable model system for functional studies of WT1 mutant cells. PMID:27213811

  10. Growth of microalgae with increased calorific values in a tubular bioreactor

    Energy Technology Data Exchange (ETDEWEB)

    Scragg, A.H.; Illman, A.M.; Carden, A.; Shales, S.W. [University of the West of England, Dept. of Environmental Sciences, Bristol (United Kingdom)

    2002-07-01

    In order to use microalgae as a fuel the algae should be of high calorific value and must be capable of growth in large volumes. Chlorella vulgaris and C. emersonii have been shown to grow in a 230 I pumped tubular photobioreactor in Watanabe's medium and a low nitrogen medium. The low nitrogen medium induces higher lipid accumulation in both algae, which increased their calorific value. The highest calorific value was obtained with C. vulgaris (28 kJg{sup -1}) grown in low nitrogen medium. However, the biomass productivity was 24 mg dry wtl {sup -1} d{sup -1} in the low nitrogen medium which was lower than in Watanabe's medium (40 mg dry wtl{sup -1} d{sup -1}) and represents a reduced energy recovery. (Author)

  11. Delayed recovery of skeletal muscle mass following hindlimb immobilization in mTOR heterozygous mice.

    Directory of Open Access Journals (Sweden)

    Susan M Lang

    Full Text Available The present study addressed the hypothesis that reducing mTOR, as seen in mTOR heterozygous (+/- mice, would exaggerate the changes in protein synthesis and degradation observed during hindlimb immobilization as well as impair normal muscle regrowth during the recovery period. Atrophy was produced by unilateral hindlimb immobilization and data compared to the contralateral gastrocnemius. In wild-type (WT mice, the gradual loss of muscle mass plateaued by day 7. This response was associated with a reduction in basal protein synthesis and development of leucine resistance. Proteasome activity was consistently elevated, but atrogin-1 and MuRF1 mRNAs were only transiently increased returning to basal values by day 7. When assessed 7 days after immobilization, the decreased muscle mass and protein synthesis and increased proteasome activity did not differ between WT and mTOR(+/- mice. Moreover, the muscle inflammatory cytokine response did not differ between groups. After 10 days of recovery, WT mice showed no decrement in muscle mass, and this accretion resulted from a sustained increase in protein synthesis and a normalization of proteasome activity. In contrast, mTOR(+/- mice failed to fully replete muscle mass at this time, a defect caused by the lack of a compensatory increase in protein synthesis. The delayed muscle regrowth of the previously immobilized muscle in the mTOR(+/- mice was associated with a decreased raptor•4EBP1 and increased raptor•Deptor binding. Slowed regrowth was also associated with a sustained inflammatory response (e.g., increased TNFα and CD45 mRNA during the recovery period and a failure of IGF-I to increase as in WT mice. These data suggest mTOR is relatively more important in regulating the accretion of muscle mass during recovery than the loss of muscle during the atrophy phase, and that protein synthesis is more sensitive than degradation to the reduction in mTOR during muscle regrowth.

  12. Delayed recovery of skeletal muscle mass following hindlimb immobilization in mTOR heterozygous mice.

    Science.gov (United States)

    Lang, Susan M; Kazi, Abid A; Hong-Brown, Ly; Lang, Charles H

    2012-01-01

    The present study addressed the hypothesis that reducing mTOR, as seen in mTOR heterozygous (+/-) mice, would exaggerate the changes in protein synthesis and degradation observed during hindlimb immobilization as well as impair normal muscle regrowth during the recovery period. Atrophy was produced by unilateral hindlimb immobilization and data compared to the contralateral gastrocnemius. In wild-type (WT) mice, the gradual loss of muscle mass plateaued by day 7. This response was associated with a reduction in basal protein synthesis and development of leucine resistance. Proteasome activity was consistently elevated, but atrogin-1 and MuRF1 mRNAs were only transiently increased returning to basal values by day 7. When assessed 7 days after immobilization, the decreased muscle mass and protein synthesis and increased proteasome activity did not differ between WT and mTOR(+/-) mice. Moreover, the muscle inflammatory cytokine response did not differ between groups. After 10 days of recovery, WT mice showed no decrement in muscle mass, and this accretion resulted from a sustained increase in protein synthesis and a normalization of proteasome activity. In contrast, mTOR(+/-) mice failed to fully replete muscle mass at this time, a defect caused by the lack of a compensatory increase in protein synthesis. The delayed muscle regrowth of the previously immobilized muscle in the mTOR(+/-) mice was associated with a decreased raptor•4EBP1 and increased raptor•Deptor binding. Slowed regrowth was also associated with a sustained inflammatory response (e.g., increased TNFα and CD45 mRNA) during the recovery period and a failure of IGF-I to increase as in WT mice. These data suggest mTOR is relatively more important in regulating the accretion of muscle mass during recovery than the loss of muscle during the atrophy phase, and that protein synthesis is more sensitive than degradation to the reduction in mTOR during muscle regrowth.

  13. A comparison of efficacy between conventional and modified ...

    African Journals Online (AJOL)

    PRECIOUS

    2009-11-02

    Nov 2, 2009 ... model (P < 0.001). Postoperative resumption of normal behaviors and activities was quicker in the ... open-chest models with direct surgical coronary artery ..... Toyota E, Kawaguchi Y, Ogasawara Y, Watanabe N, Neishi Y,.

  14. Genome sequence of M6, a diploid inbred clone of the high glycoalkaloid-producing tuber-bearing potato species Solanum chacoense, reveals residual heterozygosity

    Science.gov (United States)

    Background: Potato (Solanum tuberosum) is the world’s most important vegetable crop and central to global food security. Cultivated potato is a highly heterozygous autotetraploid that presents challenges in genome analyses and breeding. Numerous wild potato species serve as a resource for introgress...

  15. Genome-wide prediction methods in highly diverse and heterozygous species: proof-of-concept through simulation in grapevine.

    Directory of Open Access Journals (Sweden)

    Agota Fodor

    Full Text Available Nowadays, genome-wide association studies (GWAS and genomic selection (GS methods which use genome-wide marker data for phenotype prediction are of much potential interest in plant breeding. However, to our knowledge, no studies have been performed yet on the predictive ability of these methods for structured traits when using training populations with high levels of genetic diversity. Such an example of a highly heterozygous, perennial species is grapevine. The present study compares the accuracy of models based on GWAS or GS alone, or in combination, for predicting simple or complex traits, linked or not with population structure. In order to explore the relevance of these methods in this context, we performed simulations using approx 90,000 SNPs on a population of 3,000 individuals structured into three groups and corresponding to published diversity grapevine data. To estimate the parameters of the prediction models, we defined four training populations of 1,000 individuals, corresponding to these three groups and a core collection. Finally, to estimate the accuracy of the models, we also simulated four breeding populations of 200 individuals. Although prediction accuracy was low when breeding populations were too distant from the training populations, high accuracy levels were obtained using the sole core-collection as training population. The highest prediction accuracy was obtained (up to 0.9 using the combined GWAS-GS model. We thus recommend using the combined prediction model and a core-collection as training population for grapevine breeding or for other important economic crops with the same characteristics.

  16. Effects of U.S. Navy Diver Training on Physiological Parameters, Time of Useful Consciousness and Cognitive Performance During Periods of Normobaric Hypoxia

    Science.gov (United States)

    2014-04-01

    TRAINING ON PHYSIOLOGICAL PARAMETERS, TIME OF USEFULL CONSCIOUSNESS, AND COGNITIVE PERFORMANCE DURING PERIODS OF NORMOBARIC HYPOXIA...Sato, Y. Watanabe, "Time of Usefull Consciousness Determination in Aircrew Members with Rerference to Prior Altitude Chamber Experience and Age

  17. Systematic review and metaanalysis of statins for heterozygous familial hypercholesterolemia in children: evaluation of cholesterol changes and side effects.

    LENUS (Irish Health Repository)

    O'Gorman, Clodagh S

    2012-02-01

    Heterozygous familial hypercholesterolemia (heFH) affects 1 in 500 individuals. Evidence supports the low-density lipoprotein (LDL)-lowering effect of statins for adults with heFH. However, there are concerns regarding the treatment children with heFH. By performing a systematic review and metaanalysis of the published literature, this study aimed to evaluate the efficacy and safety of statins used for children with heFH. A systematic review was performed by searching multiple medical databases and citations to identify reports of randomized controlled trials of statins used to treat children with heFH. The trials were retrieved, reviewed, and subjected to metaanalysis. The search yielded 2,174 titles. Of the 63 studies retrieved and reviewed, 56 were excluded, 7 were included in the systematic review, and 4 were included in the metaanalysis. Significant heterogeneity was detected. The metaanalysis showed significant LDL lowering, high-density lipoprotein (HDL) cholesterol elevation, and increases in height and weight with statins. The metaanalysis could not be performed for many side effects of statins, but individual trials showed no significant side effects. Quality assessment showed methodologic concerns, with potential for bias. For example, six trials analyzed statin effects without intention to treat despite such a stated intention. Metaanalysis shows significant LDL lowering with statin treatment. Further studies, including epidemiologic and multicenter studies, are required.

  18. Morphometric and agronomic characterization of 56 ginger ...

    African Journals Online (AJOL)

    SARAH

    2016-04-30

    Apr 30, 2016 ... 2011). Ginger is native to India and South East ... al., 2012), in vitro tissue culture (Hiremath, 2006 ;. Hossain et al. ... and Malaysia (Jatoi and Watanabe, 2013). However ..... conditions have a great influence on expression of.

  19. Analysis of flashing and swelling phenomena in tanks of nuclear power plants; the importance of bubble growth dynamics and bubble transport models with size tracking

    Energy Technology Data Exchange (ETDEWEB)

    Cerezo A, E [University of Caribe, Department of Basics Sciences and Engineering, Lote 1, Manzana 1, Region 78, esq. Fracc. Tabachines, 77500 Cancun, Quintana Roo (Mexico); Munoz C, J L [Department of Chemical and Nuclear Engineering, Polytechnic University of Valencia, Camino de Vera 14, 46022 Valencia (Spain)

    2004-07-01

    This paper presents a non-equilibrium model to describe flashing phenomena in tanks and cooling pools. The present model is based on Watanabe's work that we have extended by developing a realistic model for the growth of bubbles. We have made the corresponding venting model, continuity equation, gas and liquid phase energy conservation equations for the model. This model takes into account both drag and virtual mass force. The dynamics of bubble growth plays an important role in two-phase phenomena such as flashing. In our model the growth rate is assumed to be limited by the heat conduction in the liquid. The results of the analytic model were compared with the experimental data of Watanabe [1]. The results have shown that the present model evaluates fairly accurately the pressure evolution, the void fraction and the swelling level of a tank.

  20. Analysis of flashing and swelling phenomena in tanks of nuclear power plants; the importance of bubble growth dynamics and bubble transport models with size tracking

    Energy Technology Data Exchange (ETDEWEB)

    Cerezo A, E. [University of Caribe, Department of Basics Sciences and Engineering, Lote 1, Manzana 1, Region 78, esq. Fracc. Tabachines, 77500 Cancun, Quintana Roo (Mexico)]. E-mail: ecerezo@unicaribe.edu.mx; Munoz C, J.L. [Department of Chemical and Nuclear Engineering, Polytechnic University of Valencia, Camino de Vera 14, 46022 Valencia (Spain)

    2004-07-01

    This paper presents a non-equilibrium model to describe flashing phenomena in tanks and cooling pools. The present model is based on Watanabe's work that we have extended by developing a realistic model for the growth of bubbles. We have made the corresponding venting model, continuity equation, gas and liquid phase energy conservation equations for the model. This model takes into account both drag and virtual mass force. The dynamics of bubble growth plays an important role in two-phase phenomena such as flashing. In our model the growth rate is assumed to be limited by the heat conduction in the liquid. The results of the analytic model were compared with the experimental data of Watanabe [1]. The results have shown that the present model evaluates fairly accurately the pressure evolution, the void fraction and the swelling level of a tank.

  1. Assessment of Iron Overload in Homozygous and Heterozygous Beta Thalassemic Children below 5 Years of Age

    Directory of Open Access Journals (Sweden)

    Dhiraj J. Trivedi

    2014-07-01

    Full Text Available Background: Thalassemia is a genetic disease having 3-7% carrier rate in Indians. It is transfusion dependent anemia having high risk of iron overloading. A clinical symptom of iron overload becomes detectable in second decade causing progressive liver, heart and endocrine glands damage. There is a need to assess iron overload in thalassemics below 5 years of age to protect them from complications at later age of life. Aims and objectives: Present study was undertaken to estimate serum iron status and evaluate serum transferrin saturation in both homozygous & heterozygous form of thalassemia as an index of iron overload among children of one to five years of age. Materials and Methods: Clinically diagnosed thirty cases of β thalassemia major & thirty cases of β thalassemia minor having severe anemia, hepatospleenomegaly and between 1 year to 5 years of age were included in study group and same age matched healthy controls were included in the study. RBC indices and HbA, HbA2 and HbF were estimated along with serum iron & serum Total Iron Binding Capacity (TIBC and serum transferrin levels. Results: Significant difference was observed in hemoglobin levels between control and both beta thalassemia groups. Mean Corpuscular Volume (MCV and Mean Corpuscular Hemoglobin (MCH values were reduced. Hemoglobin electrophoresis showed the elevated levels of HbF and HbA2 in both beta thalassemia groups. Among serum iron parameters, serum iron, TIBC and transferrin saturation were elevated whereas serum transferrin levels were low in thalassemia major in children below 5 years of age. Conclusion: Although clinical symptoms of iron overload have been absent in thalassemic children below five years of age, biochemical iron overloading has started at much lower age which is of great concern.

  2. Physical mapping in highly heterozygous genomes: a physical contig map of the Pinot Noir grapevine cultivar

    Directory of Open Access Journals (Sweden)

    Jurman Irena

    2010-03-01

    Full Text Available Abstract Background Most of the grapevine (Vitis vinifera L. cultivars grown today are those selected centuries ago, even though grapevine is one of the most important fruit crops in the world. Grapevine has therefore not benefited from the advances in modern plant breeding nor more recently from those in molecular genetics and genomics: genes controlling important agronomic traits are practically unknown. A physical map is essential to positionally clone such genes and instrumental in a genome sequencing project. Results We report on the first whole genome physical map of grapevine built using high information content fingerprinting of 49,104 BAC clones from the cultivar Pinot Noir. Pinot Noir, as most grape varieties, is highly heterozygous at the sequence level. This resulted in the two allelic haplotypes sometimes assembling into separate contigs that had to be accommodated in the map framework or in local expansions of contig maps. We performed computer simulations to assess the effects of increasing levels of sequence heterozygosity on BAC fingerprint assembly and showed that the experimental assembly results are in full agreement with the theoretical expectations, given the heterozygosity levels reported for grape. The map is anchored to a dense linkage map consisting of 994 markers. 436 contigs are anchored to the genetic map, covering 342 of the 475 Mb that make up the grape haploid genome. Conclusions We have developed a resource that makes it possible to access the grapevine genome, opening the way to a new era both in grape genetics and breeding and in wine making. The effects of heterozygosity on the assembly have been analyzed and characterized by using several complementary approaches which could be easily transferred to the study of other genomes which present the same features.

  3. Intrinsic competition among solitary and gregarious endoparasitoid wasps and phenomenon of resource sharing

    NARCIS (Netherlands)

    Magdaraog, P.M.; Harvey, J.A.; Tanaka, T.; Gols, R.

    2012-01-01

    1. Intrinsic competition was compared in three species of braconid wasps, the solitary Meteorus pulchricornis Wesmael, and the gregarious Cotesia kariyai (Watanabe) and Cotesia ruficrus Haliday in caterpillars of their common host, the armyworm Mythimna separata Walker. Competition was determined in

  4. Intrinsic competition among solitary and gregarious endoparasitoid wasps and the phenomenon of ‘resource sharing’

    NARCIS (Netherlands)

    Magdaraog, P.M.; Harvey, J.A.; Tanaka, T.; Gols, R.

    2012-01-01

    1. Intrinsic competition was compared in three species of braconid wasps, the solitary Meteorus pulchricornis Wesmael, and the gregarious Cotesia kariyai (Watanabe) and Cotesia ruficrus Haliday in caterpillars of their common host, the armyworm Mythimna separata Walker. Competition was determined in

  5. Diagnosis of a rare double heterozygous Hb D Punjab/Hb Q India hemoglobinopathy using Sebia capillary zone electrophoresis

    Directory of Open Access Journals (Sweden)

    Sushama Parab

    2014-01-01

    Full Text Available In India, hemoglobinopathies constitute a major genetic disorder and hemoglobin variants such as Hb S, Hb D Punjab, and Hb E are the most common ones. Other variants include Hb Q India, Hb Lepore, Hb J Meerut, Hb D Iran, etc. These variants show heterozygous state along with beta thalassemia. However, compound heterozygosities among these variants are very rare. Ethylenediaminetetraacetic acid whole blood sample received for routine thalassemia screening was subjected to alkaline electrophoresis using automated capillary zone electrophoresis. Suspecting the presence of rare variants, further analysis was carried out using Bio-Rad D10 and Tosoh G8 high-performance liquid chromatography (HPLC systems. Capillary zone electrophoretograms showed the presence of peaks in zone Hb A, Hb D, a fused peak in Hb A2, and a small peak in Z1 zone. Bio-Rad and Tosoh chromatograms also indicated the presence of four peaks which are identified as Hb A, Hb D Punjab, Hb Q India, and hybrid of Hb D Punjab/Hb Q India. A peak in Hb D zone of capillary was due to co-migration of Hb D Punjab and Hb Q India variants. Small peak in Z1 zone indicated the presence of alpha chain variant Hb Q India. The findings were further confirmed by HPLC results and molecular genetic studies. The present study reports for the 1 st time a rare hemoglobinopathy of double heterozygosity for Hb D Punjab, Hb Q India on Capillarys 2 Flex Piercing analyzer and is forth reported case for this rare hemoglobinopathy.

  6. Anxiety, depression, and health-related quality of life in heterozygous familial hypercholesterolemia: A systematic review and meta-analysis.

    Science.gov (United States)

    Akioyamen, Leo E; Genest, Jacques; Shan, Shubham D; Inibhunu, Happy; Chu, Anna; Tu, Jack V

    2018-06-01

    Heterozygous familial hypercholesterolemia (FH) is a common genetic disease predisposing affected individuals to a high risk of cardiovascular disease. Yet, considerable uncertainty exists regarding its impact on psychosocial wellbeing. We performed a systematic review and meta-analysis of the association between FH and symptoms of anxiety and depression, and health-related quality of life (HRQL). We searched MEDLINE, EMBASE, Global Health, the Cochrane Library, PsycINFO, and PubMed for peer-reviewed literature published in English between January 1, 1990 and January 1, 2018. Quantitative and qualitative studies were eligible if they included patients with confirmed FH and evaluated its association with symptoms of anxiety or depression, or HRQL. We performed a narrative synthesis of studies, including thematic analysis of qualitative studies, and where data permitted, random-effects meta-analysis reporting standardized mean differences (SMD) and 95% confidence intervals. We found 10 eligible studies measuring HRQL, depression and anxiety. Random-effects meta-analysis of 4 (n = 4293) and 5 studies (n = 5098), respectively, showed that patients with FH had slightly lower symptoms of anxiety (SMD: -0.29 [95% CI: -0.53, -0.04]) and mental HRQL (SMD: -0.10 [95% -0.20, -0.00]) relative to general population controls. No significant differences existed in depressive symptoms (SMD: 0.04 [95% CI: -0.12, 0.19]) or physical HRQL scores (SMD: 0.02 [95% CI: -0.09, 0.12]). Our systematic review suggests that patients with FH may report small but measurable differences in anxiety symptoms and mental HRQL. Copyright © 2018 Elsevier Inc. All rights reserved.

  7. Whole-Exome Sequencing Identified a Novel Compound Heterozygous Mutation of LRRC6 in a Chinese Primary Ciliary Dyskinesia Patient

    Directory of Open Access Journals (Sweden)

    Lv Liu

    2018-01-01

    Full Text Available Primary ciliary dyskinesia (PCD is a clinical rare peculiar disorder, mainly featured by respiratory infection, tympanitis, nasosinusitis, and male infertility. Previous study demonstrated it is an autosomal recessive disease and by 2017 almost 40 pathologic genes have been identified. Among them are the leucine-rich repeat- (LRR- containing 6 (LRRC6 codes for a 463-amino-acid cytoplasmic protein, expressed distinctively in motile cilia cells, including the testis cells and the respiratory epithelial cells. In this study, we applied whole-exome sequencing combined with PCD-known genes filtering to explore the genetic lesion of a PCD patient. A novel compound heterozygous mutation in LRRC6 (c.183T>G/p.N61K; c.179-1G>A was identified and coseparated in this family. The missense mutation (c.183T>G/p.N61K may lead to a substitution of asparagine by lysine at position 61 in exon 3 of LRRC6. The splice site mutation (c.179-1G>A may cause a premature stop codon in exon 4 and decrease the mRNA levels of LRRC6. Both mutations were not present in our 200 local controls, dbSNP, and 1000 genomes. Three bioinformatics programs also predicted that both mutations are deleterious. Our study not only further supported the importance of LRRC6 in PCD, but also expanded the spectrum of LRRC6 mutations and will contribute to the genetic diagnosis and counseling of PCD patients.

  8. Novel Compound Heterozygous CLCNKB Gene Mutations (c.1755A>G/ c.848_850delTCT) Cause Classic Bartter Syndrome.

    Science.gov (United States)

    Wang, Chunli; Chen, Ying; Zheng, Bixia; Zhu, Mengshu; Fan, Jia; Wang, Juejin; Jia, Zhanjun; Huang, Songming; Zhang, Aihua

    2018-02-14

    Inactivated variants in CLCNKB gene encoding the basolateral chloride channel ClC-Kb cause classic Bartter syndrome characterized by hypokalemic metabolic alkalosis and hyperreninemic hyperaldosteronism. Here we identified two cBS siblings presenting hypokalemia in a Chinese family due to novel compound heterozygous CLCNKB mutations (c.848_850delTCT/c.1755A>G). Compound heterozygosity was confirmed by amplifying and sequencing the patient's genomic DNA. The synonymous mutation c.1755A>G (Thr585Thr) was located at +2bp from the 5' splice donor site in exon 15, further transcript analysis demonstrated that this single nucleotide mutation causes exclusion of exon 15 in the cDNA from the proband and his mother. Furthermore, we investigated the expression and protein trafficking change of c.848_850delTCT (TCT) and exon 15 deletion(E15)mutation in vitro. The E15 mutation markedly decreased the expression of ClC-Kb and resulted in a low-molecular-weight band (~55kD) trapping in the endoplasmic reticulum, while the TCT mutant only decreased the total and plasma membrane ClC-Kb protein expression but did not affect the subcellular localization. Finally, we studied the physiological functions of mutations by using whole-cell patch clamp and found that E15 or TCT mutation decreased the current of ClC-Kb/barttin channel. These results suggested that the compound defective mutations of CLCNKB gene are the molecular mechanism of the two cBS siblings.

  9. Leptin regulates proliferation and apoptosis of colorectal carcinoma ...

    Indian Academy of Sciences (India)

    ways, including Ras/Raf/mitogen-activated protein kinase http://www.ias.ac.in/ ... After blocking with 3% skim milk, the sections were incubated with primary ..... Liu Z, Uesaka T, Watanabe H and Kato N 2001 High fat diet enhances colonic cell ...

  10. African Journal of Biotechnology - Vol 8, No 6 (2009)

    African Journals Online (AJOL)

    Single nucleotide polymorphism genotyping and its application on mapping and marker-assisted plant breeding ... HH Musa, Y Xu, B Dai, X Kang, C Zhu, G Zhu ... YJ Wang, ZQ Han, B Shui, GD Liu, TX Gao, SA Nwafili, S Watanabe, YP Zhang ...

  11. Bulletin of Materials Science | Indian Academy of Sciences

    Indian Academy of Sciences (India)

    MOHAMMOD AMINUZZAMAN1 LIM POH YING1 WEE-SHENOG GOH1 AKIRA WATANABE2. Department of Chemical Science, Faculty of Science, Universiti Tunku Abdul Rahman (UTAR), Perak Campus, Jalan Universiti, Bandar Barat, 31900 Kampar, Malaysia; Institute of Multidisciplinary Research for Advanced Materials ...

  12. Analysis by the IRSN of a study having shown morphological defects in populations of Japanese firs around the Fukushima power plant - Published in Nature Scientific Reports on August 28, 2015 [Watanabe Y., Ichikawa S., Kubota M., Hoshino J., Kubota Y., Maruyama K., Fuma S., Kawaguchi I., Yoschenko V.I., Yoshida S. Morphological defects in native Japanese fir trees around the Fukushima Daiichi Nuclear Power Plant. Sci. Rep., 5, 13232; doi: 10.1038/srep13232 (2015)

    International Nuclear Information System (INIS)

    2015-01-01

    After the accident at the Fukushima Daiichi Nuclear Power Plant (F1NPP) in March 2011, much attention has been paid to the biological consequences of the released radionuclides into the surrounding area. A Japanese team investigated the morphological changes in Japanese fir, a Japanese endemic native conifer, at locations near the F1NPP. Japanese fir populations near the F1NPP showed a significantly increased number of morphological defects, involving deletions of leader shoots of the main axis, compared to a control population far from the F1NPP. The frequency of the defects corresponded to the radioactive contamination levels of the observation sites. A significant increase in deletions of the leader shoots became apparent in those that elongated after the spring of 2012, a year after the accident. These results suggest possibility that the contamination by radionuclides contributed to the morphological defects in Japanese fir trees in the area near the F1NPP. This paper provides an analysis of the publication of these results by Watanabe, Y. et al. in 'Nature Scientific Reports' on August 28, 2015. The original article is attached to the document

  13. Embryonal rhabdomyosarcoma in a patient with a heterozygous frameshift variant in the DICER1 gene and additional manifestations of the DICER1 syndrome.

    Science.gov (United States)

    Fremerey, Julia; Balzer, Stefan; Brozou, Triantafyllia; Schaper, Joerg; Borkhardt, Arndt; Kuhlen, Michaela

    2017-07-01

    Germline mutations in the DICER1 gene are associated with an inherited cancer predisposition syndrome also known as the DICER1-syndrome, which is implicated in a broad range of tumors including pleuropulmonary blastoma, ovarian Sertoli-Leydig cell tumors, ciliary body medulloepithelioma (CBME), pituitary blastoma, embryonal rhabdomyosarcoma (eRMS), anaplastic renal sarcoma as well as ocular, sinonasal tumors ovarian sex-cord tumors, thyroid neoplasia and cystic nephroma. This study describes a novel, heterozygous frameshift DICER1 mutation in a patient, who is affected by different tumors of the DICER1-syndrome, including eRMS, CBME and suspected pleuropulmonary blastoma type I. By whole-exome sequencing of germline material using peripheral blood-derived DNA, we identified a single base pair duplication within the DICER1 gene (c.3405 dupA) that leads to a frameshift and results in a premature stop in exon 21 (p.Gly1136Arg). The metachronous occurrence of two unrelated tumor entities (eRMS and CBME) in a very young child within a short timeframe should have raised the suspicion of an underlying cancer susceptibility syndrome and should be prompt tested for DICER1.

  14. Atp1a3-deficient heterozygous mice show lower rank in the hierarchy and altered social behavior.

    Science.gov (United States)

    Sugimoto, H; Ikeda, K; Kawakami, K

    2017-10-23

    Atp1a3 is the Na-pump alpha3 subunit gene expressed mainly in neurons of the brain. Atp1a3-deficient heterozygous mice (Atp1a3 +/- ) show altered neurotransmission and deficits of motor function after stress loading. To understand the function of Atp1a3 in a social hierarchy, we evaluated social behaviors (social interaction, aggression, social approach and social dominance) of Atp1a3 +/- and compared the rank and hierarchy structure between Atp1a3 +/- and wild-type mice within a housing cage using the round-robin tube test and barbering observations. Formation of a hierarchy decreases social conflict and promote social stability within the group. The hierarchical rank is a reflection of social dominance within a cage, which is heritable and can be regulated by specific genes in mice. Here we report: (1) The degree of social interaction but not aggression was lower in Atp1a3 +/- than wild-type mice, and Atp1a3 +/- approached Atp1a3 +/- mice more frequently than wild type. (2) The frequency of barbering was lower in the Atp1a3 +/- group than in the wild-type group, while no difference was observed in the mixed-genotype housing condition. (3) Hierarchy formation was not different between Atp1a3 +/- and wild type. (4) Atp1a3 +/- showed a lower rank in the mixed-genotype housing condition than that in the wild type, indicating that Atp1a3 regulates social dominance. In sum, Atp1a3 +/- showed unique social behavior characteristics of lower social interaction and preference to approach the same genotype mice and a lower ranking in the hierarchy. © 2017 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  15. Heterozygous ambra1 deficiency in mice: a genetic trait with autism-like behavior restricted to the female gender.

    Science.gov (United States)

    Dere, Ekrem; Dahm, Liane; Lu, Derek; Hammerschmidt, Kurt; Ju, Anes; Tantra, Martesa; Kästner, Anne; Chowdhury, Kamal; Ehrenreich, Hannelore

    2014-01-01

    Autism-spectrum disorders (ASD) are heterogeneous, highly heritable neurodevelopmental conditions affecting around 0.5% of the population across cultures, with a male/female ratio of approximately 4:1. Phenotypically, ASD are characterized by social interaction and communication deficits, restricted interests, repetitive behaviors, and reduced cognitive flexibility. Identified causes converge at the level of the synapse, ranging from mutation of synaptic genes to quantitative alterations in synaptic protein expression, e.g., through compromised transcriptional or translational control. We wondered whether reduced turnover and degradation of synapses, due to deregulated autophagy, would lead to similar phenotypical consequences. Ambra1, strongly expressed in cortex, hippocampus, and striatum, is a positive regulator of Beclin1, a principal player in autophagosome formation. While homozygosity of the Ambra1 null mutation causes embryonic lethality, heterozygous mice with reduced Ambra1 expression are viable, reproduce normally, and lack any immediately obvious phenotype. Surprisingly, comprehensive behavioral characterization of these mice revealed an autism-like phenotype in Ambra1 (+/-) females only, including compromised communication and social interactions, a tendency of enhanced stereotypies/repetitive behaviors, and impaired cognitive flexibility. Reduced ultrasound communication was found in adults as well as pups, which achieved otherwise normal neurodevelopmental milestones. These features were all absent in male Ambra1 (+/-) mice. As a first hint explaining this gender difference, we found a much stronger reduction of Ambra1 protein in the cortex of Ambra1 (+/-) females compared to males. To conclude, Ambra1 deficiency can induce an autism-like phenotype. The restriction to the female gender of autism-generation by a defined genetic trait is unique thus far and warrants further investigation.

  16. Heterozygous Ambra1 deficiency in mice: A genetic trait with autism-like behavior restricted to the female gender

    Directory of Open Access Journals (Sweden)

    Ekrem eDere

    2014-05-01

    Full Text Available Autism spectrum disorders (ASD are heterogeneous, highly heritable neurodevelopmental conditions affecting around 0.5% of the population across cultures, with a male/female ratio of ~4:1. Phenotypically, ASD are characterized by social interaction and communication deficits, restricted interests, repetitive behaviors, and reduced cognitive flexibility. Identified causes converge at the level of the synapse, ranging from mutation of synaptic genes to quantitative alterations in synaptic protein expression, e.g. through compromised transcriptional or translational control. We wondered whether reduced turnover and degradation of synapses, due to deregulated autophagy, would lead to similar phenotypical consequences. Ambra1, strongly expressed in cortex, hippocampus and striatum, is a positive regulator of Beclin1, a principal player in autophagosome formation. While homozygosity of the Ambra1 null mutation causes embryonic lethality, heterozygous mice with reduced Ambra1 expression are viable, reproduce normally, and lack any immediately obvious phenotype. Surprisingly, comprehensive behavioral characterization of these mice revealed an autism-like phenotype in Ambra1+/- females only, including compromised communication and social interactions, a tendency of enhanced stereotypies/repetitive behaviors, and impaired cognitive flexibility. Reduced ultrasound communication was found in adults as well as pups which achieved otherwise normal neurodevelopmental milestones. These features were all absent in male Ambra1+/- mice. As a first hint explaining this gender difference, we found a much stronger reduction of Ambra1 protein in the cortex of Ambra1+/- females compared to males. To conclude, Ambra1 deficiency can induce an autism-like phenotype. The restriction to the female gender of autism-generation by a defined genetic trait is unique thus far and warrants further investigation.

  17. Effects of prenatal hypoxia on schizophrenia-related phenotypes in heterozygous reeler mice: a gene × environment interaction study.

    Science.gov (United States)

    Howell, Kristy R; Pillai, Anilkumar

    2014-08-01

    Both genetic and environmental factors play important roles in the pathophysiology of schizophrenia. Although prenatal hypoxia is a potential environmental factor implicated in schizophrenia, very little is known about the consequences of combining models of genetic risk factor with prenatal hypoxia. Heterozygous reeler (haploinsufficient for reelin; HRM) and wild-type (WT) mice were exposed to prenatal hypoxia (9% oxygen for two hour) or normoxia at embryonic day 17 (E17). Behavioral (Prepulse inhibition, Y-maze and Open field) and functional (regional volume in frontal cortex and hippocampus as well as hippocampal blood flow) tests were performed at 3 months of age. The levels of hypoxia and stress-related molecules such as hypoxia-inducible factor-1 α (HIF-1α), vascular endothelial factor (VEGF), VEGF receptor-2 (VEGFR2/Flk1) and glucocorticoid receptor (GR) were examined in frontal cortex and hippocampus at E18, 1 month and 3 months of age. In addition, serum VEGF and corticosterone levels were also examined. Prenatal hypoxia induced anxiety-like behavior in both HRM and WT mice. A significant reduction in hippocampal blood flow, but no change in brain regional volume was observed following prenatal hypoxia. Significant age and region-dependent changes in HIF-1α, VEGF, Flk1 and GR were found following prenatal hypoxia. Serum VEGF and corticosterone levels were found decreased following prenatal hypoxia. None of the above prenatal hypoxia-induced changes were either diminished or exacerbated due to reelin deficiency. These results argue against any gene-environment interaction between hypoxia and reelin deficiency. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

  18. A physical map of the heterozygous grapevine 'Cabernet Sauvignon' allows mapping candidate genes for disease resistance

    Directory of Open Access Journals (Sweden)

    Scalabrin Simone

    2008-06-01

    Full Text Available Abstract Background Whole-genome physical maps facilitate genome sequencing, sequence assembly, mapping of candidate genes, and the design of targeted genetic markers. An automated protocol was used to construct a Vitis vinifera 'Cabernet Sauvignon' physical map. The quality of the result was addressed with regard to the effect of high heterozygosity on the accuracy of contig assembly. Its usefulness for the genome-wide mapping of genes for disease resistance, which is an important trait for grapevine, was then assessed. Results The physical map included 29,727 BAC clones assembled into 1,770 contigs, spanning 715,684 kbp, and corresponding to 1.5-fold the genome size. Map inflation was due to high heterozygosity, which caused either the separation of allelic BACs in two different contigs, or local mis-assembly in contigs containing BACs from the two haplotypes. Genetic markers anchored 395 contigs or 255,476 kbp to chromosomes. The fully automated assembly and anchorage procedures were validated by BAC-by-BAC blast of the end sequences against the grape genome sequence, unveiling 7.3% of chimerical contigs. The distribution across the physical map of candidate genes for non-host and host resistance, and for defence signalling pathways was then studied. NBS-LRR and RLK genes for host resistance were found in 424 contigs, 133 of them (32% were assigned to chromosomes, on which they are mostly organised in clusters. Non-host and defence signalling genes were found in 99 contigs dispersed without a discernable pattern across the genome. Conclusion Despite some limitations that interfere with the correct assembly of heterozygous clones into contigs, the 'Cabernet Sauvignon' physical map is a useful and reliable intermediary step between a genetic map and the genome sequence. This tool was successfully exploited for a quick mapping of complex families of genes, and it strengthened previous clues of co-localisation of major NBS-LRR clusters and

  19. De novo assembly of the perennial ryegrass transcriptome using an RNA-Seq strategy.

    Directory of Open Access Journals (Sweden)

    Jacqueline D Farrell

    Full Text Available Perennial ryegrass is a highly heterozygous outbreeding grass species used for turf and forage production. Heterozygosity can affect de-Bruijn graph assembly making de novo transcriptome assembly of species such as perennial ryegrass challenging. Creating a reference transcriptome from a homozygous perennial ryegrass genotype can circumvent the challenge of heterozygosity. The goals of this study were to perform RNA-sequencing on multiple tissues from a highly inbred genotype to develop a reference transcriptome. This was complemented with RNA-sequencing of a highly heterozygous genotype for SNP calling.De novo transcriptome assembly of the inbred genotype created 185,833 transcripts with an average length of 830 base pairs. Within the inbred reference transcriptome 78,560 predicted open reading frames were found of which 24,434 were predicted as complete. Functional annotation found 50,890 transcripts with a BLASTp hit from the Swiss-Prot non-redundant database, 58,941 transcripts with a Pfam protein domain and 1,151 transcripts encoding putative secreted peptides. To evaluate the reference transcriptome we targeted the high-affinity K+ transporter gene family and found multiple orthologs. Using the longest unique open reading frames as the reference sequence, 64,242 single nucleotide polymorphisms were found. One thousand sixty one open reading frames from the inbred genotype contained heterozygous sites, confirming the high degree of homozygosity.Our study has developed an annotated, comprehensive transcriptome reference for perennial ryegrass that can aid in determining genetic variation, expression analysis, genome annotation, and gene mapping.

  20. Heterozygous deletion at the RLN1 locus in a family with testicular germ cell cancer identified by integrating copy number variation data with phenome and interactome information

    DEFF Research Database (Denmark)

    Edsgärd, D; Scheel, M; Hansen, N T

    2011-01-01

    -associated genes among loci targeted by CNVs. The top-ranked candidate, RLN1, encoding a Relaxin-H1 peptide, although only detected in one of the families, was selected for further investigations. Validation of the CNV at the RLN1 locus was performed as an association study using qPCR with 106 sporadic testicular...... GCT patients and 200 healthy controls. Observed CNV frequencies of 1.9% among cases and 1.5% amongst controls were not significantly different and this was further confirmed by CNV data extracted from a genome-wide analysis of 189 cases and 380 controls, where similar frequencies of 2.2% were observed....... Collectively, the findings show that a heterozygous loss at the RLN1 locus is not a genetic factor mediating high population-wide risk for testicular germ cell tumour, but do not exclude a contribution of this aberration in some cases of cancer. The preliminary expression data suggest a possible role...

  1. Heterozygous deletion at the RLN1 locus in a family with testicular germ cell cancer identified by integrating copy number variation data with phenome and interactome information

    DEFF Research Database (Denmark)

    Edsgard, Stefan Daniel; Scheel, M.; Hansen, Niclas Tue

    2011-01-01

    ‐associated genes among loci targeted by CNVs. The top‐ranked candidate, RLN1, encoding a Relaxin‐H1 peptide, although only detected in one of the families, was selected for further investigations. Validation of the CNV at the RLN1 locus was performed as an association study using qPCR with 106 sporadic testicular...... GCT patients and 200 healthy controls. Observed CNV frequencies of 1.9% among cases and 1.5% amongst controls were not significantly different and this was further confirmed by CNV data extracted from a genome‐wide analysis of 189 cases and 380 controls, where similar frequencies of 2.2% were observed...... and spermatids. Collectively, the findings show that a heterozygous loss at the RLN1 locus is not a genetic factor mediating high population‐wide risk for testicular germ cell tumour, but do not exclude a contribution of this aberration in some cases of cancer. The preliminary expression data suggest a possible...

  2. A Rare Variant in PGAP2 Causes Autosomal Recessive Hyperphosphatasia with Mental Retardation Syndrome, with a Mild Phenotype in Heterozygous Carriers

    Directory of Open Access Journals (Sweden)

    Yonatan Perez

    2017-01-01

    Full Text Available Mutations in genes involved in the biosynthesis of the glycosylphosphatidylinositol (GPI anchor cause autosomal recessive glycosylation defects, with a wide phenotypic spectrum of intellectual disability, seizures, minor facial dysmorphism, hypotonia, and elevated serum alkaline phosphatase. We now describe consanguineous Bedouin kindred presenting with an autosomal recessive syndrome of intellectual disability and elevated serum alkaline phosphatase. Genome-wide linkage analysis identified 6 possible disease-associated loci. Whole-exome sequencing followed by Sanger sequencing validation identified a single variant in PGAP2 as the disease-causing mutation (C.554G>A; p.185(R>Q, segregating as expected within the kindred and not found in 150 Bedouin controls. The mutation replaces a highly conserved arginine residue with glutamine within the Frag1 (FGF receptor activating domain of PGAP2. Interestingly, this mutation is a known dbSNP variant (rs745521288, build 147 with a very low allele frequency (0.00000824 in dbSNP, no homozygotes reported, highlighting the fact that dbSNP variants should not be automatically ruled out as disease-causing mutations. We further showed that PGAP2 is ubiquitously expressed, but in line with the disease phenotype, it is highly transcribed in human brain, skeletal muscle, and liver. Interestingly, a mild phenotype of slightly elevated serum levels of alkaline phosphatase and significant learning disabilities was observed in heterozygous carriers.

  3. 76 FR 41526 - Centennial Challenges 2011 Strong Tether Challenge

    Science.gov (United States)

    2011-07-14

    ... NATIONAL AERONAUTICS AND SPACE ADMINISTRATION [Notice (11-063)] Centennial Challenges 2011 Strong... scheduled and teams that wish to compete may register. Centennial Challenges is a program of prize... NASA Centennial Challenges Program please visit: http://www.nasa.gov/challenges . General questions and...

  4. Influence of ROM Exercise on the Joint Components during Immobilization

    OpenAIRE

    松﨑, 太郎; Matsuzaki, Taro

    2013-01-01

    博士論文要旨Abstract 要約Outline 以下に掲載:Journal of Physical Therapy Science 25(12) pp.1547-1551 2013. The Society of Physical Therapy Science. 共著者:Taro Matsuzaki, Shinya Yoshida, Satoshi Kojima, Masanori Watanabe, Masahiro Hoso

  5. A noncommutative mean ergodic theorem for partial W*-dynamical semigroups

    International Nuclear Information System (INIS)

    Ekhaguere, G.O.S.

    1992-12-01

    A noncommutative mean ergodic theorem for dynamical semigroups of maps on partial W*-algebras of linear operators from a pre-Hilbert space into its completion is proved. This generalizes a similar result of Watanabe for dynamical semigroups of maps on W*-algebras of operators. (author). 14 refs

  6. Lipoprotein-associated phospholipase A2 mass and activity in children with heterozygous familial hypercholesterolemia and unaffected siblings: effect of pravastatin.

    Science.gov (United States)

    Ryu, Sung Kee; Hutten, Barbara A; Vissers, Maud N; Wiegman, Albert; Kastelein, John J P; Tsimikas, Sotirios

    2011-01-01

    Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an independent risk factor of cardiovascular disease and a target of treatment. Lp-PLA(2) levels in children have not been previously reported. The effect of statin therapy on Lp-PLA(2) mass and activity in children with familial hypercholesterolemia (FH) is also not known. Lp-PLA(2) mass and activity levels were measured at baseline and after 2 years in 178 children with FH randomized to pravastatin or placebo and in 78 unaffected and untreated siblings. At the end of the randomized period, all FH children were then placed on pravastatin for an additional 2 years, and Lp-PLA(2) mass and activity levels were correlated with changes in carotid intima-media thickness during 4 years of follow-up. Baseline levels of Lp-PLA(2) mass and activity were significantly greater in children with FH compared with unaffected siblings (mass: 240.3 ± 41.6 vs 222.1 ± 36.5 ng/mL, P = .002; activity: 205.7 ± 41.6 vs 124.3±23.0 nmol/min/mL, P vs 231.5 ± 34.8 ng/mL, P = .001) and activity (178.8 ± 37.3 vs 206.2 ± 33.5 nmol/min/mL, P children with heterozygous FH compared with unaffected siblings and are significantly reduced by pravastatin therapy. Copyright © 2011 National Lipid Association. Published by Elsevier Inc. All rights reserved.

  7. Utility of whole exome sequencing in the diagnosis of Usher syndrome: Report of novel compound heterozygous MYO7A mutations.

    Science.gov (United States)

    Ramzan, Khushnooda; Al-Owain, Mohammed; Huma, Rozeena; Al-Hazzaa, Selwa A F; Al-Ageel, Sarah; Imtiaz, Faiqa; Al-Sayed, Moeenaldeen

    2018-05-01

    Next generation sequencing (NGS), such as targeted panel sequencing, whole-exome sequencing and whole-genome sequencing has led to an exponential increase of elucidated genetic causes in both rare diseases, and common but heterogeneous disorders. NGS is applied in both research and clinical settings, and the clinical exome sequencing (CES), which provides not only the sequence variation data but also clinical interpretation, aids in reaching a final conclusion with regards to a genetic diagnosis. Usher syndrome is a group of disorders, characterized by bilateral sensorineural hearing loss, with or without vestibular dysfunction and retinitis pigmentosa. The index patient, a 2-year-old child was initially diagnosed with nonsyndromic hearing impairment. Homozygosity mapping followed by CES was utilized as a diagnostic tool to identify the genetic basis of his hearing loss. A paternally inherited novel insertion, c.198_199insA (p.Val67Serfs*73) and a maternally inherited novel deletion, c.1219_1226del (p.Phe407Aspfs*33) in gene MYO7A were found in compound heterozygous state in the index patient. The result expands the mutational spectrum of MYO7A. In addition it helped in early diagnosis of the syndrome, for planning and adjustments for the patient, and as well as for future family planning. This study highlights the clinical effectiveness of CES for Usher syndrome diagnosis in a child presented with congenital hearing loss. Copyright © 2018. Published by Elsevier B.V.

  8. 78 FR 19742 - Centennial Challenges: 2014 Night Rover Challenge

    Science.gov (United States)

    2013-04-02

    ... NATIONAL AERONAUTICS AND SPACE ADMINISTRATION [Notice 13-032] Centennial Challenges: 2014 Night... Centennial Challenges 2014 Night Rover Challenge. SUMMARY: This notice is issued in accordance with 51 U.S.C.... Centennial Challenges is a program of prize competitions to stimulate innovation in technologies of interest...

  9. Gender, identity and culture in learning physics

    Science.gov (United States)

    Corbett, Katelin

    2016-06-01

    Student engagement in science, as defined by Iva Gurgel, Mauricio Pietrocola, and Graciella Watanabe, is of great importance because a student's perceived compatibility with science learning is highly influenced by personal identities, or how students see themselves in relations to the world. This can greatly impact their learning experiences. In this forum, I build on the work of Gurgel, Pietrocola, and Watanabe by exploring the relationships between engagement in physics and gender, and by looking at the expansive nature of the concept of culture. I expand the conversation by investigating ways in which learning science has impacted my own identity/worldview, particularly how it affects my personal teaching and learning experiences. I focus the conversation around the relationship between gender and the experience of learning science to further the dialogue concerning identity and how it impacts engagement in science. I also look at the role of didactic transposition in the perceived disconnect with science. I reveal my experiences and analysis through a personal narrative.

  10. 17 beta-estradiol but not the phytoestrogen naringenin attenuates aortic cholesterol accumulation in WHHL rabbits

    DEFF Research Database (Denmark)

    Mortensen, Alicja; Breinholt, V.; Dalsgaard, T.

    2001-01-01

    The effects of 17 beta -estradiol (17 beta -E-2) or the phytoestrogen naringenin on spontaneous atherosclerosis were studied in 36 ovariectomized homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits receiving a semisynthetic control diet; this diet added 0.0040% 17 beta -E-2, or 0.20% nari...... and its antiatherogenic effect. - Mortensen, A., V. Breinholt, T. Dalsgaard, H. Frandsen, S. T. Lauridsen, J. Laigaard, B. Ottesen, and J-J. Larsen. 17 beta -Estradiol but not the phytoestrogen naringenin attenuates aortic cholesterol accumulation in WHHL rabbits.......The effects of 17 beta -estradiol (17 beta -E-2) or the phytoestrogen naringenin on spontaneous atherosclerosis were studied in 36 ovariectomized homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits receiving a semisynthetic control diet; this diet added 0.0040% 17 beta -E-2, or 0.......20% naringenin, for 16 weeks. The uterine weight was increased (P 17 beta -E-2 group compared with the controls. Total plasma cholesterol and triglycerides were not different from those in the controls, In lipoproteins, HDL...

  11. 77 FR 70835 - Centennial Challenges 2013 Sample Return Robot Challenge

    Science.gov (United States)

    2012-11-27

    ... NATIONAL AERONAUTICS AND SPACE ADMINISTRATION Centennial Challenges 2013 Sample Return Robot... Challenge is scheduled and teams that wish to compete may register. Centennial Challenges is a program of... Challenge, please visit: http://challenge.wpi.edu . For general information on the NASA Centennial...

  12. 76 FR 56819 - Centennial Challenges 2012 Sample Return Robot Challenge

    Science.gov (United States)

    2011-09-14

    ... NATIONAL AERONAUTICS AND SPACE ADMINISTRATION [Notice (11-079)] Centennial Challenges 2012 Sample... Challenge is scheduled and teams that wish to compete may register. Centennial Challenges is a program of... Challenge, please visit: http://wp.wpi.edu/challenge/ . For general information on the NASA Centennial...

  13. Mobile Manipulators for Assisted Living in Residential Settings

    Science.gov (United States)

    2007-01-01

    unplanned “bumps” and reduces the probability of damage to itself, the client, or the environment. These trade - offs mean that it will not initially be able...Sakagami, Y.; Watanabe, R.; Aoyama, C.; Matsunaga, S.; Higaki, N.; and Fujimura, K. 2002. The intelli- gent ASIMO: System overview and intergration

  14. 77 FR 76740 - Endangered and Threatened Species; Threatened Status for the Beringia and Okhotsk Distinct...

    Science.gov (United States)

    2012-12-28

    ... bearded seals therefore requires a focus on observed and projected changes in sea ice, ocean temperature... over the nursing period, and perhaps beyond (Watanabe et al., 2009). Learning to forage in a sub-optimal habitat could impair a pup's ability to learn effective foraging skills, potentially impacting its...

  15. Cerebral infarction and femoral venous thrombosis detected in a patient with diabetic ketoacidosis and heterozygous factor V Leiden G1691A and PAI-1 4G/5G mutations.

    Science.gov (United States)

    Yaroglu Kazanci, Selcen; Yesilbas, Osman; Ersoy, Melike; Kihtir, Hasan Serdar; Yildirim, Hamdi Murat; Sevketoglu, Esra

    2015-09-01

    Cerebral infarction is one of the serious neurological complications of diabetic ketoacidosis (DKA). Especially in patients who are genetically prone to thrombosis, cerebral infarction may develop due to inflammation, dehydration, and hyperviscocity secondary to DKA. A 6-year-old child with DKA is diagnosed with cerebral infarction after respiratory insufficiency, convulsion, and altered level of consciousness. Femoral and external iliac venous thrombosis also developed in a few hours after central femoral catheter had been inserted. Heterozygous type of factor V Leiden and PAI-14G/5G mutation were detected. In patients with DKA, cerebral infarction may be suspected other than cerebral edema when altered level of consciousness, convulsion, and respiratory insufficiency develop and once cerebral infarction occurs the patients should also be evaluated for factor V Leiden and PAI-14G/5G mutation analysis in addition to the other prothrombotic risk factors.

  16. Effect of Geranylgeranylacetone on Ultraviolet Radiation Type B-Induced Cataract in Heat-Shock Transcription Factor 1 Heterozygous Mouse.

    Science.gov (United States)

    Ogasawara, Satoshi; Hashizume, Kouhei; Okuno, Takashi; Imaizumi, Toshiyasu; Inomata, Yui; Tezuka, Yu; Sanbe, Atushi; Kurosaka, Daijiro

    2017-05-01

    We investigated whether heat-shock transcription factor 1 (HSF1) was involved in ultraviolet radiation type B (UVR-B)-induced lens opacity (cataract) using HSF1 heterozygous mice. We also examined the effects of geranylgeranylacetone (GGA), an inducer of heat-shock proteins via activation of HSF, on the UVR-B-induced cataract. Male HSF1 +/- and WT mice were unilaterally exposed to UVR-B (total: 1200mJ) at 16 weeks of age. At 48 h after the last UVR-B irradiation, the lens was isolated and the induction of the cataract was quantified as the cataract area ratio (opacity area/anterior capsule). GGA was orally administered at a dosage of 500 mg/kg once a day for two days before the first UVR-B exposure until the end of the experiment (21days in total). The HSF1 expression was more greatly decreased in the lens from HSF1 +/- mice than in that from WT mice (p B exposure could mainly induce cataracts in the anterior capsule in both HSF1 +/- and WT mice, while the opacity of the lens was markedly enhanced in HSF 1+/- mice compared to that in WT mice(p (0.01). GGA treatment could prevent the induction of lens opacity by UVR-B exposure in both WT and HSF1 +/- mice as compared with the non-administration group (p B radiation was seen in lens protein levels of αA-crystallin, αB-crystallin, or γ-crystallin with or without GGA administration among all groups of mice. In contrast to the crystallins, the lens protein level of HSP25 was decreased by UVR-B exposure in both HSF1 +/- and WT mice, and was significantly recovered in WT mice by the GGA treatment (p B-induced cataracts, possibly via regulation of HSPs such as HSP25.

  17. 78 FR 49296 - Centennial Challenges 2014 Sample Return Robot Challenge

    Science.gov (United States)

    2013-08-13

    ... NATIONAL AERONAUTICS AND SPACE ADMINISTRATION [Notice 13-093] Centennial Challenges 2014 Sample... Centennial Challenges 2014 Sample Return Robot Challenge. SUMMARY: This notice is issued in accordance with... compete may register. Centennial Challenges is a program of prize competitions to stimulate innovation in...

  18. Impaired Insulin Signaling is Associated with Hepatic Mitochondrial Dysfunction in IR+/−-IRS-1+/− Double Heterozygous (IR-IRS1dh Mice

    Directory of Open Access Journals (Sweden)

    Andras Franko

    2017-05-01

    Full Text Available Mitochondria play a pivotal role in energy metabolism, but whether insulin signaling per se could regulate mitochondrial function has not been identified yet. To investigate whether mitochondrial function is regulated by insulin signaling, we analyzed muscle and liver of insulin receptor (IR+/−-insulin receptor substrate-1 (IRS-1+/− double heterozygous (IR-IRS1dh mice, a well described model for insulin resistance. IR-IRS1dh mice were studied at the age of 6 and 12 months and glucose metabolism was determined by glucose and insulin tolerance tests. Mitochondrial enzyme activities, oxygen consumption, and membrane potential were assessed using spectrophotometric, respirometric, and proton motive force analysis, respectively. IR-IRS1dh mice showed elevated serum insulin levels. Hepatic mitochondrial oxygen consumption was reduced in IR-IRS1dh animals at 12 months of age. Furthermore, 6-month-old IR-IRS1dh mice demonstrated enhanced mitochondrial respiration in skeletal muscle, but a tendency of impaired glucose tolerance. On the other hand, 12-month-old IR-IRS1dh mice showed improved glucose tolerance, but normal muscle mitochondrial function. Our data revealed that deficiency in IR/IRS-1 resulted in normal or even elevated skeletal muscle, but impaired hepatic mitochondrial function, suggesting a direct cross-talk between insulin signaling and mitochondria in the liver.

  19. Meso-scale atmospheric events promote phytoplankton blooms in the coastal Bay of Bengal

    Digital Repository Service at National Institute of Oceanography (India)

    Maneesha, K.; Sarma, V.V.S.S.; Reddy, N.P.C.; Sadhuram, Y.; Murty, T.V.R.; Sarma, V.V.; DileepKumar, M.

    mixing does not cool SST in the post monsoon north Bay of Bengal; Atmos. Sci. Letts. 9 1–6. Senjyu T and Watanabe T 1999 A sudden temperature decrease along the Sanin coast induced by a typhoon; Umi to Sora 75 1–8 (in Japanese with English abstract...

  20. 76 FR 57951 - Certain Lined Paper Products From the People's Republic of China: Notice of Final Rescission of...

    Science.gov (United States)

    2011-09-19

    ... Group based on evidence on the record indicating that Leo/Denmax, Lian Li, and the Watanabe Group had no...; Address books; Columnar pads & tablets, with or without covers, primarily suited for the recording of... denier polyester, coated on the backside with PVC (poly vinyl chloride) coating, and extending the entire...

  1. Teaching Art with Art: Flowers in Art.

    Science.gov (United States)

    Hubbard, Guy

    1998-01-01

    Justifies examining still-life pictures of flowers to provide students with an opportunity to learn how one distinguishes between deeply artistic pictures full of emotion and pictures lacking this quality. Claims that students will develop their own artistic expression. Offers pictures by Diego Rivera, Watanabe Shiko, Consuelo Kanaga, and Rachel…

  2. 76 FR 23288 - Certain Lined Paper Products From the People's Republic of China: Notice of Final Results of the...

    Science.gov (United States)

    2011-04-26

    ... measurement purposes, pages with tapered or rounded edges shall be measured at their longest and widest points... storage. Both ends of the spiral wire are cut and then bent backwards to overlap with the previous coil... the credibility of the Department's verification as well as the reliability of Watanabe's books and...

  3. Pramana – Journal of Physics | Indian Academy of Sciences

    Indian Academy of Sciences (India)

    Annual Meetings · Mid Year Meetings · Discussion Meetings · Public Lectures · Lecture Workshops · Refresher Courses · Symposia · Live Streaming. Home; Journals; Pramana – Journal of Physics; Volume 73; Issue 4. Application of FIRE for the calculation of photon matrix elements. Norihisa Watanabe. Volume 73 Issue 4 ...

  4. The Mock LISA Data Challenges: from Challenge 1B to Challenge 3

    International Nuclear Information System (INIS)

    Babak, Stanislav; Porter, Edward K; Gair, Jonathan; Baker, John G; Arnaud, Keith; Benacquista, Matthew J; Cornish, Neil J; Crowder, Jeff; Vallisneri, Michele; Cutler, Curt; Larson, Shane L; Plagnol, Eric; Vecchio, Alberto; Barack, Leor; Blaut, Arkadiusz; Fairhurst, Stephen; Harry, Ian; Gong Xuefei; Khurana, Deepak; Krolak, Andrzej

    2008-01-01

    The Mock LISA Data Challenges are a programme to demonstrate and encourage the development of LISA data-analysis capabilities, tools and techniques. At the time of this workshop, three rounds of challenges had been completed, and the next was about to start. In this paper we provide a critical analysis of the entries to the latest completed round, Challenge 1B. The entries confirm the consolidation of a range of data-analysis techniques for galactic and massive-black-hole binaries, and they include the first convincing examples of detection and parameter estimation of extreme-mass-ratio inspiral sources. In this paper we also introduce the next round, Challenge 3. Its data sets feature more realistic waveform models (e.g., galactic binaries may now chirp, and massive-black-hole binaries may precess due to spin interactions), as well as new source classes (bursts from cosmic strings, isotropic stochastic backgrounds) and more complicated nonsymmetric instrument noise

  5. Characterization of a Case of Pigmentary Retinopathy in Sanfilippo Syndrome Type IIIA Associated with Compound Heterozygous Mutations in the SGSH Gene.

    Science.gov (United States)

    Wilkin, Justin; Kerr, Natalie C; Byrd, Kathryn W; Ward, Jewell C; Iannaccone, Alessandro

    2016-06-01

    To report longitudinal phenotypic findings in a patient with Sanfilippo syndrome type IIIA, harboring SGSH mutations, one of which is novel. Heparan-N-sulfatidase enzyme function testing in skin fibroblasts and white blood cells and SGSH gene sequencing were obtained. Clinical office examinations, examinations under anesthesia, electroretinogram, spectral domain optical coherence tomography (SD-OCT), and fundus photography were performed over a 5-year period. Fundus examination revealed a progressive breadcrumb-like pigmentary retinopathy with perifoveal pigmentary involvement. SD-OCT showed loss of normal neuroretinal lamination and cystic macular changes responsive to treatment with carbonic anhydrase inhibitors. Electroretinography exhibited complex characteristics indicative of a generalized retinal rod > cone dysfunction with significant ON > OFF postreceptoral response compromise. Sequencing revealed compound heterozygous mutations in the SGSH gene, the novel c.88G > C (p.A30P) change and a second, previously reported one (c.734G > A, p.R245H). We have identified ocular features of a patient with Sanfilippo syndrome type IIIA harboring a novel SGHS mutation that were not previously known to occur in this disease - namely, a progressive retinopathy with distinctive features, cystic macular changes responsive to carbonic anhydrase inhibitors, and complex electroretinographic abnormalities consistent with postreceptoral dysfunction. SD-OCT imaging revealed retinal lamination changes consistent with previously reported histologic studies. Both the SD-OCT and the electroretinogram changes appear attributable to intraretinal deposition of heparan sulfate.

  6. Book Review: Robotic Surgery by G Watanabe | Dawka | Archives of ...

    African Journals Online (AJOL)

    The PDF file you selected should load here if your Web browser has a PDF reader plug-in installed (for example, a recent version of Adobe Acrobat Reader). If you would like more information about how to print, save, and work with PDFs, Highwire Press provides a helpful Frequently Asked Questions about PDFs.

  7. Book Review: Robotic Surgery by G Watanabe | Dawka | Archives of ...

    African Journals Online (AJOL)

    Archives of Medical and Biomedical Research. Journal Home · ABOUT THIS JOURNAL · Advanced Search · Current Issue · Archives · Journal Home > Vol 1, No 3 (2014) >. Log in or Register to get access to full text downloads. Username, Password, Remember me, or Register. Book Review: Robotic Surgery by G ...

  8. 75 FR 47316 - Centennial Challenges 2010 Strong Tether Challenge

    Science.gov (United States)

    2010-08-05

    ... NATIONAL AERONAUTICS AND SPACE ADMINISTRATION Centennial Challenges 2010 Strong Tether Challenge... teams that wish to compete may register. Centennial Challenges is a program of prize competitions to..., please visit: http://www.spaceward.org/elevator2010-ts . For general information on the NASA Centennial...

  9. Prion infectivity in the spleen of a PRNP heterozygous individual with subclinical variant Creutzfeldt-Jakob disease.

    Science.gov (United States)

    Bishop, Matthew T; Diack, Abigail B; Ritchie, Diane L; Ironside, James W; Will, Robert G; Manson, Jean C

    2013-04-01

    Blood transfusion has been identified as a source of human-to-human transmission of variant Creutzfeldt-Jakob disease. Three cases of variant Creutzfeldt-Jakob disease have been identified following red cell transfusions from donors who subsequently developed variant Creutzfeldt-Jakob disease and an asymptomatic red cell transfusion recipient, who did not die of variant Creutzfeldt-Jakob disease, has been identified with prion protein deposition in the spleen and a lymph node, but not the brain. This individual was heterozygous (MV) at codon 129 of the prion protein gene (PRNP), whereas all previous definite and probable cases of variant Creutzfeldt-Jakob disease have been methionine homozygotes (MM). A critical question for public health is whether the prion protein deposition reported in peripheral tissues from this MV individual correlates with infectivity. Additionally it is important to establish whether the PRNP codon 129 genotype has influenced the transmission characteristics of the infectious agent. Brain and spleen from the MV blood recipient were inoculated into murine strains that have consistently demonstrated transmission of the variant Creutzfeldt-Jakob disease agent. Mice were assessed for clinical and pathological signs of disease and transmission data were compared with other transmission studies in variant Creutzfeldt-Jakob disease, including those on the spleen and brain of the donor to the index case. Transmission of variant Creutzfeldt-Jakob disease was observed from the MV blood recipient spleen, but not from the brain, whereas there was transmission from both spleen and brain tissues from the red blood cell donor. Longer incubation times were observed for the blood donor spleen inoculum compared with the blood donor brain inoculum, suggesting lower titres of infectivity in the spleen. The distribution of vacuolar pathology and abnormal prion protein in infected mice were similar following inoculation with both donor and recipient spleen

  10. Prion infectivity in the spleen of a PRNP heterozygous individual with subclinical variant Creutzfeldt–Jakob disease

    Science.gov (United States)

    Bishop, Matthew T.; Diack, Abigail B.; Ritchie, Diane L.; Ironside, James W.; Will, Robert G.

    2013-01-01

    Blood transfusion has been identified as a source of human-to-human transmission of variant Creutzfeldt–Jakob disease. Three cases of variant Creutzfeldt–Jakob disease have been identified following red cell transfusions from donors who subsequently developed variant Creutzfeldt–Jakob disease and an asymptomatic red cell transfusion recipient, who did not die of variant Creutzfeldt–Jakob disease, has been identified with prion protein deposition in the spleen and a lymph node, but not the brain. This individual was heterozygous (MV) at codon 129 of the prion protein gene (PRNP), whereas all previous definite and probable cases of variant Creutzfeldt–Jakob disease have been methionine homozygotes (MM). A critical question for public health is whether the prion protein deposition reported in peripheral tissues from this MV individual correlates with infectivity. Additionally it is important to establish whether the PRNP codon 129 genotype has influenced the transmission characteristics of the infectious agent. Brain and spleen from the MV blood recipient were inoculated into murine strains that have consistently demonstrated transmission of the variant Creutzfeldt–Jakob disease agent. Mice were assessed for clinical and pathological signs of disease and transmission data were compared with other transmission studies in variant Creutzfeldt–Jakob disease, including those on the spleen and brain of the donor to the index case. Transmission of variant Creutzfeldt–Jakob disease was observed from the MV blood recipient spleen, but not from the brain, whereas there was transmission from both spleen and brain tissues from the red blood cell donor. Longer incubation times were observed for the blood donor spleen inoculum compared with the blood donor brain inoculum, suggesting lower titres of infectivity in the spleen. The distribution of vacuolar pathology and abnormal prion protein in infected mice were similar following inoculation with both donor and

  11. The Mock LISA Data Challenges: from challenge 3 to challenge 4

    International Nuclear Information System (INIS)

    Babak, Stanislav; Petiteau, Antoine; Robinson, Emma L; Baker, John G; McWilliams, Sean T; Arnaud, Keith A; Benacquista, Matthew J; Cornish, Neil J; Adams, Matt; Larson, Shane L; Mandel, Ilya; Porter, Edward K; Vallisneri, Michele; Cutler, Curt; Vecchio, Alberto; Blaut, Arkadiusz; Bridges, Michael; Feroz, Farhan; Cohen, Michael; Gair, Jonathan R.

    2010-01-01

    The Mock LISA Data Challenges are a program to demonstrate LISA data-analysis capabilities and to encourage their development. Each round of challenges consists of one or more datasets containing simulated instrument noise and gravitational waves from sources of undisclosed parameters. Participants analyze the datasets and report best-fit solutions for the source parameters. Here we present the results of the third challenge, issued in April 2008, which demonstrated the positive recovery of signals from chirping galactic binaries, from spinning supermassive-black-hole binaries (with optimal SNRs between ∼10 and 2000), from simultaneous extreme-mass-ratio inspirals (SNRs of 10-50), from cosmic-string-cusp bursts (SNRs of 10-100), and from a relatively loud isotropic background with Ω gw (f) ∼ 10 -11 , slightly below the LISA instrument noise.

  12. The Mock LISA Data Challenges: from challenge 3 to challenge 4

    Energy Technology Data Exchange (ETDEWEB)

    Babak, Stanislav; Petiteau, Antoine; Robinson, Emma L [Max-Planck-Institut fuer Gravitationsphysik (Albert-Einstein-Institut), Am Muehlenberg 1, D-14476 Golm bei Potsdam (Germany); Baker, John G; McWilliams, Sean T; Arnaud, Keith A [Gravitational Astrophysics Laboratory, NASA Goddard Space Flight Center, 8800 Greenbelt Rd, Greenbelt, MD 20771 (United States); Benacquista, Matthew J [Center for Gravitational Wave Astronomy, University of Texas at Brownsville, Brownsville, TX 78520 (United States); Cornish, Neil J; Adams, Matt [Department of Physics, Montana State University, Bozeman, MT 59717 (United States); Larson, Shane L [Department of Physics, Utah State University, Logan, UT 84322 (United States); Mandel, Ilya [Department of Physics and Astronomy, Northwestern University, Evanston, IL (United States); Porter, Edward K [APC, UMR 7164, University Paris 7 Denis Diderot, 10, rue Alice Domon et Leonie Duquet, 75025 Paris Cedex 13 (France); Vallisneri, Michele; Cutler, Curt [Jet Propulsion Laboratory, California Institute of Technology, Pasadena, CA 91109 (United States); Vecchio, Alberto [School of Physics and Astronomy, University of Birmingham, Edgbaston, Birmingham B152TT (United Kingdom); Blaut, Arkadiusz [Institute of Theoretical Physics, University of Wroclaw, Wroclaw (Poland); Bridges, Michael; Feroz, Farhan [Astrophysics Group, Cavendish Laboratory, University of Cambridge, Cambridge CB30HE (United Kingdom); Cohen, Michael [Theoretical Astrophysics, California Institute of Technology, Pasadena, CA 91125 (United States); Gair, Jonathan R., E-mail: Michele.Vallisneri@jpl.nasa.go [Institute of Astronomy, University of Cambridge, Cambridge CB30HA (United Kingdom)

    2010-04-21

    The Mock LISA Data Challenges are a program to demonstrate LISA data-analysis capabilities and to encourage their development. Each round of challenges consists of one or more datasets containing simulated instrument noise and gravitational waves from sources of undisclosed parameters. Participants analyze the datasets and report best-fit solutions for the source parameters. Here we present the results of the third challenge, issued in April 2008, which demonstrated the positive recovery of signals from chirping galactic binaries, from spinning supermassive-black-hole binaries (with optimal SNRs between approx10 and 2000), from simultaneous extreme-mass-ratio inspirals (SNRs of 10-50), from cosmic-string-cusp bursts (SNRs of 10-100), and from a relatively loud isotropic background with OMEGA{sub gw}(f) approx 10{sup -11}, slightly below the LISA instrument noise.

  13. A note on technology shocks and the Great Depression

    NARCIS (Netherlands)

    Inklaar, Robert; de Jong, Harmen; Gouma, Fokke Reitze

    2016-01-01

    The role of technology shocks as a driver of the Great Depression is the topic of our own earlier work and the paper by Watanabe in this issue. While the two studies differ in their data and assumptions, they complement each other and strengthen the conclusion of both papers: technology shocks were

  14. De novo assembly of the perennial ryegrass transcriptome using an RNA-seq strategy

    DEFF Research Database (Denmark)

    Farrell, Jacqueline Danielle; Byrne, Stephen; Paina, Cristiana

    2014-01-01

    a homozygous perennial ryegrass genotype can circumvent the challenge of heterozygosity. The goals of this study were to perform RNA-sequencing on multiple tissues from a highly inbred genotype to develop a reference transcriptome. This was complemented with RNA-sequencing of a highly heterozygous genotype...... for SNP calling. Result De novo transcriptome assembly of the inbred genotype created 185,833 transcripts with an average length of 830 base pairs. Within the inbred reference transcriptome 78,560 predicted open reading frames were found of which 24,434 were predicted as complete. Functional annotation...... multiple orthologs. Using the longest unique open reading frames as the reference sequence, 64,242 single nucleotide polymorphisms were found. One thousand sixty one open reading frames from the inbred genotype contained heterozygous sites, confirming the high degree of homozygosity. Conclusion Our study...

  15. Role of lysophosphatidic acid receptor LPA2 in the development of allergic airway inflammation in a murine model of asthma

    Directory of Open Access Journals (Sweden)

    Chun Jerold

    2009-11-01

    Full Text Available Abstract Background Lysophosphatidic acid (LPA plays a critical role in airway inflammation through G protein-coupled LPA receptors (LPA1-3. We have demonstrated that LPA induced cytokine and lipid mediator release in human bronchial epithelial cells. Here we provide evidence for the role of LPA and LPA receptors in Th2-dominant airway inflammation. Methods Wild type, LPA1 heterozygous knockout mice (LPA1+/-, and LPA2 heterozygous knockout mice (LPA2+/- were sensitized with inactivated Schistosoma mansoni eggs and local antigenic challenge with Schistosoma mansoni soluble egg Ag (SEA in the lungs. Bronchoalveolar larvage (BAL fluids and lung tissues were collected for analysis of inflammatory responses. Further, tracheal epithelial cells were isolated and challenged with LPA. Results BAL fluids from Schistosoma mansoni egg-sensitized and challenged wild type mice (4 days of challenge showed increase of LPA level (~2.8 fold, compared to control mice. LPA2+/- mice, but not LPA1+/- mice, exposed to Schistosoma mansoni egg revealed significantly reduced cell numbers and eosinophils in BAL fluids, compared to challenged wild type mice. Both LPA2+/- and LPA1+/- mice showed decreases in bronchial goblet cells. LPA2+/- mice, but not LPA1+/- mice showed the decreases in prostaglandin E2 (PGE2 and LPA levels in BAL fluids after SEA challenge. The PGE2 production by LPA was reduced in isolated tracheal epithelial cells from LPA2+/- mice. These results suggest that LPA and LPA receptors are involved in Schistosoma mansoni egg-mediated inflammation and further studies are proposed to understand the role of LPA and LPA receptors in the inflammatory process.

  16. Determining Cloze Item Difficulty from Item and Passage Characteristics across Different Learner Backgrounds

    Science.gov (United States)

    Trace, Jonathan; Brown, James Dean; Janssen, Gerriet; Kozhevnikova, Liudmila

    2017-01-01

    Cloze tests have been the subject of numerous studies regarding their function and use in both first language and second language contexts (e.g., Jonz & Oller, 1994; Watanabe & Koyama, 2008). From a validity standpoint, one area of investigation has been the extent to which cloze tests measure reading ability beyond the sentence level.…

  17. Note on transmitted complexity for quantum dynamical systems

    Science.gov (United States)

    Watanabe, Noboru; Muto, Masahiro

    2017-10-01

    Transmitted complexity (mutual entropy) is one of the important measures for quantum information theory developed recently in several ways. We will review the fundamental concepts of the Kossakowski, Ohya and Watanabe entropy and define a transmitted complexity for quantum dynamical systems. This article is part of the themed issue `Second quantum revolution: foundational questions'.

  18. Acceleration of bone development and regeneration through the Wnt/β-catenin signaling pathway in mice heterozygously deficient for GSK-3β

    International Nuclear Information System (INIS)

    Arioka, Masaki; Takahashi-Yanaga, Fumi; Sasaki, Masanori; Yoshihara, Tatsuya; Morimoto, Sachio; Takashima, Akihiko; Mori, Yoshihide; Sasaguri, Toshiyuki

    2013-01-01

    Highlights: •The Wnt/β-catenin signaling pathway was activated in GSK-3β +/− mice. •The cortical and trabecular bone volumes were increased in GSK-3β +/− mice. •Regeneration of a partial bone defect was accelerated in GSK-3β +/− mice. -- Abstract: Glycogen synthase kinase (GSK)-3β plays an important role in osteoblastogenesis by regulating the Wnt/β-catenin signaling pathway. Therefore, we investigated whether GSK-3β deficiency affects bone development and regeneration using mice heterozygously deficient for GSK-3β (GSK-3β +/− ). The amounts of β-catenin, c-Myc, cyclin D1, and runt-related transcription factor-2 (Runx2) in the bone marrow cells of GSK-3β +/− mice were significantly increased compared with those of wild-type mice, indicating that Wnt/β-catenin signals were enhanced in GSK-3β +/− mice. Microcomputed tomography of the distal femoral metaphyses demonstrated that the volumes of both the cortical and trabecular bones were increased in GSK-3β +/− mice compared with those in wild-type mice. Subsequently, to investigate the effect of GSK-3β deficiency on bone regeneration, we established a partial bone defect in the femur and observed new bone at 14 days after surgery. The volume and mineral density of the new bone were significantly higher in GSK-3β +/− mice than those in wild-type mice. These results suggest that bone formation and regeneration in vivo are accelerated by inhibition of GSK-3β, probably through activation of the Wnt/β-catenin signaling pathway

  19. Cognitive Challenges

    Science.gov (United States)

    ... Privacy Policy Sitemap Learn Engage Donate About TSC Cognitive Challenges Approximately 45% to 60% of individuals with TSC develop cognitive challenges (intellectual disabilities), although the degree of intellectual ...

  20. The Challenging Experience Questionnaire: Characterization of challenging experiences with psilocybin mushrooms.

    Science.gov (United States)

    Barrett, Frederick S; Bradstreet, Matthew P; Leoutsakos, Jeannie-Marie S; Johnson, Matthew W; Griffiths, Roland R

    2016-12-01

    Acute adverse psychological reactions to classic hallucinogens ("bad trips" or "challenging experiences"), while usually benign with proper screening, preparation, and support in controlled settings, remain a safety concern in uncontrolled settings (such as illicit use contexts). Anecdotal and case reports suggest potential adverse acute symptoms including affective (panic, depressed mood), cognitive (confusion, feelings of losing sanity), and somatic (nausea, heart palpitation) symptoms. Responses to items from several hallucinogen-sensitive questionnaires (Hallucinogen Rating Scale, the States of Consciousness Questionnaire, and the Five-Dimensional Altered States of Consciousness questionnaire) in an Internet survey of challenging experiences with the classic hallucinogen psilocybin were used to construct and validate a Challenging Experience Questionnaire. The stand-alone Challenging Experience Questionnaire was then validated in a separate sample. Seven Challenging Experience Questionnaire factors (grief, fear, death, insanity, isolation, physical distress, and paranoia) provide a phenomenological profile of challenging aspects of experiences with psilocybin. Factor scores were associated with difficulty, meaningfulness, spiritual significance, and change in well-being attributed to the challenging experiences. The factor structure did not differ based on gender or prior struggle with anxiety or depression. The Challenging Experience Questionnaire provides a basis for future investigation of predictors and outcomes of challenging experiences with classic hallucinogens. © The Author(s) 2016.

  1. Comment on autogenic training and hypertension.

    Science.gov (United States)

    Sakai, M; Sato, T; Takeichi, M; Fakunishi, I

    1997-06-01

    We comment on a report by Watanabe, et al. regarding the effects of autogenic training on hypertension. Using previous reports in the United States, we mention methodological problems on how to evaluate the effects of autogenic training and express our hope that they would provide further research to clarify the effects of autogenic training on hypertension.

  2. author's correction 1..1

    Indian Academy of Sciences (India)

    J. Genet. 89, e25Ye29 (http://www.ias.ac.in/jgenet/OnlineResources/90/e25.pdf). In table 1, for locus Aaz1, the core motif should be (ACAT)8 ATAAA(TG)6 and not (ACAT)8. Genetic polymorphism of serotonin transporter 5-HTTLPR: involvement in smoking behaviour. Maria Angelica Ehara Watanabe, Sandra Odebrechet ...

  3. 75 FR 21044 - Notice of Centennial Challenges 2011 CAFE Green Flight Challenge

    Science.gov (United States)

    2010-04-22

    ... NATIONAL AERONAUTICS AND SPACE ADMINISTRATION [Notice (10-045)] Notice of Centennial Challenges...: Notice of Centennial Challenges 2011 CAFE Green Flight Challenge. SUMMARY: This notice is issued in... to compete may register. Centennial Challenges is a program of prize competitions to stimulate...

  4. Wild-type offspring of heterozygous prolactin receptor-null female mice have maladaptive β-cell responses during pregnancy.

    Science.gov (United States)

    Huang, Carol

    2013-03-01

    Abstract  β-Cell mass increases during pregnancy in adaptation to the insulin resistance of pregnancy. This increase is accompanied by an increase in β-cell proliferation, a process that requires intact prolactin receptor (Prlr) signalling. Previously, it was found that during pregnancy, heterozygous prolactin receptor-null (Prlr(+/-)) mice had lower number of β-cells, lower serum insulin and higher blood glucose levels than wild-type (Prlr(+/+)) mice. An unexpected observation was that the glucose homeostasis of the experimental mouse depends on the genotype of her mother, such that within the Prlr(+/+) group, the Prlr(+/+) offspring derived from Prlr(+/+) mothers (Prlr(+/+(+/+))) had higher β-cell mass and lower blood glucose than those derived from Prlr(+/-) mothers (Prlr(+/+(+/-))). Pathways that are known to regulate β-cell proliferation during pregnancy include insulin receptor substrate-2, Akt, menin, the serotonin synthetic enzyme tryptophan hydroxylase-1, Forkhead box M1 and Forkhead box D3. The aim of the present study was to determine whether dysregulation in these signalling molecules in the islets could explain the maternal effect on the phenotype of the offspring. It was found that the pregnancy-induced increases in insulin receptor substrate-2 and Akt expression in the islets were attenuated in the Prlr(+/+(+/-)) mice in comparison to the Prlr(+/+(+/+)) mice. The expression of Forkhead box D3, which plays a permissive role for β-cell proliferation during pregnancy, was also lower in the Prlr(+/+(+/-)) mice. In contrast, the pregnancy-induced increases in phospho-Jak2, tryptophan hydroxylase-1 and FoxM1, as well as the pregnancy-associated reduction in menin expression, were comparable between the two groups. There was also no difference in expression levels of genes that regulate insulin synthesis and secretion (i.e. glucose transporter 2, glucokinase and pancreatic and duodenal homeobox-1) between these two groups. Taken together, these

  5. Production of a mouse strain with impaired glucose tolerance by systemic heterozygous knockout of the glucokinase gene and its feasibility as a prediabetes model

    Science.gov (United States)

    SAITO, Mikako; KANEDA, Asako; SUGIYAMA, Tae; IIDA, Ryousuke; OTOKUNI, Keiko; KABURAGI, Misako; MATSUOKA, Hideaki

    2015-01-01

    Exon II of glucokinase (Gk) was deleted to produce a systemic heterozygous Gk knockout (Gk+/−) mouse. The relative expression levels of Gk in the heart, lung, liver, stomach, and pancreas in Gk+/− mice ranged from 0.41–0.68 versus that in wild (Gk+/+) mice. On the other hand, its expression levels in the brain, adipose tissue, and muscle ranged from 0.95–1.03, and its expression levels in the spleen and kidney were nearly zero. Gk knockout caused no remarkable off-target effect on the expression of 7 diabetes causing genes (Shp, Hnf1a, Hnf1b, Irs1, Irs2, Kir6.2, and Pdx1) in 10 organs. The glucose tolerance test was conducted to determine the blood glucose concentrations just after fasting for 24 h (FBG) and at 2 h after high-glucose application (GTT2h). The FBG-GTT2h plots obtained with the wild strain fed the control diet (CD), Gk+/− strain fed the CD, and Gk+/− strain fed the HFD were distributed in separate areas in the FBG-GTT2h diagram. The respective areas could be defined as the normal state, prediabetes state, and diabetes state, respectively. Based on the results, the criteria for prediabetes could be defined for the Gk+/− strain developed in this study. PMID:25765873

  6. Simulation of hydrothermal recoveries by adopting symbiotic urban scenario in the Japanese megalopolis

    Science.gov (United States)

    Nakayama, T.; Fujita, T.; Hashimoto, S.; Hamano, H.

    2008-05-01

    The heat island phenomenon in summer has become a serious environmental problem with the expansion of cities and industrial areas in Japan. The present research evaluated the positive cooling effect of new material pavement (water-holding blocks) in comparison with the passive cooling effect of lawn. We coupled the process- based NIES Integrated Catchment-based Eco-hydrology (NICE) model (Nakayama, 2008; Nakayama and Watanabe, 2004, 2006, 2007; Nakayama et al., 2006, 2007) to an urban canopy model (Nakayama and Fujita, 2008) and the Regional Atmospheric Modeling System (RAMS) in order to simulate the effect of this newly symbiotic pavement on the hydrologic budget and the regional climate at the Kawasaki eco-town in Japan, with a grid spacing of 200 m. The model simulated the water and heat budgets in various types of natural and artificial pavements (covered by lawn, concrete, steel plate, synthetic rubber sheet, infiltration and water-holding blocks), and to evaluate the role of water-holding blocks in promoting evaporation and cooling to counter the heat island phenomenon (2 degrees lower than that at the lawn), by comparing with the simplified empirical model. The heat budget analysis of observation data showed that the latent heat flux at the water-holding pavement has a strong impact on the cooling temperature, which could be reproduced well by the simulation. Because the water temperature in an aquifer is almost constant throughout the year, it is estimated that the use of groundwater as a heat sink would be very effective for tackling the urban heat island phenomenon, particularly during the summer (Ministry of Environment, 2003). We evaluated the relationship between the effect of groundwater use to ameliorate the heat island phenomenon and the effect of infiltration on the water cycle in the catchment. The procedure to integrate the model simulation with political scenario for the effective selection and use of ecosystem service sites in this study would

  7. Overcoming challenges

    Medline Plus

    Full Text Available ... section Back to section menu It's Only Natural Planning ahead Breastfeeding and baby basics Making breastfeeding work ... It's Only Natural Overcoming challenges It's Only Natural Planning ahead Addressing breastfeeding myths Overcoming challenges Common questions ...

  8. Overcoming challenges

    Medline Plus

    Full Text Available ... breastfeeding Overcoming challenges Common questions about breastfeeding and pain Breastfeeding checklist: How to get a good latch Finding ... myths Overcoming challenges Common questions about breastfeeding and pain Breastfeeding checklist: How to get a good latch Finding ...

  9. Acceleration of bone development and regeneration through the Wnt/β-catenin signaling pathway in mice heterozygously deficient for GSK-3β

    Energy Technology Data Exchange (ETDEWEB)

    Arioka, Masaki [Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka (Japan); Department of Oral and Maxillofacial Surgery, Faculty of Dental Science, Kyushu University, Fukuoka (Japan); Takahashi-Yanaga, Fumi, E-mail: yanaga@clipharm.med.kyushu-u.ac.jp [Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka (Japan); Global Medical Science Education Unit, Faculty of Medical Sciences, Kyushu University, Fukuoka (Japan); Sasaki, Masanori [Department of Oral and Maxillofacial Surgery, Faculty of Dental Science, Kyushu University, Fukuoka (Japan); Yoshihara, Tatsuya; Morimoto, Sachio [Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka (Japan); Takashima, Akihiko [Department of Aging Neurobiology, National Center for Geriatrics and Gerontology, Oobu (Japan); Mori, Yoshihide [Department of Oral and Maxillofacial Surgery, Faculty of Dental Science, Kyushu University, Fukuoka (Japan); Sasaguri, Toshiyuki [Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka (Japan)

    2013-11-01

    Highlights: •The Wnt/β-catenin signaling pathway was activated in GSK-3β{sup +/−} mice. •The cortical and trabecular bone volumes were increased in GSK-3β{sup +/−} mice. •Regeneration of a partial bone defect was accelerated in GSK-3β{sup +/−} mice. -- Abstract: Glycogen synthase kinase (GSK)-3β plays an important role in osteoblastogenesis by regulating the Wnt/β-catenin signaling pathway. Therefore, we investigated whether GSK-3β deficiency affects bone development and regeneration using mice heterozygously deficient for GSK-3β (GSK-3β{sup +/−}). The amounts of β-catenin, c-Myc, cyclin D1, and runt-related transcription factor-2 (Runx2) in the bone marrow cells of GSK-3β{sup +/−} mice were significantly increased compared with those of wild-type mice, indicating that Wnt/β-catenin signals were enhanced in GSK-3β{sup +/−} mice. Microcomputed tomography of the distal femoral metaphyses demonstrated that the volumes of both the cortical and trabecular bones were increased in GSK-3β{sup +/−} mice compared with those in wild-type mice. Subsequently, to investigate the effect of GSK-3β deficiency on bone regeneration, we established a partial bone defect in the femur and observed new bone at 14 days after surgery. The volume and mineral density of the new bone were significantly higher in GSK-3β{sup +/−} mice than those in wild-type mice. These results suggest that bone formation and regeneration in vivo are accelerated by inhibition of GSK-3β, probably through activation of the Wnt/β-catenin signaling pathway.

  10. JPRS Report, Science & Technology, Japan, 27th Aircraft Symposium, Part 3

    Science.gov (United States)

    1991-02-14

    Kaoru Wakairo, et al.] Aircraft-Mounted Optical Data Bus (3): Bus Control Software, Performance Evaluation Test [Mitsumi Mayanägi, Minoru...Article by Hiroyasu Kawahara, Kaoru Wakairo, and Akira Watanabe, National Aerospace Laboratory; Tomoyuli Udagawa, Kengo Takeda, and Noboru Shobayashi...89 pp 518-521 [Article by Tadao Uchida, Mitsumi Mayanagi, Minoru Takizawa, Toshiharu Inagaki, Koki Hozumi, and Kazutoshi Ishikawa , National

  11. Draft Genome Sequence of Cupriavidus pauculus Strain KF709, a Biphenyl-Utilizing Bacterium Isolated from Biphenyl-Contaminated Soil.

    Science.gov (United States)

    Watanabe, Takahito; Yamazoe, Atsushi; Hosoyama, Akira; Fujihara, Hidehiko; Suenaga, Hikaru; Hirose, Jun; Futagami, Taiki; Goto, Masatoshi; Kimura, Nobutada; Furukawa, Kensuke

    2015-03-26

    We report the draft genome sequence of Cupriavidus pauculus strain KF709, which comprises 6,826,799 bp with 6,272 coding sequences. The strain KF709 utilizes biphenyl and degrades low-chlorinated biphenyls; however, it possesses fewer coding sequences involved in the degradation of aromatic compounds than other strains belonging to the Betaproteobacteria. Copyright © 2015 Watanabe et al.

  12. Comprehensive and Critical Literature Review on Insitu Micro-Sensors for Application in Tribology

    Science.gov (United States)

    1994-04-01

    Tsugai, Masahiro; Bessho, Mikio ; Araki, Toru; Onishi, Masayoshi; Sesekura, Takashi Source: SAE Technical Paper Series. Publ by SAE, Warrendale, PA, USA...MONITORING OF HYDROGEN ASSISTED CRACKING OF LOW ALLOY STEEL. Author. Hayashi, Yasuhisa; Takemoto, Mikio Source: Boshoku Gijutsu/Corrosion Engineering v...METALS AND ITS APPLICATION TO AE SENSOR. Author. Shimizu, Hiroshi; Watanabe, Hiroshi; Sato , Michio Source:. Japanese Journal of Applied Physics, Supplement

  13. The GREAT3 challenge

    International Nuclear Information System (INIS)

    Miyatake, H; Mandelbaum, R; Rowe, B

    2014-01-01

    The GRavitational lEnsing Accuracy Testing 3 (GREAT3) challenge is an image analysis competition that aims to test algorithms to measure weak gravitational lensing from astronomical images. The challenge started in October 2013 and ends 30 April 2014. The challenge focuses on testing the impact on weak lensing measurements of realistically complex galaxy morphologies, realistic point spread function, and combination of multiple different exposures. It includes simulated ground- and space-based data. The details of the challenge are described in [1], and the challenge website and its leader board can be found at http://great3challenge.info and http://great3.projects.phys.ucl.ac.uk/leaderboard/, respectively

  14. Molecular Pathogenesis of EBV Susceptibility in XLP as Revealed by Analysis of Female Carriers with Heterozygous Expression of SAP

    Science.gov (United States)

    Palendira, Umaimainthan; Low, Carol; Chan, Anna; Hislop, Andrew D.; Ho, Edwin; Phan, Tri Giang; Deenick, Elissa; Cook, Matthew C.; Riminton, D. Sean; Choo, Sharon; Loh, Richard; Alvaro, Frank; Booth, Claire; Gaspar, H. Bobby; Moretta, Alessandro; Khanna, Rajiv; Rickinson, Alan B.; Tangye, Stuart G.

    2011-01-01

    X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency caused by mutations in SH2D1A which encodes SAP. SAP functions in signalling pathways elicited by the SLAM family of leukocyte receptors. A defining feature of XLP is exquisite sensitivity to infection with EBV, a B-lymphotropic virus, but not other viruses. Although previous studies have identified defects in lymphocytes from XLP patients, the unique role of SAP in controlling EBV infection remains unresolved. We describe a novel approach to this question using female XLP carriers who, due to random X-inactivation, contain both SAP+ and SAP− cells. This represents the human equivalent of a mixed bone marrow chimera in mice. While memory CD8+ T cells specific for CMV and influenza were distributed across SAP+ and SAP− populations, EBV-specific cells were exclusively SAP+. The preferential recruitment of SAP+ cells by EBV reflected the tropism of EBV for B cells, and the requirement for SAP expression in CD8+ T cells for them to respond to Ag-presentation by B cells, but not other cell types. The inability of SAP− clones to respond to Ag-presenting B cells was overcome by blocking the SLAM receptors NTB-A and 2B4, while ectopic expression of NTB-A on fibroblasts inhibited cytotoxicity of SAP− CD8+ T cells, thereby demonstrating that SLAM receptors acquire inhibitory function in the absence of SAP. The innovative XLP carrier model allowed us to unravel the mechanisms underlying the unique susceptibility of XLP patients to EBV infection in the absence of a relevant animal model. We found that this reflected the nature of the Ag-presenting cell, rather than EBV itself. Our data also identified a pathological signalling pathway that could be targeted to treat patients with severe EBV infection. This system may allow the study of other human diseases where heterozygous gene expression from random X-chromosome inactivation can be exploited. PMID:22069374

  15. Molecular pathogenesis of EBV susceptibility in XLP as revealed by analysis of female carriers with heterozygous expression of SAP.

    Directory of Open Access Journals (Sweden)

    Umaimainthan Palendira

    2011-11-01

    Full Text Available X-linked lymphoproliferative disease (XLP is a primary immunodeficiency caused by mutations in SH2D1A which encodes SAP. SAP functions in signalling pathways elicited by the SLAM family of leukocyte receptors. A defining feature of XLP is exquisite sensitivity to infection with EBV, a B-lymphotropic virus, but not other viruses. Although previous studies have identified defects in lymphocytes from XLP patients, the unique role of SAP in controlling EBV infection remains unresolved. We describe a novel approach to this question using female XLP carriers who, due to random X-inactivation, contain both SAP(+ and SAP(- cells. This represents the human equivalent of a mixed bone marrow chimera in mice. While memory CD8(+ T cells specific for CMV and influenza were distributed across SAP(+ and SAP(- populations, EBV-specific cells were exclusively SAP(+. The preferential recruitment of SAP(+ cells by EBV reflected the tropism of EBV for B cells, and the requirement for SAP expression in CD8(+ T cells for them to respond to Ag-presentation by B cells, but not other cell types. The inability of SAP(- clones to respond to Ag-presenting B cells was overcome by blocking the SLAM receptors NTB-A and 2B4, while ectopic expression of NTB-A on fibroblasts inhibited cytotoxicity of SAP(- CD8(+ T cells, thereby demonstrating that SLAM receptors acquire inhibitory function in the absence of SAP. The innovative XLP carrier model allowed us to unravel the mechanisms underlying the unique susceptibility of XLP patients to EBV infection in the absence of a relevant animal model. We found that this reflected the nature of the Ag-presenting cell, rather than EBV itself. Our data also identified a pathological signalling pathway that could be targeted to treat patients with severe EBV infection. This system may allow the study of other human diseases where heterozygous gene expression from random X-chromosome inactivation can be exploited.

  16. The Challenging Experience Questionnaire: Characterization of challenging experiences with psilocybin mushrooms

    Science.gov (United States)

    Barrett, Frederick S.; Bradstreet, Matthew P.; Leoutsakos, Jeannie-Marie S.; Johnson, Matthew W.; Griffiths, Roland R.

    2017-01-01

    Acute adverse psychological reactions to classic hallucinogens (“bad trips”, or “challenging experiences”), while usually benign with proper screening, preparation, and support in controlled settings, remain a safety concern in uncontrolled settings (such as illicit use contexts). Anecdotal and case reports suggest potential adverse acute symptoms including affective (panic, depressed mood), cognitive (confusion, feelings of losing sanity), and somatic (nausea, heart palpitation) symptoms. Responses to items from several hallucinogen-sensitive questionnaires (Hallucinogen Rating Scale, the States of Consciousness Questionnaire, and the 5-Dimensional Altered States of Consciousness questionnaire) in an internet survey of challenging experiences with the classic hallucinogen psilocybin were used to construct and validate a Challenging Experience Questionnaire (CEQ). The stand-alone CEQ was then validated in a separate sample. Seven CEQ factors (grief, fear, death, insanity, isolation, physical distress, and paranoia) provide a phenomenological profile of challenging aspects of experiences with psilocybin. Factor scores were associated with the difficulty, meaningfulness, spiritual significance, and change in well-being attributed to the challenging experiences. The factor structure did not differ based on gender or prior struggle with anxiety or depression. The CEQ provides a basis for future investigation of predictors and outcomes of challenging experiences with psilocybin, and should be explored as a measure of challenging experiences with the broad class of classic hallucinogens. PMID:27856683

  17. Dynamics of heterogeneous oscillator ensembles in terms of collective variables

    Science.gov (United States)

    Pikovsky, Arkady; Rosenblum, Michael

    2011-04-01

    We consider general heterogeneous ensembles of phase oscillators, sine coupled to arbitrary external fields. Starting with the infinitely large ensembles, we extend the Watanabe-Strogatz theory, valid for identical oscillators, to cover the case of an arbitrary parameter distribution. The obtained equations yield the description of the ensemble dynamics in terms of collective variables and constants of motion. As a particular case of the general setup we consider hierarchically organized ensembles, consisting of a finite number of subpopulations, whereas the number of elements in a subpopulation can be both finite or infinite. Next, we link the Watanabe-Strogatz and Ott-Antonsen theories and demonstrate that the latter one corresponds to a particular choice of constants of motion. The approach is applied to the standard Kuramoto-Sakaguchi model, to its extension for the case of nonlinear coupling, and to the description of two interacting subpopulations, exhibiting a chimera state. With these examples we illustrate that, although the asymptotic dynamics can be found within the framework of the Ott-Antonsen theory, the transients depend on the constants of motion. The most dramatic effect is the dependence of the basins of attraction of different synchronous regimes on the initial configuration of phases.

  18. Big data challenges

    DEFF Research Database (Denmark)

    Bachlechner, Daniel; Leimbach, Timo

    2016-01-01

    Although reports on big data success stories have been accumulating in the media, most organizations dealing with high-volume, high-velocity and high-variety information assets still face challenges. Only a thorough understanding of these challenges puts organizations into a position in which...... they can make an informed decision for or against big data, and, if the decision is positive, overcome the challenges smoothly. The combination of a series of interviews with leading experts from enterprises, associations and research institutions, and focused literature reviews allowed not only...... framework are also relevant. For large enterprises and startups specialized in big data, it is typically easier to overcome the challenges than it is for other enterprises and public administration bodies....

  19. Stable isotope views on ecosystem function: challenging or challenged?

    Science.gov (United States)

    Resco, Víctor; Querejeta, José I; Ogle, Kiona; Voltas, Jordi; Sebastià, Maria-Teresa; Serrano-Ortiz, Penélope; Linares, Juan C; Moreno-Gutiérrez, Cristina; Herrero, Asier; Carreira, José A; Torres-Cañabate, Patricia; Valladares, Fernando

    2010-06-23

    Stable isotopes and their potential for detecting various and complex ecosystem processes are attracting an increasing number of scientists. Progress is challenging, particularly under global change scenarios, but some established views have been challenged. The IX meeting of the Spanish Association of Terrestrial Ecology (AAET, Ubeda, 18-22 October 2009) hosted a symposium on the ecology of stable isotopes where the linear mixing model approach of partitioning sinks and sources of carbon and water fluxes within an ecosystem was challenged, and new applications of stable isotopes for the study of plant interactions were evaluated. Discussion was also centred on the need for networks that monitor ecological processes using stable isotopes and key ideas for fostering future research with isotopes.

  20. Night Rover Challenge

    Data.gov (United States)

    National Aeronautics and Space Administration — The objective of the Night Rover Challenge was to foster innovations in energy storage technology. Specifically, this challenge asked competitors to create an energy...

  1. The Role of Peripheral Nerve Function in Age-Related Bone Loss and Changes in Bone Adaptation

    Science.gov (United States)

    2015-12-01

    E Production of Osteoblasts, and Attenuates the Inflammatory Bone Loss Induced by Lipopolysaccharide. ISRN Pharmacol, 2012. 2012: p. 439860. 17...Kobayashi M, Watanabe K, Yokoyama S, et al. Capsaicin, a TRPV1 Ligand, Suppresses Bone Resorption by Inhibit- ing the Prostaglandin E Production of...example, mechanoreceptors in the skin respond to bending and stretching and can provide information about touch. Pacini’s corpuscle consists of onion like

  2. Preprint server seeks way to halt plagiarists

    CERN Multimedia

    Giles, J

    2003-01-01

    "An unusual case of plagiarism has struck ArXiv, the popular physics preprint server at Cornell University in Ithaca, New York, resulting in the withdrawal of 22 papers...The plagiarism case traces its origins to June 2002, when Yasushi Watanabe, a high-energy physicist at the Tokyo Insitute of Technology, was contacted by Ramy Noboulsi, who said he was a mathematical physicist" (1 page)

  3. Does perceptual learning require consciousness or attention?

    Science.gov (United States)

    Meuwese, Julia D I; Post, Ruben A G; Scholte, H Steven; Lamme, Victor A F

    2013-10-01

    It has been proposed that visual attention and consciousness are separate [Koch, C., & Tsuchiya, N. Attention and consciousness: Two distinct brain processes. Trends in Cognitive Sciences, 11, 16-22, 2007] and possibly even orthogonal processes [Lamme, V. A. F. Why visual attention and awareness are different. Trends in Cognitive Sciences, 7, 12-18, 2003]. Attention and consciousness converge when conscious visual percepts are attended and hence become available for conscious report. In such a view, a lack of reportability can have two causes: the absence of attention or the absence of a conscious percept. This raises an important question in the field of perceptual learning. It is known that learning can occur in the absence of reportability [Gutnisky, D. A., Hansen, B. J., Iliescu, B. F., & Dragoi, V. Attention alters visual plasticity during exposure-based learning. Current Biology, 19, 555-560, 2009; Seitz, A. R., Kim, D., & Watanabe, T. Rewards evoke learning of unconsciously processed visual stimuli in adult humans. Neuron, 61, 700-707, 2009; Seitz, A. R., & Watanabe, T. Is subliminal learning really passive? Nature, 422, 36, 2003; Watanabe, T., Náñez, J. E., & Sasaki, Y. Perceptual learning without perception. Nature, 413, 844-848, 2001], but it is unclear which of the two ingredients-consciousness or attention-is not necessary for learning. We presented textured figure-ground stimuli and manipulated reportability either by masking (which only interferes with consciousness) or with an inattention paradigm (which only interferes with attention). During the second session (24 hr later), learning was assessed neurally and behaviorally, via differences in figure-ground ERPs and via a detection task. Behavioral and neural learning effects were found for stimuli presented in the inattention paradigm and not for masked stimuli. Interestingly, the behavioral learning effect only became apparent when performance feedback was given on the task to measure learning

  4. Stable isotope views on ecosystem function: challenging or challenged?

    Science.gov (United States)

    Resco, Víctor; Querejeta, José I.; Ogle, Kiona; Voltas, Jordi; Sebastià, Maria-Teresa; Serrano-Ortiz, Penélope; Linares, Juan C.; Moreno-Gutiérrez, Cristina; Herrero, Asier; Carreira, José A.; Torres-Cañabate, Patricia; Valladares, Fernando

    2010-01-01

    Stable isotopes and their potential for detecting various and complex ecosystem processes are attracting an increasing number of scientists. Progress is challenging, particularly under global change scenarios, but some established views have been challenged. The IX meeting of the Spanish Association of Terrestrial Ecology (AAET, Úbeda, 18–22 October 2009) hosted a symposium on the ecology of stable isotopes where the linear mixing model approach of partitioning sinks and sources of carbon and water fluxes within an ecosystem was challenged, and new applications of stable isotopes for the study of plant interactions were evaluated. Discussion was also centred on the need for networks that monitor ecological processes using stable isotopes and key ideas for fostering future research with isotopes. PMID:20015858

  5. Cutting export subsidies, cropping domestic production: input-output analysis of the Swiss dairy sector after abolishment of the ‘Chocolate law’ subsidies

    Directory of Open Access Journals (Sweden)

    Seyhan KÂHYA

    2017-02-01

    Full Text Available The `Chocolate law’ in Switzerland enables subsidies for dairy and wheat farmers, bound to the condition that their products are exported after processing (Swiss Federation, 2011. Though the Ministerial Conference of the World Trade Organization has decided in December 2015 that this law has to be abolished by 2021 [WTO, 2015]. Cutting subsidies might lead to a demand shock and consequently a cropped domestic production (Miller and Blair, 1985. We analysed in this study the interdependence of the agro-food sectors by a Leontief input-output model and their linkages to other sectors (Chereny and Watanabe, 1958, Leontief 1986 and additionally, the amount, direction and dispersion of the possible demand shock.  Hence, non-meat food processors and dairy processing were determined as key sectors as they have strong linkage effects and are rather concentrated to few sectors. Both sectors rely strongly on the output of the raw milk producers and have few sectors to sell their products. Outside of the cut sectors, these sectors will be challenged the most from this new policy.

  6. Employment challenges in the future

    DEFF Research Database (Denmark)

    2011-01-01

    Discussion of challenges in employment challenges in Europe and a brief discription of the Danish flexicurity system......Discussion of challenges in employment challenges in Europe and a brief discription of the Danish flexicurity system...

  7. Whole Exome Sequencing Identified a Novel Heterozygous Mutation in HMBS Gene in a Chinese Patient With Acute Intermittent Porphyria With Rare Type of Mild Anemia

    Directory of Open Access Journals (Sweden)

    Yongjiang Zheng

    2018-04-01

    Full Text Available Acute intermittent porphyria (AIP is a rare hereditary metabolic disease with an autosomal dominant mode of inheritance. Germline mutations of HMBS gene causes AIP. Mutation of HMBS gene results into the partial deficiency of the heme biosynthetic enzyme hydroxymethylbilane synthase. AIP is clinically manifested with abdominal pain, vomiting, and neurological complaints. Additionally, an extreme phenotypic heterogeneity has been reported in AIP patients with mutations in HMBS gene. Here, we investigated a Chinese patient with AIP. The proband is a 28-year-old Chinese male manifested with severe stomach ache, constipation, nausea and depression. Proband’s father and mother is normal. Proband’s blood sample was collected and genomic DNA was extracted. Whole exome sequencing and Sanger sequencing identified a heterozygous novel single nucleotide deletion (c.809delC in exon 12 of HMBS gene in the proband. This mutation leads to frameshift followed by formation of a truncated (p.Ala270Valfs∗2 HMBS protein with 272 amino acids comparing with the wild type HMBS protein of 361 amino acids. This mutation has not been found in proband’s unaffected parents as well as in 100 healthy normal control. According to the variant interpretation guidelines of American College of Medical Genetics and Genomics (ACMG, this variant is classified as “likely pathogenic” variant. Our findings expand the mutational spectra of HMBS gene related AIP which are significant for screening and genetic diagnosis for AIP.

  8. Reducing false-positive incidental findings with ensemble genotyping and logistic regression based variant filtering methods.

    Science.gov (United States)

    Hwang, Kyu-Baek; Lee, In-Hee; Park, Jin-Ho; Hambuch, Tina; Choe, Yongjoon; Kim, MinHyeok; Lee, Kyungjoon; Song, Taemin; Neu, Matthew B; Gupta, Neha; Kohane, Isaac S; Green, Robert C; Kong, Sek Won

    2014-08-01

    As whole genome sequencing (WGS) uncovers variants associated with rare and common diseases, an immediate challenge is to minimize false-positive findings due to sequencing and variant calling errors. False positives can be reduced by combining results from orthogonal sequencing methods, but costly. Here, we present variant filtering approaches using logistic regression (LR) and ensemble genotyping to minimize false positives without sacrificing sensitivity. We evaluated the methods using paired WGS datasets of an extended family prepared using two sequencing platforms and a validated set of variants in NA12878. Using LR or ensemble genotyping based filtering, false-negative rates were significantly reduced by 1.1- to 17.8-fold at the same levels of false discovery rates (5.4% for heterozygous and 4.5% for homozygous single nucleotide variants (SNVs); 30.0% for heterozygous and 18.7% for homozygous insertions; 25.2% for heterozygous and 16.6% for homozygous deletions) compared to the filtering based on genotype quality scores. Moreover, ensemble genotyping excluded > 98% (105,080 of 107,167) of false positives while retaining > 95% (897 of 937) of true positives in de novo mutation (DNM) discovery in NA12878, and performed better than a consensus method using two sequencing platforms. Our proposed methods were effective in prioritizing phenotype-associated variants, and an ensemble genotyping would be essential to minimize false-positive DNM candidates. © 2014 WILEY PERIODICALS, INC.

  9. Inferring Variation in Copy Number Using High Throughput Sequencing Data in R.

    Science.gov (United States)

    Knaus, Brian J; Grünwald, Niklaus J

    2018-01-01

    Inference of copy number variation presents a technical challenge because variant callers typically require the copy number of a genome or genomic region to be known a priori . Here we present a method to infer copy number that uses variant call format (VCF) data as input and is implemented in the R package vcfR . This method is based on the relative frequency of each allele (in both genic and non-genic regions) sequenced at heterozygous positions throughout a genome. These heterozygous positions are summarized by using arbitrarily sized windows of heterozygous positions, binning the allele frequencies, and selecting the bin with the greatest abundance of positions. This provides a non-parametric summary of the frequency that alleles were sequenced at. The method is applicable to organisms that have reference genomes that consist of full chromosomes or sub-chromosomal contigs. In contrast to other software designed to detect copy number variation, our method does not rely on an assumption of base ploidy, but instead infers it. We validated these approaches with the model system of Saccharomyces cerevisiae and applied it to the oomycete Phytophthora infestans , both known to vary in copy number. This functionality has been incorporated into the current release of the R package vcfR to provide modular and flexible methods to investigate copy number variation in genomic projects.

  10. Alterations in grooming activity and syntax in heterozygous SERT and BDNF knockout mice: the utility of behavior-recognition tools to characterize mutant mouse phenotypes.

    Science.gov (United States)

    Kyzar, Evan J; Pham, Mimi; Roth, Andrew; Cachat, Jonathan; Green, Jeremy; Gaikwad, Siddharth; Kalueff, Allan V

    2012-12-01

    Serotonin transporter (SERT) and brain-derived neurotrophic factor (BDNF) are key modulators of molecular signaling, cognition and behavior. Although SERT and BDNF mutant mouse phenotypes have been extensively characterized, little is known about their self-grooming behavior. Grooming represents an important behavioral domain sensitive to environmental stimuli and is increasingly used as a model for repetitive behavioral syndromes, such as autism and attention deficit/hyperactivity disorder. The present study used heterozygous ((+/-)) SERT and BDNF male mutant mice on a C57BL/6J background and assessed their spontaneous self-grooming behavior applying both manual and automated techniques. Overall, SERT(+/-) mice displayed a general increase in grooming behavior, as indicated by more grooming bouts and more transitions between specific grooming stages. SERT(+/-) mice also aborted more grooming bouts, but showed generally unaltered activity levels in the observation chamber. In contrast, BDNF(+/-) mice displayed a global reduction in grooming activity, with fewer bouts and transitions between specific grooming stages, altered grooming syntax, as well as hypolocomotion and increased turning behavior. Finally, grooming data collected by manual and automated methods (HomeCageScan) significantly correlated in our experiments, confirming the utility of automated high-throughput quantification of grooming behaviors in various genetic mouse models with increased or decreased grooming phenotypes. Taken together, these findings indicate that mouse self-grooming behavior is a reliable behavioral biomarker of genetic deficits in SERT and BDNF pathways, and can be reliably measured using automated behavior-recognition technology. Copyright © 2012 Elsevier Inc. All rights reserved.

  11. Physiological studies in heterozygous calcium sensing receptor (CaSR gene-ablated mice confirm that the CaSR regulates calcitonin release in vivo

    Directory of Open Access Journals (Sweden)

    Kovacs Christopher S

    2004-04-01

    Full Text Available Abstract Background The calcium sensing receptor (CaSR regulates serum calcium by suppressing secretion of parathyroid hormone; it also regulates renal tubular calcium excretion. Inactivating mutations of CaSR raise serum calcium and reduce urine calcium excretion. Thyroid C-cells (which make calcitonin express CaSR and may, therefore, be regulated by it. Since calcium stimulates release of calcitonin, the higher blood calcium caused by inactivation of CaSR should increase serum calcitonin, unless CaSR mutations alter the responsiveness of calcitonin to calcium. To demonstrate regulatory effects of CaSR on calcitonin release, we studied calcitonin responsiveness to calcium in normal and CaSR heterozygous-ablated (Casr+/- mice. Casr+/- mice have hypercalcemia and hypocalciuria, and live normal life spans. Each mouse received either 500 μl of normal saline or one of two doses of elemental calcium (500 μmol/kg or 5 mmol/kg by intraperitoneal injection. Ionized calcium was measured at baseline and 10 minutes, and serum calcitonin was measured on the 10 minute sample. Results At baseline, Casr+/- mice had a higher blood calcium, and in response to the two doses of elemental calcium, had greater increments and peak levels of ionized calcium than their wild type littermates. Despite significantly higher ionized calcium levels, the calcitonin levels of Casr+/- mice were consistently lower than wild type at any ionized calcium level, indicating that the dose-response curve of calcitonin to increases in ionized calcium had been significantly blunted or shifted to the right in Casr+/- mice. Conclusions These results confirm that the CaSR is a physiological regulator of calcitonin; therefore, in response to increases in ionized calcium, the CaSR inhibits parathyroid hormone secretion and stimulates calcitonin secretion.

  12. A homozygous nonsense CEP250 mutation combined with a heterozygous nonsense C2orf71 mutation is associated with atypical Usher syndrome.

    Science.gov (United States)

    Khateb, Samer; Zelinger, Lina; Mizrahi-Meissonnier, Liliana; Ayuso, Carmen; Koenekoop, Robert K; Laxer, Uri; Gross, Menachem; Banin, Eyal; Sharon, Dror

    2014-07-01

    Usher syndrome (USH) is a heterogeneous group of inherited retinitis pigmentosa (RP) and sensorineural hearing loss (SNHL) caused by mutations in at least 12 genes. Our aim is to identify additional USH-related genes. Clinical examination included visual acuity test, funduscopy and electroretinography. Genetic analysis included homozygosity mapping and whole exome sequencing (WES). A combination of homozygosity mapping and WES in a large consanguineous family of Iranian Jewish origin revealed nonsense mutations in two ciliary genes: c.3289C>T (p.Q1097*) in C2orf71 and c.3463C>T (p.R1155*) in centrosome-associated protein CEP250 (C-Nap1). The latter has not been associated with any inherited disease and the c.3463C>T mutation was absent in control chromosomes. Patients who were double homozygotes had SNHL accompanied by early-onset and severe RP, while patients who were homozygous for the CEP250 mutation and carried a single mutant C2orf71 allele had SNHL with mild retinal degeneration. No ciliary structural abnormalities in the respiratory system were evident by electron microscopy analysis. CEP250 expression analysis of the mutant allele revealed the generation of a truncated protein lacking the NEK2-phosphorylation region. A homozygous nonsense CEP250 mutation, in combination with a heterozygous C2orf71 nonsense mutation, causes an atypical form of USH, characterised by early-onset SNHL and a relatively mild RP. The severe retinal involvement in the double homozygotes indicates an additive effect caused by nonsense mutations in genes encoding ciliary proteins. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  13. A faunistic study of genus Chasmogenus Sharp, 1882 of China (Coleoptera, Hydrophilidae).

    Science.gov (United States)

    Jia, Fenglong; Tang, Yu-Dan

    2018-01-01

    Chasmogenus Sharp, 1882 is newly reported from the Chinese Mainland. A new species, C. parorbus sp. n. , is described from China (Yunnan). Chasmogenus orbus Watanabe, 1987 is reported from Hong Kong, the first record outside Japan. Chasmogenus abnormalis (Sharp, 1890) is reported from the Chinese mainland for the first time. The male genitalia of each species are illustrated. A key to the Chinese species of the genus is provided.

  14. CE Challenges : Work to Do

    NARCIS (Netherlands)

    Stjepandic, J; Verhagen, W.J.C.; Wognum, P.M.

    2015-01-01

    CE has been used for more than two decades now. Despite many successes and advantages, there are still many challenges to be addressed. These challenges are both technical and organisational. In the paper we will address the current challenges of CE. Many challenges

  15. An All-School Library Challenge

    Science.gov (United States)

    Quirk, Connie

    2005-01-01

    The library media center is hosting an all-school team challenge, designed to celebrate reading and library skills. Students could choose from the contest categories like "Lord of the Rings", "Harry Potter", Author Facts Challenge and Opening Lines Challenge for the competition and those students who read more challenging books show their…

  16. Novel compound heterozygous Thyroglobulin mutations c.745+1G>A/c.7036+2T>A associated with congenital goiter and hypothyroidism in a Vietnamese family. Identification of a new cryptic 5' splice site in the exon 6.

    Science.gov (United States)

    Citterio, Cintia E; Morales, Cecilia M; Bouhours-Nouet, Natacha; Machiavelli, Gloria A; Bueno, Elena; Gatelais, Frédérique; Coutant, Regis; González-Sarmiento, Rogelio; Rivolta, Carina M; Targovnik, Héctor M

    2015-03-15

    Several patients were identified with dyshormonogenesis caused by mutations in the thyroglobulin (TG) gene. These defects are inherited in an autosomal recessive manner and affected individuals are either homozygous or compound heterozygous for the mutations. The aim of the present study was to identify new TG mutations in a patient of Vietnamese origin affected by congenital hypothyroidism, goiter and low levels of serum TG. DNA sequencing identified the presence of compound heterozygous mutations in the TG gene: the maternal mutation consists of a novel c.745+1G>A (g.IVS6 + 1G>A), whereas the hypothetical paternal mutation consists of a novel c.7036+2T>A (g.IVS40 + 2T>A). The father was not available for segregation analysis. Ex-vivo splicing assays and subsequent RT-PCR analyses were performed on mRNA isolated from the eukaryotic-cells transfected with normal and mutant expression vectors. Minigene analysis of the c.745+1G>A mutant showed that the exon 6 is skipped during pre-mRNA splicing or partially included by use of a cryptic 5' splice site located to 55 nucleotides upstream of the authentic exon 6/intron 6 junction site. The functional analysis of c.7036+2T>A mutation showed a complete skipping of exon 40. The theoretical consequences of splice site mutations, predicted with the bioinformatics tool NNSplice, Fsplice, SPL, SPLM and MaxEntScan programs were investigated and evaluated in relation with the experimental evidence. These analyses predicted that both mutant alleles would result in the abolition of the authentic splice donor sites. The c.745+1G>A mutation originates two putative truncated proteins of 200 and 1142 amino acids, whereas c.7036+2T>A mutation results in a putative truncated protein of 2277 amino acids. In conclusion, we show that the c.745+1G>A mutation promotes the activation of a new cryptic donor splice site in the exon 6 of the TG gene. The functional consequences of these mutations could be structural changes in the protein

  17. Big Data Challenges

    Directory of Open Access Journals (Sweden)

    Alexandru Adrian TOLE

    2013-10-01

    Full Text Available The amount of data that is traveling across the internet today, not only that is large, but is complex as well. Companies, institutions, healthcare system etc., all of them use piles of data which are further used for creating reports in order to ensure continuity regarding the services that they have to offer. The process behind the results that these entities requests represents a challenge for software developers and companies that provide IT infrastructure. The challenge is how to manipulate an impressive volume of data that has to be securely delivered through the internet and reach its destination intact. This paper treats the challenges that Big Data creates.

  18. Challenge and Change

    Science.gov (United States)

    Mehaffy, George L.

    2012-01-01

    In the past twenty years, various industries have been forever altered by technology: newspapers, book publishing, the photography business, and many more. Higher education too faces unprecedented challenges primarily driven by rapid changes in technology. To meet these challenges and adapt to these changes, new models are needed. Six challenges…

  19. 78 FR 59974 - Centennial Challenges 2014 Unmanned Aircraft Systems (UAS) Airspace Operations Challenge (AOC)

    Science.gov (United States)

    2013-09-30

    ... NATIONAL AERONAUTICS AND SPACE ADMINISTRATION Centennial Challenges 2014 Unmanned Aircraft Systems... wish to compete may now register. Centennial Challenges is a program of prize competitions to stimulate...: http://www.uasaoc.org For general information on the NASA Centennial Challenges Program please visit...

  20. Challenges as enablers for high quality Linked Data: insights from the Semantic Publishing Challenge

    Directory of Open Access Journals (Sweden)

    Anastasia Dimou

    2017-01-01

    Full Text Available While most challenges organized so far in the Semantic Web domain are focused on comparing tools with respect to different criteria such as their features and competencies, or exploiting semantically enriched data, the Semantic Web Evaluation Challenges series, co-located with the ESWC Semantic Web Conference, aims to compare them based on their output, namely the produced dataset. The Semantic Publishing Challenge is one of these challenges. Its goal is to involve participants in extracting data from heterogeneous sources on scholarly publications, and producing Linked Data that can be exploited by the community itself. This paper reviews lessons learned from both (i the overall organization of the Semantic Publishing Challenge, regarding the definition of the tasks, building the input dataset and forming the evaluation, and (ii the results produced by the participants, regarding the proposed approaches, the used tools, the preferred vocabularies and the results produced in the three editions of 2014, 2015 and 2016. We compared these lessons to other Semantic Web Evaluation Challenges. In this paper, we (i distill best practices for organizing such challenges that could be applied to similar events, and (ii report observations on Linked Data publishing derived from the submitted solutions. We conclude that higher quality may be achieved when Linked Data is produced as a result of a challenge, because the competition becomes an incentive, while solutions become better with respect to Linked Data publishing best practices when they are evaluated against the rules of the  challenge.

  1. Numerical simulation of coal gasification process using the modifying Watanabe - Otaka model.

    Energy Technology Data Exchange (ETDEWEB)

    T. Papadopoulos; M. Losurdo; H. Spliethoff

    2009-07-01

    High-pressure entrained flow coal gasification is becoming increasingly important particularly in the development of Integrated Coal Gasification Combined Cycle (IGCC) technology for the production of electricity. However, there is a lack of knowledge worldwide for the gasification process and more especially for the chemical reactions (reactions rates) that take place under high pressure and temperature. Therefore a gasifier has been designed and is being built at the Institute for Energy Systems (Lehrstuhl fuer Energisysteme - LES) at the Technische Universitaet Muenchen (TUM). This gasifier is an entrained flow gasifier and has the advantage that it can operate to very high conditions of pressure and temperature, up to 50 bar pressure and 1800{sup o}C temperature. In an ongoing project, a great variety of experiments are planned to determine chemical reactions rates at high pressure conditions. In addition to the experimental work, CFD numerical simulations of pulverized coal gasification are being performed. The aim is to use numerical investigations for preliminary assessment of the facility. The goal is to develop a gasification model suitable for high pressure and condition tailored on the experiments to be used in CFD computations to predict chemical reactions, the heat transfer and the turbulence inside the gasifier. 9 refs., 2 figs., 2 tabs.

  2. First Aid Challenge

    Science.gov (United States)

    Roman, Harry T.

    2011-01-01

    This article describes a challenge wherein students will be asked to design a portable first aid kit that is normally carried in a recreational vehicle (RV), but can also be hand-carried or backpacked off road for distances of approximately 1-2 miles. This can be a very practical challenge for the students because it touches everyone. Everybody…

  3. The heterozygous disproportionate micromelia (dmm) mouse: morphological changes in fetal cartilage precede postnatal dwarfism and compared with lethal homozygotes can explain the mild phenotype.

    Science.gov (United States)

    Seegmiller, Robert E; Bomsta, Brandon D; Bridgewater, Laura C; Niederhauser, Cindy M; Montaño, Carolina; Sudweeks, Sterling; Eyre, David R; Fernandes, Russell J

    2008-11-01

    The disproportionate micromelia (Dmm) mouse has a mutation in the C-propeptide coding region of the Col2a1 gene that causes lethal dwarfism when homozygous (Dmm/Dmm) but causes only mild dwarfism observable approximately 1-week postpartum when heterozygous (Dmm/+). The purpose of this study was 2-fold: first, to analyze and quantify morphological changes that precede the expression of mild dwarfism in Dmm/+ animals, and second, to compare morphological alterations between Dmm/+ and Dmm/Dmm fetal cartilage that may correlate with the marked skeletal differences between mild and lethal dwarfism. Light and electron transmission microscopy were used to visualize structure of chondrocytes and extracellular matrix (ECM) of fetal rib cartilage. Both Dmm/+ and Dmm/Dmm fetal rib cartilage had significantly larger chondrocytes, greater cell density, and less ECM per unit area than +/+ littermates. Quantitative RT-PCR showed a decrease in aggrecan mRNA in Dmm/+ vs +/+ cartilage. Furthermore, the cytoplasm of chondrocytes in Dmm/+ and Dmm/Dmm cartilage was occupied by significantly more distended rough endoplasmic reticulum (RER) compared with wild-type chondrocytes. Fibril diameters and packing densities of +/+ and Dmm/+ cartilage were similar, but Dmm/Dmm cartilage showed thinner, sparsely distributed fibrils. These findings support the prevailing hypothesis that a C-propeptide mutation could interrupt the normal assembly and secretion of Type II procollagen trimers, resulting in a buildup of proalpha1(II) chains in the RER and a reduced rate of matrix synthesis. Thus, intracellular entrapment of proalpha1(II) seems to be primarily responsible for the dominant-negative effect of the Dmm mutation in the expression of dwarfism.

  4. Offshore northern Europe, the challenges

    International Nuclear Information System (INIS)

    Bergseth, S.

    1996-01-01

    This paper relates to challenges of the offshore activity in the North Sea. It is appropriate to address these challenges in the context of generating values through efficient management of resources, markets, safety and technology, as the challenges lie therein. The petroleum industry is built to turn natural resources into market value, assuring broad benefits to stake holders and shareholders. In the following, the challenges facing the industry the industry offshore Northern Europe is examined on this background

  5. A faunistic study of genus Chasmogenus Sharp, 1882 of China (Coleoptera, Hydrophilidae

    Directory of Open Access Journals (Sweden)

    Fenglong Jia

    2018-02-01

    Full Text Available Chasmogenus Sharp, 1882 is newly reported from the Chinese Mainland. A new species, C. parorbus sp. n., is described from China (Yunnan. Chasmogenus orbus Watanabe, 1987 is reported from Hong Kong, the first record outside Japan. Chasmogenus abnormalis (Sharp, 1890 is reported from the Chinese mainland for the first time. The male genitalia of each species are illustrated. A key to the Chinese species of the genus is provided.

  6. Traditional vs. secular values and work-life well being across Europe

    OpenAIRE

    Georgellis, Y; Lange, T

    2007-01-01

    This paper examines how culture, defined in our analysis by reference to traditional versus secular values, affects the work-life balance across Europe. Specifically, we focus on the factors that affect the propensity of individuals across 30 European countries to exhibit behavioural patterns in the work and life domains consistent with the segmentation, spillover or compensation hypotheses. Testing the latter assertions, our empirical analysis replicates the study by Judge and Watanabe (1994...

  7. 地震研究所マグニチュードとモーメントマグニチュードの関係の理論的考察

    OpenAIRE

    井出, 哲

    2003-01-01

    Magnitude of Earthquake Research Institute (ERI), University of Tokyo, ME, is determined using an empirical equation of Watanabe (1971). Based on the omega-square source model, constant stress drop scaling, constant Q, and instrumental response, we calculated a typical waveform for each event with a given seismic moment and MW to estimate its ME. This leads to theoretical relationships, which show 1)saturation for MW>6, 2)overestimation of ME for 3

  8. A newly designed attachment device of multipurpose frame for neuronavigator. Technical note.

    Science.gov (United States)

    Singh, A K; Okudera, H; Kobayashi, S; Osawa, M; Tokushige, K

    1994-01-01

    A newly designed attachment device of the multipurpose head frame (Sugita) for Neuronavigator (Watanabe) is presented with an illustrative case of glioblastoma in an eloquent area. This has extended the usefulness of the neuronavigator for those who prefer and use the multipurpose head frame, while the requirements for keeping a stereotactic combination and the original concept of the multipurpose head frame, as well as that of the neuronavigator have been kept undisturbed.

  9. Homozygous and heterozygous GH transgenesis alters fatty acid composition and content in the liver of Amago salmon (Oncorhynchus masou ishikawae

    Directory of Open Access Journals (Sweden)

    Manabu Sugiyama

    2012-08-01

    Growth hormone (GH transgenic Amago (Oncorhynchus masou ishikawae, containing the sockeye GH1 gene fused with metallothionein-B promoter from the same species, were generated and the physiological condition through lipid metabolism compared among homozygous (Tg/Tg and heterozygous GH transgenic (Tg/+ Amago and the wild type control (+/+. Previously, we have reported that the adipose tissue was generally smaller in GH transgenic fish compared to the control, and that the Δ-6 fatty acyl desaturase gene was down-regulated in the Tg/+ fish. However, fatty acid (FA compositions have not been measured previously in these fish. In this study we compared the FAs composition and content in the liver using gas chromatography. Eleven kinds of FA were detected. The composition of saturated and monounsaturated fatty acids (SFA and MUFA such as myristic acid (14:0, palmitoleic acid (16:1n-7, and cis-vaccenic acid (cis-18:1n-7 was significantly (P<0.05 decreased in GH transgenic Amago. On the other hand, the composition of polyunsaturated fatty acids (PUFAs such as linoleic acid (18:2n-6, arachidonic acid (20:4n-6, and docosapentaenoic acid (22:5n-3 was significantly (P<0.05 increased. Levels of serum glucose and triacylglycerol were significantly (P<0.05 decreased in the GH transgenics compared with +/+ fish. Furthermore, 3′-tag digital gene expression profiling was performed using liver tissues from Tg/Tg and +/+ fish, and showed that Mid1 interacting protein 1 (Mid1ip1, which is an important factor to activate Acetyl-CoA carboxylase (ACC, was down-regulated in Tg/Tg fish, while genes involved in FA catabolism were up-regulated, including long-chain-fatty-acid–CoA ligase 1 (ACSL1 and acyl-coenzyme A oxidase 3 (ACOX3. These data suggest that liver tissue from GH transgenic Amago showed starvation by alteration in glucose and lipid metabolism due to GH overexpression. The decrease of serum glucose suppressed Mid1ip1, and caused a decrease of de novo FA synthesis, resulting

  10. National Drug IQ Challenge

    Science.gov (United States)

    ... National Drug IQ Challenge 2017 Reto nacional del coeficiente intelectual (CI) sobre las drogas y el alcohol 2016 National Drug IQ Challenge 2016 Reto nacional del coeficiente intelectual (CI) sobre las drogas y el alcohol 2015 ...

  11. The WCET Tool Challenge 2011

    DEFF Research Database (Denmark)

    Hanxleden, Reinhard von; Holsti, Niklas; Lisper, Björn

    Following the successful WCET Tool Challenges in 2006 and 2008, the third event in this series was organized in 2011, again with support from the ARTIST DESIGN Network of Excellence. Following the practice established in the previous Challenges, the WCET Tool Challenge 2011 (WCC'11) dened two kin...

  12. WCET Tool Challenge 2011: Report

    DEFF Research Database (Denmark)

    Bonenfant, Armelle; Cassé, Hugues; Bünte, Sven

    2011-01-01

    Following the successful WCET Tool Challenges in 2006 and 2008, the third event in this series was organized in 2011, again with support from the ARTIST DESIGN Network of Excellence. Following the practice established in the previous Challenges, the WCET Tool Challenge 2011 (WCC’11) defined two k...

  13. Challenges of Virtual School Leadership

    Science.gov (United States)

    Richardson, Jayson W.; LaFrance, Jason; Beck, Dennis

    2015-01-01

    The purpose of this case study was to examine challenges faced by virtual school leaders in the United States. Through semistructured interviews, the researchers explored challenges faced by eighteen leaders of fully online or blended online programs. Analysis revealed six main challenges: funding, staff, accountability, time, parents, and…

  14. The challenges of dismantling

    International Nuclear Information System (INIS)

    Sene, Monique; Lheureux, Yves; Leroyer, Veronique; Rollinger, Francois; Gauthier, Florence; Depauw, Denis; Reynal, Nathalie; Fraysse, Thierry; Burger, Eric; Bertrand, Adrien; Vallat, Christophe; Bernet, Philippe; Eimer, Michel; Boutin, Dominique; Bietrix, Philippe; Richard, Francoise; Piketty, Laurence; Mouchet, Chantal; Charre, Jean-Pierre

    2014-01-01

    This document gathers Power Point presentations which address the contexts and challenges of dismantling (legal framework, safety and radiation protection challenges, waste processing industry), and propose illustrations of dismantling challenges (example of operations to prepare EURODIF dismantling and CLIGEET work-group on EURODIF dismantling, examples of dismantling of EDF installations and CLIs' opinion on the dismantling of EDF installations, Brennilis dismantling follow-up performed by the CLI, examples of dismantling of CEA installations and opinion of a CLI on the dismantling of CEA installations)

  15. Centennial Challenges Program

    Science.gov (United States)

    Ortega, Sam; Eberly, Eric

    2015-01-01

    NASA's Centennial Challenges Program was initiated in 2005 to directly engage the public in the process of advanced technology development. The program offers incentive prizes to generate revolutionary solutions to problems of interest to NASA and the nation. The program seeks innovations from diverse and nontraditional sources. Competitors are not supported by government funding and awards are only made to successful teams when the challenges are met. In keeping with the spirit of the Wright Brothers and other American innovators, the Centennial Challenge prizes are offered to independent inventors including small businesses, student groups, and individuals. These independent inventors are sought to generate innovative solutions for technical problems of interest to NASA and the nation and to provide them with the opportunity to stimulate or create new business ventures.

  16. Challenges of serious games

    Directory of Open Access Journals (Sweden)

    B. Fernández-Manjón

    2015-11-01

    Full Text Available Although educational games have revealed to be a very effective focus in diverse situations, their use in education is still very limited. In this paper we analyse the main challenges concerning educational games that, from our perspective, have to be approached so that the use of this kind of games can be widespread. These challenges are classified in three main dimensions: socio-cultural, educational and technological. Once the challenges are identified, some possible measures are suggested to address or reduce these problems so that the use of educational games may be widespread.

  17. A microarray-based genotyping and genetic mapping approach for highly heterozygous outcrossing species enables localization of a large fraction of the unassembled Populus trichocarpa genome sequence.

    Science.gov (United States)

    Drost, Derek R; Novaes, Evandro; Boaventura-Novaes, Carolina; Benedict, Catherine I; Brown, Ryan S; Yin, Tongming; Tuskan, Gerald A; Kirst, Matias

    2009-06-01

    Microarrays have demonstrated significant power for genome-wide analyses of gene expression, and recently have also revolutionized the genetic analysis of segregating populations by genotyping thousands of loci in a single assay. Although microarray-based genotyping approaches have been successfully applied in yeast and several inbred plant species, their power has not been proven in an outcrossing species with extensive genetic diversity. Here we have developed methods for high-throughput microarray-based genotyping in such species using a pseudo-backcross progeny of 154 individuals of Populus trichocarpa and P. deltoides analyzed with long-oligonucleotide in situ-synthesized microarray probes. Our analysis resulted in high-confidence genotypes for 719 single-feature polymorphism (SFP) and 1014 gene expression marker (GEM) candidates. Using these genotypes and an established microsatellite (SSR) framework map, we produced a high-density genetic map comprising over 600 SFPs, GEMs and SSRs. The abundance of gene-based markers allowed us to localize over 35 million base pairs of previously unplaced whole-genome shotgun (WGS) scaffold sequence to putative locations in the genome of P. trichocarpa. A high proportion of sampled scaffolds could be verified for their placement with independently mapped SSRs, demonstrating the previously un-utilized power that high-density genotyping can provide in the context of map-based WGS sequence reassembly. Our results provide a substantial contribution to the continued improvement of the Populus genome assembly, while demonstrating the feasibility of microarray-based genotyping in a highly heterozygous population. The strategies presented are applicable to genetic mapping efforts in all plant species with similarly high levels of genetic diversity.

  18. Compound Heterozygous Inheritance of Mutations in Coenzyme Q8A Results in Autosomal Recessive Cerebellar Ataxia and Coenzyme Q10 Deficiency in a Female Sib-Pair.

    Science.gov (United States)

    Jacobsen, Jessie C; Whitford, Whitney; Swan, Brendan; Taylor, Juliet; Love, Donald R; Hill, Rosamund; Molyneux, Sarah; George, Peter M; Mackay, Richard; Robertson, Stephen P; Snell, Russell G; Lehnert, Klaus

    2017-11-21

    Autosomal recessive ataxias are characterised by a fundamental loss in coordination of gait with associated atrophy of the cerebellum. There is significant clinical and genetic heterogeneity amongst inherited ataxias; however, an early molecular diagnosis is essential with low-risk treatments available for some of these conditions. We describe two female siblings who presented early in life with unsteady gait and cerebellar atrophy. Whole exome sequencing revealed compound heterozygous inheritance of two pathogenic mutations (p.Leu277Pro, c.1506+1G>A) in the coenzyme Q8A gene (COQ8A), a gene central to biosynthesis of coenzyme Q (CoQ). The paternally derived p.Leu277Pro mutation is predicted to disrupt a conserved motif in the substrate-binding pocket of the protein, resulting in inhibition of CoQ 10 production. The maternal c.1506+1G>A mutation destroys a canonical splice donor site in exon 12 affecting transcript processing and subsequent protein translation. Mutations in this gene can result in primary coenzyme Q 10 deficiency type 4, which is characterized by childhood onset of cerebellar ataxia and exercise intolerance, both of which were observed in this sib-pair. Muscle biopsies revealed unequivocally low levels of CoQ 10, and the siblings were subsequently established on a therapeutic dose of CoQ 10 with distinct clinical evidence of improvement after 1 year of treatment. This case emphasises the importance of an early and accurate molecular diagnosis for suspected inherited ataxias, particularly given the availability of approved treatments for some subtypes.

  19. Budget Impact Analysis of PCSK9 Inhibitors for the Management of Adult Patients with Heterozygous Familial Hypercholesterolemia or Clinical Atherosclerotic Cardiovascular Disease.

    Science.gov (United States)

    Mallya, Usha G; Boklage, Susan H; Koren, Andrew; Delea, Thomas E; Mullins, C Daniel

    2018-01-01

    The aim of this study was to assess the budget impact of introducing the proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) alirocumab and evolocumab to market for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular (CV) disease requiring additional lowering of low-density lipoprotein cholesterol (LDL-C). A 3-year model estimated the costs of lipid-modifying therapy (LMT) and CV events to a hypothetical US health plan of 1 million members, comparing two scenarios-with and without the availability of PCSK9i as add-on therapy to statins. Proportions of patients with uncontrolled LDL-C despite receiving statins, and at risk of CV events, were estimated from real-world data. Total undiscounted annual LMT costs (2017 prices, including PCSK9i costs of $14,563.50), dispensing and healthcare costs, including the costs of CV events, were estimated for all prevalent patients in the target population, based on baseline risk factors. Maximum PCSK9i utilization of 1-5% over 3 years according to risk group (following the same pattern as current ezetimibe use), and 5-10% as a secondary scenario, were assumed. Total healthcare budget impacts per target patient (and per member) per month for years 1, 2 and 3 were $3.62($0.10), $7.22($0.20) and $10.79($0.30), respectively, assuming 1-5% maximum PCSK9i utilization, and $15.81($0.44), $31.52($0.88) and $47.12($1.31), respectively, assuming 5-10% utilization. Results were sensitive to changes in model timeframe, years to maximum PCSK9i utilization and PCSK9i costs. The budget impact of PCSK9i as add-on therapy to statins for patients with hypercholesterolemia is relatively low compared with published estimates for other specialty biologics. Drug cost rebates and discounts are likely to further reduce budget impact.

  20. Oral food challenges in children

    Directory of Open Access Journals (Sweden)

    Hye Yung Yum

    2011-01-01

    Full Text Available Many patients assume that allergic reactions against foods are responsible for triggering or worsening their allergic symptoms. Therefore, it is important to identify patients who would benefit from an elimination diet, while avoiding unnecessary dietary restrictions. The diagnosis of food allergy depends on the thorough review of the patients's medical history, results of supplemented trials of dietary elimination, and in vivo and in vitro tests for measuring specific IgE levels. However, in some cases the reliability of such procedures is suboptimal. Oral food challenges are procedures employed for making an accurate diagnosis of immediate and occasionally delayed adverse reactions to foods. The timing and type of the challenge, preparation of patients, foods to be tested, and dosing schedule should be determined on the basis of the patient's history, age, and experience. Although double-blind, placebo-controlled food challenges(DBPCFC are used to establish definitively if a food is the cause of adverse reactions, they are time-consuming, expensive and troublesome for physician and patients. In practice, An open challenge controlled by trained personnel is sufficient especially in infants and young children. The interpretation of the results and follow-up after a challenge are also important. Since theses challenges are relatively safe and informative, controlled oral food challenges could become the measure of choice in children.

  1. Overcoming Safeguards Challenges

    International Nuclear Information System (INIS)

    Henriques, Sasha

    2011-01-01

    The focus of the 2010 IAEA International Safeguards Symposium was how best, from a technical perspective, to prepare for future verification challenges during this time of change. By bringing together the leading experts in the field from across the world, this symposium provided an opportunity for stakeholders to explore possible solutions in support of the IAEA's nuclear verification mission, and to identify areas where the different stakeholders in the safeguards business can help address these challenges

  2. Dynamics of multi-frequency oscillator ensembles with resonant coupling

    Science.gov (United States)

    Lück, S.; Pikovsky, A.

    2011-07-01

    We study dynamics of populations of resonantly coupled oscillators having different frequencies. Starting from the coupled van der Pol equations we derive the Kuramoto-type phase model for the situation, where the natural frequencies of two interacting subpopulations are in relation 2:1. Depending on the parameter of coupling, ensembles can demonstrate fully synchronous clusters, partial synchrony (only one subpopulation synchronizes), or asynchrony in both subpopulations. Theoretical description of the dynamics based on the Watanabe-Strogatz approach is developed.

  3. Echo intensity obtained from ultrasonography images reflecting muscle strength in elderly men

    OpenAIRE

    Watanabe, Yuya; Yamada,Yosuke; Fukumoto,; Yokoyama,Keiichi; Yoshida,Tsukasa; Miyake,; Yamagata,Emi; Kimura,; Ishihara,

    2013-01-01

    Yuya Watanabe,1 Yosuke Yamada,1,2 Yoshihiro Fukumoto,3 Tatsuro Ishihara,4 Keiichi Yokoyama,1 Tsukasa Yoshida,1 Motoko Miyake,1 Emi Yamagata,5 Misaka Kimura1 1Laboratory of Sports and Health Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; 2Research Fellow, Japan Society for the Promotion of Science, Tokyo, Japan; 3Faculty of Rehabilitation, Kobe Gakuin University, Kobe, Japan; 4Faculty of Health and Sports Science, Doshisha University, Kyoto, Japan; 5Laboratory of Gerontologic...

  4. Haploinsufficiency in the PPARα and LDL receptor genes leads to gender- and age-specific obesity and hyperinsulinemia

    International Nuclear Information System (INIS)

    Sugiyama, Eiko; Tanaka, Naoki; Nakajima, Tamie; Kamijo, Yuji; Yokoyama, Shin; Li Yufeng; Gonzalez, Frank J.; Aoyama, Toshifumi

    2006-01-01

    When preparing peroxisome proliferator-activated receptor (PPAR)α:low-density lipoprotein receptor (LDLR) (-/-) double knockout mice, we unexpectedly found a unique gender- and age-specific obesity in the F1 generation, PPARα (+/-):LDLR (+/-), even in mice fed standard chow. Body weights of the male heterozygous mice increased up to about 60 g at 75 weeks of age, then decreased by about 30 g at 100 weeks of age. More than 95% of the heterozygous mice between 35- and 75-week-olds were overweight. Of interest, the obese heterozygous mice also exhibited hyperinsulinemia correlating with moderate insulin resistance. Hepatic gene expression of LDLR was lower than expected in the heterozygous mice, particularly at 50 and 75 weeks of age. In contrast, the hepatic expression of PPARα was higher than expected in obese heterozygous mice, but decreased in non-obese older heterozygous mice. Modulated expression of these genes may be partially associated with the onset of the hyperinsulinemia

  5. The diesel challenge

    International Nuclear Information System (INIS)

    Tobin, Geoff

    1997-01-01

    This article is focused on the challenges being faced by the diesel producer and these include a number of interesting developments which illustrate the highly competitive world of the European refiner. These include: The tightening quality requirements being legislated coupled with the availability of the ''city diesel'' from Scandinavia and elsewhere which is already being sold into the market. For a time there will be a clear means of product differentiation. One of the key questions is whether the consumer will value the quality difference; a growing demand for diesel which is outstripping the growth in gasoline demand and causing refiners headaches when it comes to balancing their supply/demand barrels; the emergence of alternative fuels which are challenging the traditional markets of the refiner and in particular, the niche markets for the higher quality diesel fuels. All of this at a time of poor margins and over-capacity in the industry with further major challenges ahead such as fuel oil disposal, tighter environmental standards and the likelihood of heavier, higher sulphur crude oils in the future. Clearly, in such a difficult and highly-competitive business environment it will be important to find low-cost solutions to the challenges of the diesel quality changes. An innovative approach will be required to identify the cheapest and best route to enable the manufacture of the new quality diesel. (Author)

  6. Challenges: a state and compact perspective

    International Nuclear Information System (INIS)

    Brown, H.

    1987-01-01

    The challenges facing states and compacts in their efforts to implement the Low-Level Waste Policy Amendments Act are described. Institutional challenges include: small-volume sites; compact maintenance; shifting agencies and changing personnel; and timing of progress. The technical challenge lies in the enormous number of plans, procedures, and regulations that have to be developed over the next four years. There are two main fiscal challenges: funding of day-to-day operations of compact commissions; and financing the siting and construction of new disposal sites. There are also two main regulatory challenges: host states must develop regulations for siting and selection of technology; and all states have to await federal regulations to be completed. The final challenge is political: whether a region can overcome public opposition and actually site a facility

  7. Virtual Bridge Design Challenge

    Science.gov (United States)

    Mitts, Charles R.

    2013-01-01

    This design/problem-solving activity challenges students to design a replacement bridge for one that has been designated as either structurally deficient or functionally obsolete. The Aycock MS Technology/STEM Magnet Program Virtual Bridge Design Challenge is an authentic introduction to the engineering design process. It is a socially relevant…

  8. Challenges for Nordic VET-systems

    DEFF Research Database (Denmark)

    Jørgensen, Christian Helms

    2015-01-01

    , this challenge is not new. It has been on the agenda since the late 1960s following the crisis for apprenticeship and the growing demand for equal access to all levels of education. What is new, however, is that the challenge has intensified and the solutions developed since the 1970s don’t appear tenable today......The systems of vocational education and training (VET) in the Nordic Countries all face a similar challenge: to offer double qualifications. The Nordic VET-systems are expected to give access not only to skilled employment, but also to higher education. As an increasing share of young people....... This situation calls for new solutions to tackle the challenge of double qualifications. The question, which I will examine in this chapter, is how the Nordic VET-systems have handled this challenge in different ways and what these systems can learn from Switzerland, which is often highlighted as a model...

  9. The medical leadership challenge in healthcare is an identity challenge.

    Science.gov (United States)

    Andersson, Thomas

    2015-01-01

    The purpose of this article is to describe and analyse the identity challenges that physicians with medical leadership positions face. Four qualitative case studies were performed to address the fact that identity is processual, relational and situational. Physicians with managerial roles were interviewed, as well as their peers, supervisors and subordinates. Furthermore, observations were made to understand how different identities are displayed in action. This study illustrates that medical leadership implies identity struggles when physicians have manager positions, because of the different characteristics of the social identities of managers and physicians. Major differences are related between physicians as autonomous individuals in a system and managers as subordinates to the organizational system. There are psychological mechanisms that evoke the physician identity more often than the managerial identity among physicians who are managers, which explains why physicians who are managers tend to remain foremost physicians. The implications of the findings, that there are major identity challenges by being both a physician and manager, suggest that managerial physicians might not be the best prerequisite for medical leadership, but instead, cooperative relationships between physicians and non-physician managers might be a less difficult way to support medical leadership. Acknowledging and addressing identity challenges can be important both in creating structures in organizations and designing the training for managers in healthcare (both physicians and non-physicians) to support medical leadership. Medical leadership is most often related to organizational structure and/or leadership skills, but this paper discusses identity requirements and challenges related to medical leadership.

  10. Challenges in diagnosing tuberculosis in children

    DEFF Research Database (Denmark)

    Rahman, Nadia; Pedersen, Karin Kæreby; Rosenfeldt, Vibeke

    2012-01-01

    Clinical investigations of childhood tuberculosis (TB) are challenged by the paucibacillary nature of the disease and the difficulties in obtaining specimens. We investigated the challenges in diagnosing TB in children in a low-incidence country.......Clinical investigations of childhood tuberculosis (TB) are challenged by the paucibacillary nature of the disease and the difficulties in obtaining specimens. We investigated the challenges in diagnosing TB in children in a low-incidence country....

  11. Dewey's Challenge to Teachers

    Science.gov (United States)

    Fishman, Stephen M.; McCarthy, Lucille

    2010-01-01

    Given the serious social problems confronting Americans and others worldwide, the authors propose that Dewey's 1932 challenge to teachers is worthy of reconsideration by educators at all levels. In times similar to our own, Dewey challenged teachers to cultivate students' capacities to identify their happiness with what they can do to improve the…

  12. Overcoming challenges

    Medline Plus

    Full Text Available ... facts about babies, breastmilk, and breastfeeding Overcoming challenges Common questions about breastfeeding and pain Breastfeeding checklist: How to get a good latch Finding support It takes a village: Building ...

  13. Builders Challenge Quality Criteria Support Document

    Energy Technology Data Exchange (ETDEWEB)

    None

    2009-06-01

    This document provides guidance to U.S. home builders participating in Builders Challenge. To qualify for the Builders Challenge, a home must score 70 or less on the EnergySmart Home Scale (E-Scale). Homes also must meet the Builders Challenge Quality Cri

  14. Challenges in fingertip replantation.

    Science.gov (United States)

    Kim, Jin-Soo; Yang, Jae-Won; Lee, Dong-Chul; Ki, Sae-Hwi; Roh, Si-Young

    2013-11-01

    Fingertip amputation is a challenging injury to manage. Among various reconstructive procedures, replantation results in superior outcome, but is seldom considered in many institutions. From the identification of vessel ends to reanastomosis of the submillimeter vessels, fingertip's highly specialized anatomy requires technical excellence. By addressing these anatomic challenges, fingertip replantation can be a routine reconstructive option for microvascular surgeons.

  15. Challenges in Fingertip Replantation

    OpenAIRE

    Kim, Jin-Soo; Yang, Jae-Won; Lee, Dong-Chul; Ki, Sae-Hwi; Roh, Si-Young

    2013-01-01

    Fingertip amputation is a challenging injury to manage. Among various reconstructive procedures, replantation results in superior outcome, but is seldom considered in many institutions. From the identification of vessel ends to reanastomosis of the submillimeter vessels, fingertip's highly specialized anatomy requires technical excellence. By addressing these anatomic challenges, fingertip replantation can be a routine reconstructive option for microvascular surgeons.

  16. Challenges in obesity research.

    Science.gov (United States)

    Palou, Andreu; Bonet, M Luisa

    2013-09-01

    Obesity is the main nutritional problem and one of the most important health problems in developed societies. Central to the challenge of obesity prevention and management is a thoroughly understanding of its determinants. Multiple socio-cultural, socio-economic, behavioural and biological factors--often interrelated and many of them still unknown or poorly understood--can contribute to the establishment and perpetuation of obese phenotypes. Here, we address current research challenges regarding basic aspects of obesity and emerging science for its control, including brown adipose tissue thermogenesis and browning of white fat as possible therapeutic targets for obesity, the influence of the microbioma, and genetics, epigenetics, nutrigenomics and nutrigenetics of obesity. We also highlight hot topics in relation to food and lifestyle as determinants of obesity, including the brain mechanisms underlying environmental motivation to eat, the biological control of spontaneous physical activity, the possible role of concrete foods and food components, and the importance of early life nutrition and environment. Challenges regarding the connections of obesity with other alterations and pathologies are also briefly addressed, as well as social and economical challenges in relation to healthy food production and lifestyle for the prevention of obesity, and technological challenges in obesity research and management. The objective is to give a panoramic of advances accomplished and still ahead relevant to the different stakeholders engaged in understanding and combating obesity. Copyright © AULA MEDICA EDICIONES 2013. Published by AULA MEDICA. All rights reserved.

  17. Mobility Challenges

    DEFF Research Database (Denmark)

    Jensen, Ole B.; Lassen, Claus

    2011-01-01

    This article takes point of departure in the challenges to understand the importance of contemporary mobility. The approach advocated is a cross-disciplinary one drawing on sociology, geography, urban planning and design, and cultural studies. As such the perspective is to be seen as a part...... of the so-called ‘mobility turn’ within social science. The perspective is illustrative for the research efforts at the Centre for Mobility and Urban Studies (C-MUS), Aalborg University. The article presents the contours of a theoretical perspective meeting the challenges to research into contemporary urban...... mobilities. In particular the article discusses 1) the physical city, its infrastructures and technological hardware/software, 2) policies and planning strategies for urban mobility and 3) the lived everyday life in the city and the region....

  18. Report : business process intelligence challenge 2013

    NARCIS (Netherlands)

    Dongen, van B.F.; Weber, B.; Ferreira, D.R.; De Weerdt, J.; Lohmann, N.; Song, M.; Wohed, P.

    2014-01-01

    For the third time, the Business Process Intelligence workshop hosted the Business Process Intelligence Challenge. The goal of this challenge is twofold. On the one hand, the challenge allows researchers and practitioners in the field to show their analytical capabilities to a broader audience. On

  19. Work Group report: oral food challenge testing.

    Science.gov (United States)

    Nowak-Wegrzyn, Anna; Assa'ad, Amal H; Bahna, Sami L; Bock, S Allan; Sicherer, Scott H; Teuber, Suzanne S

    2009-06-01

    Oral food challenges are procedures conducted by allergists/immunologists to make an accurate diagnosis of immediate, and occasionally delayed, adverse reactions to foods. The timing of the challenge is carefully chosen based on the individual patient history and the results of skin prick tests and food specific serum IgE values. The type of the challenge is determined by the history, the age of the patient, and the likelihood of encountering subjective reactions. The food challenge requires preparation of the patient for the procedure and preparation of the office for the organized conduct of the challenge, for a careful assessment of the symptoms and signs and the treatment of reactions. The starting dose, the escalation of the dosing, and the intervals between doses are determined based on experience and the patient's history. The interpretation of the results of the challenge and arrangements for follow-up after a challenge are important. A negative oral food challenge result allows introduction of the food into the diet, whereas a positive oral food challenge result provides a sound basis for continued avoidance of the food.

  20. 6 CFR 7.30 - Classification challenges.

    Science.gov (United States)

    2010-01-01

    ... 6 Domestic Security 1 2010-01-01 2010-01-01 false Classification challenges. 7.30 Section 7.30... INFORMATION Classified Information § 7.30 Classification challenges. (a) Authorized holders of information... classified are encouraged and expected to challenge the classification status of that information pursuant to...

  1. Preventing and managing challenging behaviour.

    Science.gov (United States)

    Hallett, Nutmeg

    2018-02-21

    Patients exhibiting challenging behaviour, which includes any non-verbal, verbal or physical behaviour, is a significant issue in healthcare settings. Preventing such behaviour and the harm it can cause is important for healthcare organisations and individuals, and involves following a public health model comprised of three tiers: primary, secondary and tertiary prevention. Primary prevention aims to reduce the risk of challenging behaviour occurring in the first instance; secondary prevention involves reducing the risk associated with imminent challenging behaviour and its potential escalation; and tertiary prevention focuses on minimising the physical and emotional harm caused by challenging behaviours, during and after an event. De-escalation should be the first-line response to challenging behaviour, and healthcare staff should use a range of techniques - maintaining safety, self-regulation, effective communication, and assessment and actions - to reduce the incidence of challenging behaviour. In some situations, physical interventions may be required to protect the safety of the individual, healthcare staff and other individuals involved, and healthcare staff should be aware of local policies and procedures for this. Following a serious incident, where there was potential or actual harm to patients and healthcare staff, healthcare organisations should use post-incident reviews to learn from the situation, while healthcare staff should be offered the opportunity for debriefing. Positive responses to challenging behaviour at an organisational and individual level can lead to improved work environments for healthcare staff and optimal patient care and outcomes. ©2018 RCN Publishing Company Ltd. All rights reserved. Not to be copied, transmitted or recorded in any way, in whole or part, without prior permission of the publishers.

  2. Machine Learning wins the Higgs Challenge

    CERN Multimedia

    Abha Eli Phoboo

    2014-01-01

    The winner of the four-month-long Higgs Machine Learning Challenge, launched on 12 May, is Gábor Melis from Hungary, followed closely by Tim Salimans from the Netherlands and Pierre Courtiol from France. The challenge explored the potential of advanced machine learning methods to improve the significance of the Higgs discovery.   Winners of the Higgs Machine Learning Challenge: Gábor Melis and Tim Salimans (top row), Tianqi Chen and Tong He (bottom row). Participants in the Higgs Machine Learning Challenge were tasked with developing an algorithm to improve the detection of Higgs boson signal events decaying into two tau particles in a sample of simulated ATLAS data* that contains few signal and a majority of non-Higgs boson “background” events. No knowledge of particle physics was required for the challenge but skills in machine learning - the training of computers to recognise patterns in data – were essential. The Challenge, hosted by Ka...

  3. A Cidade e a Criança

    Directory of Open Access Journals (Sweden)

    Maurícia Santos de Holanda Bezerra

    2013-01-01

    A autora Mayumi Watanabe de Souza Lima (1934-1994 foi arquiteta, sua carreira foi dedicada ao planejamento, projeto e construção de equipamentos públicos para a educação de crianças e de jovens. Suas obras, A Cidade e a Criança (1989 e Arquitetura e Educação (1995 revelam a preocupação com os projetos dos espaços de parques e escolas, principalmente, com os seus usuários.

  4. General Recommendations on Fatigue Risk Management for the Canadian Forces

    Science.gov (United States)

    2010-04-01

    package. Tea 8 - 90 mg/cup Caffeine depends on how strong is the brew. Cola drinks 35 mg/250 ml Often contains much sugar. Cocoa and chocolates 10...70 mg/cup Caffeine content depends on how strong the brew is, and other chemical content in the product. Chocolate bars 20 - 60 mg/200g Contains...hygiene practices of good and poor sleepers in the United State: an internet based study. Behavior Therapy . 40(1):1-9. Hayashi M., Watanabe M

  5. Unique Identification Project Issues and Challenges Unique ...

    Indian Academy of Sciences (India)

    Multiple authentication methods · UID adoption can help improve pro-poor delivery systems · Technology Challenges … Biometric Challenges · Rural Biometric Challenges · Biometric De-Duplication · Architecture Challenges · Network Infrastructure · Security, Fraud Detection · Managing multiple risks · UID goals can be ...

  6. Challenges in Designing Mechatronic Systems

    DEFF Research Database (Denmark)

    Torry-Smith, Jonas; Qamar, Ahsan; Achiche, Sofiane

    2013-01-01

    Development of mechatronic products is traditionally carried out by several design experts from different design domains. Performing development of mechatronic products is thus greatly challenging. In order to tackle this, the critical challenges in mechatronics have to be well understood and well...... supported through applicable methods and tools. This paper aims at identifying the major challenges, by conducting a systematic and thorough survey of the most relevant research work in mechatronic design. Solutions proposed in literature are assessed and illustrated through a case study in order...... to investigate if the challenges can be handled appropriately by the methods, tools, and mindsets suggested by the mechatronic community. Using a real world mechatronics case, the paper identifies the areas where further research is required, by showing a clear connection between the actual problems faced during...

  7. Overcoming challenges

    Medline Plus

    Full Text Available ... menu It's Only Natural Planning ahead Breastfeeding and baby basics Making breastfeeding work for you Addressing breastfeeding ... in the African-American community Incredible facts about babies, breastmilk, and breastfeeding Overcoming challenges Common questions about ...

  8. Overcoming challenges

    Medline Plus

    Full Text Available ... Disease and Stroke HIV and AIDS Mental Health Pain Pregnancy Reproductive Health Sexual Health Sexually Transmitted Infections ... breastfeeding Overcoming challenges Common questions about breastfeeding and pain Breastfeeding checklist: How to get a good latch ...

  9. Overcoming challenges

    Medline Plus

    Full Text Available ... into your life Breastfeeding in daily life: At home and in public Laws that support breastfeeding 10 ... and jobs View all pages in this section Home It's Only Natural Overcoming challenges It's Only Natural ...

  10. Grand Challenges facing Storage Systems

    CERN Multimedia

    CERN. Geneva

    2004-01-01

    In this talk, we will discuss the future of storage systems. In particular, we will focus on several big challenges which we are facing in storage, such as being able to build, manage and backup really massive storage systems, being able to find information of interest, being able to do long-term archival of data, and so on. We also present ideas and research being done to address these challenges, and provide a perspective on how we expect these challenges to be resolved as we go forward.

  11. Challenges in aerospace medicine education.

    Science.gov (United States)

    Grenon, S Marlene; Saary, Joan

    2011-11-01

    Aerospace medicine training and research represents a dream for many and a challenge for most. In Canada, although some opportunities exist for the pursuit of education and research in the aerospace medicine field, they are limited despite the importance of this field for enabling safe human space exploration. In this commentary, we aim to identify some of the challenges facing individuals wishing to get involved in the field as well as the causal factors for these challenges. We also explore strategies to mitigate against these.

  12. Cognitive Challenges

    Science.gov (United States)

    ... Alliance Our Story Our Vision Our Team Our Leadership Our Results Our Corporate Policies FAQs Careers Contact Us Media Store Privacy Policy Sitemap Learn Engage Donate About TSC Cognitive Challenges Approximately 45% to 60% of individuals with TSC ...

  13. The competitive challenge in banking

    NARCIS (Netherlands)

    Boot, A.W.A.; Schmeits, A.

    2005-01-01

    The increasingly competitive environment poses challenges to bankers. This paper emphasizes relationship banking as a prime source of the banks' comparative advantage. The proliferation of transaction-oriented banking (trading and financial market activities) does however seriously challenge

  14. [Molecular genetic analysis for a pedigree with severe hereditary coagulation factor VII deficiency].

    Science.gov (United States)

    Ding, Qiu-lan; Wang, Hong-li; Wang, Xue-feng; Wang, Ming-shan; Fu, Qi-hua; Wu, Wen-man; Hu, Yi-qun; Wang, Zhen-yi

    2003-10-01

    To identify the genetic mutations of a severe inherited coagulation factor VII (FVII) deficiency pedigree. The diagnosis was validated by coagulant and haemostatic parameters. FVII gene mutations were screened in the propositus and his family members by DNA direct sequencing and confirmed by digestions of the restriction enzymes of the PCR production. Two heterozygous missense mutations were found in the propositus of the pedigree: a G to T transversion at position 9482 in exon 6 and a C to T mutation at position 11348 in exon 8 resulting in the amino acid substitution of Arg152 with Leu and Arg304 with Trp, respectively. A heterozygous single nucleotide deletion (C) at position 11487-11489(CCC) within exon 8 was identified, which predicted the frameshift mutation at position His351 followed by the changes of six corresponding amino acids and appearance of a premature protein caused by stop codon. The heterozygous mutations identified in the proband were derived from his father (Arg152 to Leu) and his mother (Arg304 to Trp mutation) and a heterozygous deletion (C) at position 11487-9(CCC). By tracing the other pedigree members, it was found that his grandmother had a heterozygous mutation of Arg304Trp and a heterozygous polymorphism of Arg353Gln and his grandfather had a heterozygous Arg152Leu mutation. Three heterozygous mutations were found in a pedigree with hereditary coagulation factor VII deficiency. Arg152Leu and deletion C at position 11487-9(CCC) were novel mutations.

  15. Designing the robot inclusive space challenge

    Directory of Open Access Journals (Sweden)

    Rajesh Elara Mohan

    2015-11-01

    Full Text Available A novel robotic challenge, namely the robot inclusive spaces (RIS challenge, is proposed in this paper, which is a cross disciplinary and design focused initiative. It aims to foster the roboticists, architects, and designers towards realizing robot friendly social spaces. Contrary to conventional robotics competitions focusing on designing robots and its component technologies, robot inclusive spaces challenge adopts an interdisciplinary “design for robots” strategy to overcome the traditional research problem in real world deployments of social robots. In order to realize the RIS, various architectural elements must be adapted including: design principles for inclusive spaces, lighting schemes, furniture choices and arrangement, wall and floor surfaces, pathways among others. This paper introduces the format and design principles of RIS challenge, presents a first run of the challenge, and gives the corresponding analysis.

  16. iSTEM: The Aerospace Engineering Challenge

    Science.gov (United States)

    English, Lyn D.; King, Donna T.; Hudson, Peter; Dawes, Les

    2014-01-01

    The authors developed The Paper Plane Challenge as one of a three-part response to The Aerospace Engineering Challenge. The Aerospace Engineering Challenge was the second of three multi-part activities that they had developed with the teachers during the year. Their aim was to introduce students to the exciting world of engineering, where they…

  17. Overcoming challenges

    Medline Plus

    Full Text Available ... breastfeeding means to them. Subscribe To receive Breastfeeding email updates Enter email Submit Overcoming challenges Breastfeeding has a long list ... breastfeeding means to them. Subscribe To receive Breastfeeding email updates Enter email Submit All material contained on ...

  18. 2010 Panel on the Biomaterials Grand Challenges

    Science.gov (United States)

    Reichert, William “Monty”; Ratner, Buddy D.; Anderson, James; Coury, Art; Hoffman, Allan S.; Laurencin, Cato T.; Tirrell, David

    2014-01-01

    In 2009, the National Academy for Engineering issued the Grand Challenges for Engineering in the 21st Century comprised of 14 technical challenges that must be addressed to build a healthy, profitable, sustainable, and secure global community (http://www.engineeringchallenges.org). Although crucial, none of the NEA Grand Challenges adequately addressed the challenges that face the biomaterials community. In response to the NAE Grand Challenges, Monty Reichert of Duke University organized a panel entitled Grand Challenges in Biomaterials at the at the 2010 Society for Biomaterials Annual Meeting in Seattle. Six members of the National Academies—Buddy Ratner, James Anderson, Allan Hoffman, Art Coury, Cato Laurencin, and David Tirrell—were asked to propose a grand challenge to the audience that, if met, would significantly impact the future of biomaterials and medical devices. Successfully meeting these challenges will speed the 60-plus year transition from commodity, off-the-shelf biomaterials to bioengineered chemistries, and biomaterial devices that will significantly advance our ability to address patient needs and also to create new market opportunities. PMID:21171147

  19. Statistics Poster Challenge for Schools

    Science.gov (United States)

    Payne, Brad; Freeman, Jenny; Stillman, Eleanor

    2013-01-01

    The analysis and interpretation of data are important life skills. A poster challenge for schoolchildren provides an innovative outlet for these skills and demonstrates their relevance to daily life. We discuss our Statistics Poster Challenge and the lessons we have learned.

  20. [A clinical case of young, oral combined contraceptive using women, heterozygous carrier of the Factor V (Leiden) which revealed thrombosis of the left internal jugular vein and brain ischemia with cerebral infarction and ischemic stroke].

    Science.gov (United States)

    Kovachev, S; Ramshev, K; Ramsheva, Z; Ivanov, A; Ganovska, A

    2013-01-01

    Thrombophilia is associated with increased risks of venous thrombosis in women taking oral contraceptive preparations. Universal thrombophilia screening in women prior to prescribing oral contraceptive preparations is not supported by current evidence. The case is presented of a 23 year-old women with a personal history of interruption and on the same day started with oral contraceptive (0.03 microg ethynil estradiol - 0.075 microg gestodene), which due on a 18 pill/day to acute headache, increasing vomiting and speaking defects. Physical/neurologic/gynecologic examinations observed a normal status. The MRI and CT revealed thrombosis of the left internal jugular vein and brain ischemia with cerebral infarction and ischemic stroke. The acute therapy of thrombotic findings was accompanied with many tests. The thrombophilia PCR-Real time - test finds heterozygous carrier of the Factor V (Leiden). This case shows the need of large prospective studies that should be undertaken to refine the risks and establish the associations of thrombophilias with venous thrombosis among contraceptive users. The key to a prompt diagnosis is to know the risk factors. The relative value of a thrombophilia screening programme before contraceptive using needs to be established.

  1. Motor pathway excitability in ATP13A2 mutation carriers

    DEFF Research Database (Denmark)

    Zittel, S; Kroeger, J; van der Vegt, J P M

    2012-01-01

    OBJECTIVE: To describe excitability of motor pathways in Kufor-Rakeb syndrome (PARK9), an autosomal recessive nigro-striatal-pallidal-pyramidal neurodegeneration caused by a mutation in the ATP13A2 gene, using transcranial magnetic stimulation (TMS). METHODS: Five members of a Chilean family...... with an ATP13A2 mutation (one affected mutation carrier (MC) with a compound heterozygous mutation, 4 asymptomatic MC with a single heterozygous mutation) and 11 healthy subjects without mutations were studied. We measured motor evoked potentials (MEP), the contralateral silent period (cSP), short interval....... RESULTS: CSP duration was increased in the symptomatic ATP13A2 MC. The iSP measurements revealed increased interhemispheric inhibition in both the compound heterozygous and the heterozygous MC. CONCLUSION: A compound heterozygous mutation in the ATP13A2 gene is associated with increased intracortical...

  2. Estimating challenge load due to disease outbreaks and other challenges using reproduction records of sows.

    Science.gov (United States)

    Mathur, P K; Herrero-Medrano, J M; Alexandri, P; Knol, E F; ten Napel, J; Rashidi, H; Mulder, H A

    2014-12-01

    A method was developed and tested to estimate challenge load due to disease outbreaks and other challenges in sows using reproduction records. The method was based on reproduction records from a farm with known disease outbreaks. It was assumed that the reduction in weekly reproductive output within a farm is proportional to the magnitude of the challenge. As the challenge increases beyond certain threshold, it is manifested as an outbreak. The reproduction records were divided into 3 datasets. The first dataset called the Training dataset consisted of 57,135 reproduction records from 10,901 sows from 1 farm in Canada with several outbreaks of porcine reproductive and respiratory syndrome (PRRS). The known disease status of sows was regressed on the traits number born alive, number of losses as a combination of still birth and mummified piglets, and number of weaned piglets. The regression coefficients from this analysis were then used as weighting factors for derivation of an index measure called challenge load indicator. These weighting factors were derived with i) a two-step approach using residuals or year-week solutions estimated from a previous step, and ii) a single-step approach using the trait values directly. Two types of models were used for each approach: a logistic regression model and a general additive model. The estimates of challenge load indicator were then compared based on their ability to detect PRRS outbreaks in a Test dataset consisting of records from 65,826 sows from 15 farms in the Netherlands. These farms differed from the Canadian farm with respect to PRRS virus strains, severity and frequency of outbreaks. The single-step approach using a general additive model was best and detected 14 out of the 15 outbreaks. This approach was then further validated using the third dataset consisting of reproduction records of 831,855 sows in 431 farms located in different countries in Europe and America. A total of 41 out of 48 outbreaks detected

  3. Challenges in obesity research

    OpenAIRE

    Palou, Andreu; Bonet, M. Luisa

    2013-01-01

    Obesity is the main nutritional problem and one of the most important health problems in developed societies. Central to the challenge of obesity prevention and management is a thoroughly understanding of its determinants. Multiple socio-cultural, socio-economic, behavioural and biological factors -often interrelated and many of them still unknown or poorly understood- can contribute to the establishment and perpetuation of obese phenotypes. Here, we address current research challenges regard...

  4. Overcoming challenges

    Medline Plus

    Full Text Available ... Contact Us Blog Popular topics Vision and mission Leadership Programs and activities In your community Funding opportunities Internships and jobs View all pages in this section Home It's Only Natural Overcoming challenges It's Only Natural Planning ahead Addressing breastfeeding myths ...

  5. The challenge of sustainability

    International Nuclear Information System (INIS)

    Orr, D.W.

    1993-01-01

    This paper discusses sustainability in a world that has changed rapidly. The author suggests that ecological assumptions embedded in communism and capitalism are badly flawed, but the flaws were not apparent when there were fewer than a billion people on earth living at low technology levels. Sustaining the earth's vital signs is a challenge to our perception of time, and the numbers - population, environmental damage, oil consumption, waste disposal - are too large to comprehend easily. There is a global debate about what sustainability means. In fact the challenge of sustainability is 6 different challenges: overcoming the tendency to deny inconvenient realities; establishing accurate indicators of human and ecological health; questions about the kinds of technology necessary to make the transition to sustainability; education; the need for an emotional bond between man and nature; rebuilding the existing democratic institutions. 16 refs

  6. Global challenges in energy

    International Nuclear Information System (INIS)

    Dorian, James P.; Franssen, Herman T.; Simbeck, Dale R. MD

    2006-01-01

    Environmental and security concerns are stimulating global interest in hydrogen power, renewable energy, and advanced transportation technologies, but no significant movement away from oil and a carbon-based world economy is expected soon. Over the longer-term, however, a transition from fossil fuels to a non-carbon-based economy will likely occur, affecting the type of environment future generations may encounter. Key challenges will face the world's energy industry over the next few decades to ensure a smooth transition-challenges which will require government and industry solutions beginning as early as today. This paper identifies four critical challenges in energy and the choices which will have to be made on how best to confront growing pollution caused by fossil fuels and how to facilitate an eventual revolutionary-like transition to a non-carbon-based global economy

  7. Exploring the challenges faced by polytechnic students

    Science.gov (United States)

    Matore, Mohd Effendi @ Ewan Mohd; Khairani, Ahmad Zamri

    2015-02-01

    This study aims to identify other challenges besides those already faced by students, in seven polytechnics in Malaysia as a continuation to the previous research that had identified 52 main challenges faced by students using the Rasch Model. The explorative study focuses on the challenges that are not included in the Mooney Problem Checklist (MPCL). A total of 121 polytechnic students submitted 183 written responses through the open questions provided. Two hundred fifty two students had responded from a students' perspective on the dichotomous questions regarding their view on the challenges faced. The data was analysed qualitatively using the NVivo 8.0. The findings showed that students from Politeknik Seberang Perai (PSP) gave the highest response, which was 56 (30.6%) and Politeknik Metro Kuala Lumpur (PMKL) had the lowest response of 2 (1.09%). Five dominant challenges were identified, which were the English language (32, 17.5%), learning (14, 7.7%), vehicles (13, 7.1%), information technology and communication (ICT) (13, 7.1%), and peers (11, 6.0%). This article, however, focus on three apparent challenges, namely, English language, vehicles, as well as computer and ICT, as the challenges of learning and peers had been analysed in the previous MPCL. The challenge of English language that had been raised was regarding the weakness in commanding the aspects of speech and fluency. The computer and ICT challenge covered the weakness in mastering ICT and computers, as well as computer breakdowns and low-performance computers. The challenge of vehicles emphasized the unavailability of vehicles to attend lectures and go elsewhere, lack of transportation service in the polytechnic and not having a valid driving license. These challenges are very relevant and need to be discussed in an effort to prepare polytechnics in facing the transformational process of polytechnics.

  8. Five challenges for public administrations in Europe

    Directory of Open Access Journals (Sweden)

    Ongaro Edoardo

    2015-12-01

    Full Text Available This article examines five ‘challenges’ facing most administrative systems across Europe. The first challenge stems from the increasingly asymmetric nature of European multilevel governance; the second challenge arises from the missed opportunity of reforming in the absence of a dominant administrative paradigm; the third challenge lies in rescuing and transforming the welfare state; the fourth challenge is concerned with making the most of the knowledge generated in the field of strategic management for strategically managing public services; the fifth challenge lies in staff (demotivation. These challenges are pitched at very different levels: some are related to issues of public governance, some to issues of scholarly and practitioners’ collective understandings of public administration in Europe, and some to trends in the global economy, and notably the financial, economic and fiscal ‘crises’.

  9. They rose to the challenge!

    CERN Multimedia

    Anaïs Schaeffer

    2015-01-01

    The Challenge-Based Innovation programme is a Masters-level initiative developed at CERN in collaboration with many universities around the world. The first programme saw 45 students take part, and their final results were presented at an official "gala" held on 26 February.   On 26 February, after their official presentations, the six CBI teams presented their prototypes to the public in the IdeaSquare building.   As part of the IdeaSquare project, the Challenge-Based Innovation (CBI) programme is based on a very pragmatic question: can the tools and results produced by basic research (like that being carried out at CERN) be used to solve societal problems? If so, how? To answer this question, 45 students from very different professional and cultural backgrounds formed six teams, each with a specific societal challenge to solve (see here). Over a six-month period – from September 2014 to February 2015 – the six teams worked on the challenge in o...

  10. Software challenges in extreme scale systems

    International Nuclear Information System (INIS)

    Sarkar, Vivek; Harrod, William; Snavely, Allan E

    2009-01-01

    Computer systems anticipated in the 2015 - 2020 timeframe are referred to as Extreme Scale because they will be built using massive multi-core processors with 100's of cores per chip. The largest capability Extreme Scale system is expected to deliver Exascale performance of the order of 10 18 operations per second. These systems pose new critical challenges for software in the areas of concurrency, energy efficiency and resiliency. In this paper, we discuss the implications of the concurrency and energy efficiency challenges on future software for Extreme Scale Systems. From an application viewpoint, the concurrency and energy challenges boil down to the ability to express and manage parallelism and locality by exploring a range of strong scaling and new-era weak scaling techniques. For expressing parallelism and locality, the key challenges are the ability to expose all of the intrinsic parallelism and locality in a programming model, while ensuring that this expression of parallelism and locality is portable across a range of systems. For managing parallelism and locality, the OS-related challenges include parallel scalability, spatial partitioning of OS and application functionality, direct hardware access for inter-processor communication, and asynchronous rather than interrupt-driven events, which are accompanied by runtime system challenges for scheduling, synchronization, memory management, communication, performance monitoring, and power management. We conclude by discussing the importance of software-hardware co-design in addressing the fundamental challenges for application enablement on Extreme Scale systems.

  11. Heterozygous truncation mutations of the SMC1A gene cause a severe early onset epilepsy with cluster seizures in females: Detailed phenotyping of 10 new cases.

    Science.gov (United States)

    Symonds, Joseph D; Joss, Shelagh; Metcalfe, Kay A; Somarathi, Suresh; Cruden, Jamie; Devlin, Anita M; Donaldson, Alan; DiDonato, Nataliya; Fitzpatrick, David; Kaiser, Frank J; Lampe, Anne K; Lees, Melissa M; McLellan, Ailsa; Montgomery, Tara; Mundada, Vivek; Nairn, Lesley; Sarkar, Ajoy; Schallner, Jens; Pozojevic, Jelena; Parenti, Ilaria; Tan, Jeen; Turnpenny, Peter; Whitehouse, William P; Zuberi, Sameer M

    2017-04-01

    The phenotype of seizure clustering with febrile illnesses in infancy/early childhood is well recognized. To date the only genetic epilepsy consistently associated with this phenotype is PCDH19, an X-linked disorder restricted to females, and males with mosaicism. The SMC1A gene, which encodes a structural component of the cohesin complex is also located on the X chromosome. Missense variants and small in-frame deletions of SMC1A cause approximately 5% of Cornelia de Lange Syndrome (CdLS). Recently, protein truncating mutations in SMC1A have been reported in five females, all of whom have been affected by a drug-resistant epilepsy, and severe developmental impairment. Our objective was to further delineate the phenotype of SMC1A truncation. Female cases with de novo truncation mutations in SMC1A were identified from the Deciphering Developmental Disorders (DDD) study (n = 8), from postmortem testing of an affected twin (n = 1), and from clinical testing with an epilepsy gene panel (n = 1). Detailed information on the phenotype in each case was obtained. Ten cases with heterozygous de novo mutations in the SMC1A gene are presented. All 10 mutations identified are predicted to result in premature truncation of the SMC1A protein. All cases are female, and none had a clinical diagnosis of CdLS. They presented with onset of epileptic seizures between <4 weeks and 28 months of age. In the majority of cases, a marked preponderance for seizures to occur in clusters was noted. Seizure clusters were associated with developmental regression. Moderate or severe developmental impairment was apparent in all cases. Truncation mutations in SMC1A cause a severe epilepsy phenotype with cluster seizures in females. These mutations are likely to be nonviable in males. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

  12. Challenges Facing Group Work Online

    Science.gov (United States)

    Chang, Bo; Kang, Haijun

    2016-01-01

    Online group work can be complicated because of its asynchronous characteristics and lack of physical presence, and its requirements for skills in handling technology, human relationships, and content-related tasks. This study focuses on the administrative, logistical and relationship-related challenges in online group work. Challenges in areas…

  13. ITER safety challenges and opportunities

    International Nuclear Information System (INIS)

    Piet, S.J.

    1991-01-01

    Results of the Conceptual Design Activity (CDA) for the International Thermonuclear Experimental Reactor (ITER) suggest challenges and opportunities. ''ITER is capable of meeting anticipated regulatory dose limits,'' but proof is difficult because of large radioactive inventories needing stringent radioactivity confinement. We need much research and development (R ampersand D) and design analysis to establish that ITER meets regulatory requirements. We have a further opportunity to do more to prove more of fusion's potential safety and environmental advantages and maximize the amount of ITER technology on the path toward fusion power plants. To fulfill these tasks, we need to overcome three programmatic challenges and three technical challenges. The first programmatic challenge is to fund a comprehensive safety and environmental ITER R ampersand D plan. Second is to strengthen safety and environment work and personnel in the international team. Third is to establish an external consultant group to advise the ITER Joint Team on designing ITER to meet safety requirements for siting by any of the Parties. The first of the three key technical challenges is plasma engineering -- burn control, plasma shutdown, disruptions, tritium burn fraction, and steady state operation. The second is the divertor, including tritium inventory, activation hazards, chemical reactions, and coolant disturbances. The third technical challenge is optimization of design requirements considering safety risk, technical risk, and cost. Some design requirements are now too strict; some are too lax. Fuel cycle design requirements are presently too strict, mandating inappropriate T separation from H and D. Heat sink requirements are presently too lax; they should be strengthened to ensure that maximum loss of coolant accident temperatures drop

  14. Seven challenges for neuroscience.

    Science.gov (United States)

    Markram, Henry

    2013-01-01

    Although twenty-first century neuroscience is a major scientific enterprise, advances in basic research have not yet translated into benefits for society. In this paper, I outline seven fundamental challenges that need to be overcome. First, neuroscience has to become "big science" - we need big teams with the resources and competences to tackle the big problems. Second, we need to create interlinked sets of data providing a complete picture of single areas of the brain at their different levels of organization with "rungs" linking the descriptions for humans and other species. Such "data ladders" will help us to meet the third challenge - the development of efficient predictive tools, enabling us to drastically increase the information we can extract from expensive experiments. The fourth challenge goes one step further: we have to develop novel hardware and software sufficiently powerful to simulate the brain. In the future, supercomputer-based brain simulation will enable us to make in silico manipulations and recordings, which are currently completely impossible in the lab. The fifth and sixth challenges are translational. On the one hand we need to develop new ways of classifying and simulating brain disease, leading to better diagnosis and more effective drug discovery. On the other, we have to exploit our knowledge to build new brain-inspired technologies, with potentially huge benefits for industry and for society. This leads to the seventh challenge. Neuroscience can indeed deliver huge benefits but we have to be aware of widespread social concern about our work. We need to recognize the fears that exist, lay them to rest, and actively build public support for neuroscience research. We have to set goals for ourselves that the public can recognize and share. And then we have to deliver on our promises. Only in this way, will we receive the support and funding we need.

  15. Why employees with higher challenging appraisals style are more affectively engaged at work? The role of challenging stressors: a moderated mediation model.

    Science.gov (United States)

    Lin, Shin-Huei; Wu, Chia-Huei; Chen, Mei-Yen; Chen, Lung Hung

    2014-10-01

    Challenging stressors have been positively linked to various work outcomes. However, the role of individual differences in stress appraisal in shaping the function of challenging stressors and work outcomes has been rarely discussed. Drawing on the individual differences perspective, the authors propose that employees higher in challenge appraisal are more likely to have challenging stressors and are more responsive to such stressors to have a higher positive affect at work. Results obtained from 117 employees supported the hypotheses. The results indicated that challenge appraisal is positively related to challenging stressors. In addition, challenging stressors has a positive association with positive affect at work when challenge appraisal is high but has a null association when challenge appraisal is low. The findings suggest that challenging stressors does not necessarily bring positive work outcomes as suggested in past studies and highlight the importance of considering dispositional tendency in stress appraisal when looking into the function of challenging stressors and work outcomes. © 2014 International Union of Psychological Science.

  16. Eight challenges in phylodynamic inference

    Directory of Open Access Journals (Sweden)

    Simon D.W. Frost

    2015-03-01

    Full Text Available The field of phylodynamics, which attempts to enhance our understanding of infectious disease dynamics using pathogen phylogenies, has made great strides in the past decade. Basic epidemiological and evolutionary models are now well characterized with inferential frameworks in place. However, significant challenges remain in extending phylodynamic inference to more complex systems. These challenges include accounting for evolutionary complexities such as changing mutation rates, selection, reassortment, and recombination, as well as epidemiological complexities such as stochastic population dynamics, host population structure, and different patterns at the within-host and between-host scales. An additional challenge exists in making efficient inferences from an ever increasing corpus of sequence data.

  17. Overcoming challenges

    Medline Plus

    Full Text Available ... we are What we do Programs and activities Work with us Contact Us Blog Popular topics Vision and mission Leadership Programs and activities In your community Funding opportunities Internships and jobs View all pages in this section Home It's Only Natural Overcoming challenges It's Only Natural ...

  18. ITER safety challenges and opportunities

    International Nuclear Information System (INIS)

    Piet, S.J.

    1992-01-01

    This paper reports on results of the Conceptual Design Activity (CDA) for the International Thermonuclear Experimental Reactor (ITER) suggest challenges and opportunities. ITER is capable of meeting anticipated regulatory dose limits, but proof is difficult because of large radioactive inventories needing stringent radioactivity confinement. Much research and development (R ampersand D) and design analysis is needed to establish that ITER meets regulatory requirements. There is a further oportunity to do more to prove more of fusion's potential safety and environmental advantages and maximize the amount of ITER technology on the path toward fusion power plants. To fulfill these tasks, three programmatic challenges and three technical challenges must be overcome. The first step is to fund a comprehensive safety and environmental ITER R ampersand D plan. Second is to strengthen safety and environment work and personnel in the international team. Third is to establish an external consultant group to advise the ITER Joint Team on designing ITER to meet safety requirements for siting by any of the Parties. The first of three key technical challenges is plasma engineering - burn control, plasma shutdown, disruptions, tritium burn fraction, and steady state operation. The second is the divertor, including tritium inventory, activation hazards, chemical reactions, and coolant disturbances. The third technical challenge is optimization of design requirements considering safety risk, technical risk, and cost

  19. Challenging experiences: gender differences in task choice

    NARCIS (Netherlands)

    de Pater, I.E.; van Vianen, A.E.M.; Fischer, A.H.; van Ginkel, W.P.

    2009-01-01

    Purpose - The purpose of this paper is to examine: gender differences in the choice to perform challenging tasks, gender differences in the actual performance of challenging tasks, and the impact of challenging experiences on supervisors' evaluations of individuals' potential for career advancement.

  20. How does global biogeochemical cycle become complicated by terrestrial-aquatic interactions ?

    Science.gov (United States)

    Nakayama, Tadanobu; Maksyutov, Shamil

    2015-04-01

    Inland water such as river and lake are now known to be important and active components of global carbon cycle though its contribution has remained uncertain due to data scarcity (Battin et al., 2009; Aufdenkampe et al., 2011). The author has developed process-based National Integrated Catchment-based Eco-hydrology (NICE) model (Nakayama, 2008a-b, 2010, 2011a-b, 2012a-c, 2013; Nakayama and Fujita, 2010; Nakayama and Hashimoto, 2011; Nakayama and Shankman, 2013a-b; Nakayama and Watanabe, 2004, 2006, 2008a-b; Nakayama et al., 2006, 2007, 2010, 2012), which incorporates surface-groundwater interactions, includes up- and down-scaling processes between local-global scales, and can simulate iteratively nonlinear feedback between hydrologic, geomorphic, and ecological processes. In this study, NICE was coupled with various biogeochemical models to incorporate biogeochemical cycle including reaction between inorganic and organic carbons (DOC, POC, DIC, pCO2, etc.) in terrestrial and aquatic ecosystems including surface water and groundwater. The coupled model simulated CO2 evasion from inland water in global scale, was relatively in good agreement in that estimated by empirical regression model (Raymond et al., 2013). In particular, the simulated result implied importance of connectivity between terrestrial and aquatic ecosystems in addition to surface and groundwater, and hillslopes and stream channels, etc. The model further improved the accuracy of CH4 flux in wetland which is sensitive to fluctuations of shallow groundwater because the original NICE incorporates 3-D groundwater sub-model and simulates lateral subsurface flow more reasonably. This simulation system would play important role in integration of greenhouse gas budget of the biosphere, quantification of hot spots in boundless biogeochemical cycle, and bridging gap between top-down and bottom-up approaches (Cole et al., 2007; Frei et al., 2012; Kiel and Cardenas, 2014). References; Aufdenkampe, A.K., et al

  1. Millennium Challenge Account

    National Research Council Canada - National Science Library

    Tarnoff, Curt

    2008-01-01

    .... foreign aid initiative. The Millennium Challenge Account (MCA) provides assistance through a competitive selection process to developing nations that are pursing political and economic reforms in three areas...

  2. Challenging Identities

    DEFF Research Database (Denmark)

    depends on the conceptual or ideological constellation in which it takes part. This volume on one hand demonstrates the role of notions of identity in a variety of European contexts, and on the other hand highlights how there may be reasons to challenge the use of the term and corresponding social...

  3. Circuit-Adaptive Challenge Balancing in Racing Games

    NARCIS (Netherlands)

    Rietveld, A.; Bakkes, S.; Roijers, D.

    2014-01-01

    In this paper, we propose a novel approach to challenge balancing in racing games: circuit-adaptive challenge balancing. We propose to automatically adapt the actual racing circuit - while it is being played - such that the performed circuit adaptations intelligently balance the challenge for all

  4. Educational Leadership: Key Challenges and Ethical Tensions

    Science.gov (United States)

    Duignan, Patrick

    2007-01-01

    "Educational Leadership" is a major research book on contemporary leadership challenges for educational leaders. In this groundbreaking new work, educational leaders in schools, including teachers, are provided with ways of analysing and resolving common but complex leadership challenges. Ethical tensions inherent in these challenges are…

  5. 'Blue Whale Challenge': A Game or Crime?

    Science.gov (United States)

    Mukhra, Richa; Baryah, Neha; Krishan, Kewal; Kanchan, Tanuj

    2017-11-11

    A bewildering range of games are emerging every other day with newer elements of fun and entertainment to woo youngsters. Games are meant to reduce stress and enhance the cognitive development of children as well as adults. Teenagers are always curious to indulge in newer games; and e-gaming is one such platform providing an easy access and quicker means of entertainment. The particular game challenge which has taken the world by storm is the dangerous "Blue Whale Challenge" often involving vulnerable teenagers. The Blue Whale Challenge is neither an application nor internet based game but the users get a link through social media chat groups to enter this "deadly" challenge game. This probably is the only game where the participant has to end his/her life to complete the game. The innocent teenagers are being targeted based on their depressed psychology and are coercively isolated from their social milieux on the pretext of keeping the challenges confidential. To add to the woes, no option is offered to quit the challenge even if the contender is unable to complete the challenge. Blue Whale Challenge in its sheer form could be seen as an illegal, unethical and inhumane endeavor in our present society. The present communication discusses the severe effects of the game on teenagers, the ethical concerns involved and the preventive measures necessary to curb it.

  6. The Challenge of the Deanship.

    Science.gov (United States)

    Montez, Joni; Wolverton, Mimi

    This paper addresses the evolution of the kinds of challenges that deans have met over time and examines perceptions of today's deans concerning their ability to deal effectively with current challenges. A sample of deans (n=695) in the colleges of education, business, liberal arts, and nursing at 360 public and private institutions was surveyed…

  7. Anticipating flow assurance challenges through geochemistry

    Energy Technology Data Exchange (ETDEWEB)

    Flannery, M. [Fluid Evaluation and Sampling Technologies (FEAST) Team, Shell International Exploration and Production (United Kingdom)

    2008-07-01

    The behaviour of reservoir fluids pose a challenge at all stages of petroleum production, from the reservoir to refinery. The challenges sometimes stem from sub-optimal operations or inappropriate system design, with assumptions of similar fluid properties across the field. Hydrocarbon fluid phase behaviour is the product of local PVT conditions and the geochemical identity of the fluids. An appropriate development scenario along with anticipation of production challenges, can benefit from early integration of engineering and geochemical understanding of hydrocarbon fluids. This paper presented field examples of how the kerogen type and maturity, and later post-generation alteration processes such as biodegradation, water washing, TSR can influence likely flow assurance challenges in the production stream. The confounding issues of multiple charges and overlaying signatures were also discussed.

  8. Monitoring challenges and innovative ideas

    Energy Technology Data Exchange (ETDEWEB)

    O' Neill, R.V.; Hunsaker, C.T.; Levine, D.A.

    1990-01-01

    Monitoring programs are difficult to design even when they focus on specific problems. Ecosystems are complex, and it is often impossible to predetermine what aspects of system structure or dynamics will respond to a specific insult. It is equally difficult to interpret whether a response is a stabilizing compensatory mechanism or a real loss of capacity to maintain the ecosystem. The problems are compounded in a broad monitoring program designed to assess ecosystem health'' at regional and continental scales. It is challenging in the extreme to monitor ecosystem response, at any scale, to past insults as well as an unknown future array of impacts. The present paper will examine some of the fundamental issues and challenges raised by large-scale monitoring efforts. The challenges will serve as a framework and as an excuse to discuss several important topics in more detail. Following the discussion of challenges, we suggest some basic innovations that could be important across a range of monitoring programs. The innovations include integrative measures, innovative methodology, and creative interpretation. 59 refs., 1 tab.

  9. Next Generation Innovation Policy and Grand Challenges

    NARCIS (Netherlands)

    Kuhlmann, Stefan; Rip, Arie

    2018-01-01

    The paper explores transformative ways to address Grand Challenges, while locating them in a broader diagnosis of ongoing changes. Coping with Grand Challenges is a challenge in its own right, for policy as well as for science, technology, and innovation actors. The paper presents building blocks

  10. Community Challenge Grantees

    Data.gov (United States)

    Department of Housing and Urban Development — HUD's Community Challenge Grants aim to reform and reduce barriers to achieving affordable, economically vital and sustainable communities. The funds are awarded to...

  11. IT Challenges for Space Medicine

    Science.gov (United States)

    Johnson-Throop, Kathy

    2010-01-01

    This viewgraph presentation reviews the various Information Technology challenges for aerospace medicine. The contents include: 1) Space Medicine Activities; 2) Private Medical Information; 3) Lifetime Surveillance of Astronaut Health; 4) Mission Medical Support; 5) Data Repositories for Research; 6) Data Input and Output; 7) Finding Data/Information; 8) Summary of Challenges; and 9) Solutions and questions.

  12. Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1

    Directory of Open Access Journals (Sweden)

    Ullmann Reinhard

    2011-08-01

    Full Text Available Abstract Background Heterozygous copy-number and missense variants in CNTNAP2 and NRXN1 have repeatedly been associated with a wide spectrum of neuropsychiatric disorders such as developmental language and autism spectrum disorders, epilepsy and schizophrenia. Recently, homozygous or compound heterozygous defects in either gene were reported as causative for severe intellectual disability. Methods 99 patients with severe intellectual disability and resemblance to Pitt-Hopkins syndrome and/or suspected recessive inheritance were screened for mutations in CNTNAP2 and NRXN1. Molecular karyotyping was performed in 45 patients. In 8 further patients with variable intellectual disability and heterozygous deletions in either CNTNAP2 or NRXN1, the remaining allele was sequenced. Results By molecular karyotyping and mutational screening of CNTNAP2 and NRXN1 in a group of severely intellectually disabled patients we identified a heterozygous deletion in NRXN1 in one patient and heterozygous splice-site, frameshift and stop mutations in CNTNAP2 in four patients, respectively. Neither in these patients nor in eight further patients with heterozygous deletions within NRXN1 or CNTNAP2 we could identify a defect on the second allele. One deletion in NRXN1 and one deletion in CNTNAP2 occurred de novo, in another family the deletion was also identified in the mother who had learning difficulties, and in all other tested families one parent was shown to be healthy carrier of the respective deletion or mutation. Conclusions We report on patients with heterozygous defects in CNTNAP2 or NRXN1 associated with severe intellectual disability, which has only been reported for recessive defects before. These results expand the spectrum of phenotypic severity in patients with heterozygous defects in either gene. The large variability between severely affected patients and mildly affected or asymptomatic carrier parents might suggest the presence of a second hit, not

  13. Challenges of Collaborative Product Styling in Design Teams

    DEFF Research Database (Denmark)

    Ovesen, Nis

    2016-01-01

    Apart from a long list of advantages, design students face certain challenges when working collectively in groups on form, styling and aesthetics. An investigation about these challenges has been carried out and a number of challenges have been identified. The most apparent challenges relate to d...... to different aesthetic preferences, lack of tools and methods, and difficulties in establishing form related requirements. The challenges are presented and design quality, as well as some solution strategies, is discussed....

  14. Space Robotics Challenge

    Data.gov (United States)

    National Aeronautics and Space Administration — The Space Robotics Challenge seeks to infuse robot autonomy from the best and brightest research groups in the robotics community into NASA robots for future...

  15. Ecological Challenges for Closed Systems

    Science.gov (United States)

    Nelson, Mark; Dempster, William; Allen, John P.

    2012-07-01

    Closed ecological systems are desirable for a number of purposes. In space life support systems, material closure allows precious life-supporting resources to be kept inside and recycled. Closure in small biospheric systems facilitates detailed measurement of global ecological processes and biogeochemical cycles. Closed testbeds facilitate research topics which require isolation from the outside (e.g. genetically modified organisms; radioisotopes) so their ecological interactions and fluxes can be studied separate from interactions with the outside environment. But to achieve and maintain closure entails solving complex ecological challenges. These challenges include being able to handle faster cycling rates and accentuated daily and seasonal fluxes of critical life elements such as carbon dioxide, oxygen, water, macro- and mico-nutrients. The problems of achieving sustainability in closed systems for life support include how to handle atmospheric dynamics including trace gases, producing a complete human diet and recycling nutrients and maintaining soil fertility, the sustaining of healthy air and water and preventing the loss of crucial elements from active circulation. In biospheric facilities the challenge is also to produce analogues to natural biomes and ecosystems, studying processes of self-organization and adaptation in systems that allow specification or determination of state variables and cycles which may be followed through all interactions from atmosphere to soils. Other challenges include the dynamics and genetics of small populations, the psychological challenges for small isolated human groups and measures and options which may be necessary to ensure long-term operation of closed ecological systems.

  16. Globalisation and international compatibility - a challenge to ...

    African Journals Online (AJOL)

    The contexts of institutions for higher education are in flux with consequent learning challenges. One of these challenges is that of globalisation and the need for international compatibility. Another challenge is that Mode 2 learning programmes, material and methods need to be relevant to the specific context in which they ...

  17. Mechatronic Design - Still a Considerable Challenge

    DEFF Research Database (Denmark)

    Torry-Smith, Jonas; Qamar, Ahsan; Achiche, Sofiane

    2011-01-01

    Development of mechatronic products is traditionally carried out by several design experts from different design domains. Performing development of mechatronic products is thus greatly challenging. In order to tackle this, the critical challenges in mechatronics have to be well understood and well...... supported through applicable methods and tools. This paper aims at identifying the major challenges, by conducting a survey of the most relevant research work in mechatronic design. Solutions proposed in literature are assessed and illustrated through a case study in order to investigate, if the challenges...... can be handled appropriately by the methods, tools, and mindsets suggested by the mechatronic community. Using a real world mechatronics case, the paper identifies the areas where further research is required, by showing a clear connection between the actual problems faced during the design task...

  18. The challenge of conceiving

    DEFF Research Database (Denmark)

    Hansen, Claus Thorp; Jørgensen, Ulrik

    2011-01-01

    the perspective of engineering design challenges where the need for problem identification is obvious to avoid the pitfall to reproduce and piecemeal engineer already existing product or service concepts. Problem identification is not a simple desk research task as it often involves a multitude of actors having......One of the big challenges in the CDIO approach to engineering education is the first part focusing on conceiving problems to be handled and eventually solved. Traditional engineering education has been dominated by its focus on technical disciplines emphasising their individual tool box of problem...

  19. Challenges facing production grids

    Energy Technology Data Exchange (ETDEWEB)

    Pordes, Ruth; /Fermilab

    2007-06-01

    Today's global communities of users expect quality of service from distributed Grid systems equivalent to that their local data centers. This must be coupled to ubiquitous access to the ensemble of processing and storage resources across multiple Grid infrastructures. We are still facing significant challenges in meeting these expectations, especially in the underlying security, a sustainable and successful economic model, and smoothing the boundaries between administrative and technical domains. Using the Open Science Grid as an example, I examine the status and challenges of Grids operating in production today.

  20. Meeting the Challenge of Crohn's Disease

    Science.gov (United States)

    ... page please turn JavaScript on. Feature: Crohn's Disease Meeting the Challenge of Crohn's Disease Past Issues / Winter ... Living with Crohn's Disease / What Is Crohn's Disease / Meeting the Challenge of Crohn's Disease Winter 2016 Issue: ...

  1. Patients who challenge.

    Science.gov (United States)

    Ward, Michael; Savulescu, Julian

    2006-12-01

    Individuals have different values. They seek to express their individuality even when receiving medical care. It is a part of modern medical practice and respect for patient autonomy to show respect for different values. We give an account of what it means to respect different values and challenging patients in medical practice. Challenging choices are often choices which are perceived by many to be either irrational or against a person's interests, such as engaging in harmful or excessively risky activities. When the medical profession is involved in such choices, the basic medical principle of acting in a person's best interests is challenged. Often doctors refuse to respect controversial choices on paternalistic grounds. We should all respect and facilitate the controversial choices of competent individuals, subject to resource limitations, our own and others well-being and autonomy, and the public interest. But more importantly, sometimes such choices make for a better, more autonomous life. Sometimes, such choices reflect considerations of global well-being or altruism, or idiosyncratic attitudes to risk. Sometimes, they reflect unusual values. However, in some other cases, controversial choices are irrational and are not expressions of our autonomy. Doctors should assist patients to make rational if individual choices. The patient also bears the responsibility for bringing his beliefs to the attention of the clinician.

  2. Heterozygosity-based assortative mating in blue tits (Cyanistes caeruleus): implications for the evolution of mate choice

    Science.gov (United States)

    García-Navas, Vicente; Ortego, Joaquín; Sanz, Juan José

    2009-01-01

    The general hypothesis of mate choice based on non-additive genetic traits suggests that individuals would gain important benefits by choosing genetically dissimilar mates (compatible mate hypothesis) and/or more heterozygous mates (heterozygous mate hypothesis). In this study, we test these hypotheses in a socially monogamous bird, the blue tit (Cyanistes caeruleus). We found no evidence for a relatedness-based mating pattern, but heterozygosity was positively correlated between social mates, suggesting that blue tits may base their mating preferences on partner's heterozygosity. We found evidence that the observed heterozygosity-based assortative mating could be maintained by both direct and indirect benefits. Heterozygosity reflected individual quality in both sexes: egg production and quality increased with female heterozygosity while more heterozygous males showed higher feeding rates during the brood-rearing period. Further, estimated offspring heterozygosity correlated with both paternal and maternal heterozygosity, suggesting that mating with heterozygous individuals can increase offspring genetic quality. Finally, plumage crown coloration was associated with male heterozygosity, and this could explain unanimous mate preferences for highly heterozygous and more ornamented individuals. Overall, this study suggests that non-additive genetic traits may play an important role in the evolution of mating preferences and offers empirical support to the resolution of the lek paradox from the perspective of the heterozygous mate hypothesis. PMID:19474042

  3. The Terawatt Challenge

    Science.gov (United States)

    Haegel, Nancy

    In response to concerns about accelerating climate change, the world is uniting to both envision and enable a global energy system that supports a sustainable environment and broad economic prosperity. Growth in the technology and the deployment of renewable energy has been dramatic. Evidence can be seen in the growth of photovoltaics (PV) and wind as contributors to worldwide electricity production over the last decade. PV and wind provided 1.2% and 3.7% of global electricity production in 2015, compared to 0.1% and 1.3% respectively in 2005. These numbers indicate both the rapid increase in the rate of deployment, as well as the remaining work to be done to extend this trend to transform a massive energy system and provide a significant fraction of the world's future energy demand with renewable energy. Based on recent trends, it is highly likely that global cumulative PV installation will reach terawatt scale in the next few decades. The challenges, as well as the resulting impact, vary greatly depending on whether we envision 1 TW ( 15% of 2015 global electricity capacity), 3 TW ( 50% of 2015 global electricity capacity) or 10 TW, a level that could drive electrification of transportation and industrial sectors and production of solar fuels. This presentation will draw upon the work of the 2016 GA-SERI (Global Alliance of Solar Energy Research Institutes) Terawatt Workshop to assess the feasibility and summarize the challenges for PV as a primary energy source. These challenges include the continuing demand for improved efficiency and reliability, the required magnitude of capital expenditure, the need for a sustainable industry (both financially and environmentally), as well as needs for grid modernization and consistent policies that support global climate goals. Physicists can play important roles in addressing this full range of challenges, from materials science to public policy, as well as in education of the public and its future leaders.

  4. How do challenges increase customer loyalty to online games?

    Science.gov (United States)

    Teng, Ching-I

    2013-12-01

    Despite the design of various challenge levels in online games, exactly how these challenges increase customer loyalty to online games has seldom been examined. This study investigates how such challenges increase customer loyalty to online games. The study sample comprises 2,861 online gamers. Structural equation modeling is performed. Analytical results indicate that the relationship between challenge and loyalty intensifies when customers perceive that overcoming challenges takes a long time. Results of this study contribute to efforts to determine how challenges and challenge-related perceptions impact customer loyalty to online games.

  5. Neonatal High Bone Mass With First Mutation of the NF-κB Complex: Heterozygous De Novo Missense (p.Asp512Ser) RELA (Rela/p65).

    Science.gov (United States)

    Frederiksen, Anja L; Larsen, Martin J; Brusgaard, Klaus; Novack, Deborah V; Knudsen, Peter Juel Thiis; Schrøder, Henrik Daa; Qiu, Weimin; Eckhardt, Christina; McAlister, William H; Kassem, Moustapha; Mumm, Steven; Frost, Morten; Whyte, Michael P

    2016-01-01

    Heritable disorders that feature high bone mass (HBM) are rare. The etiology is typically a mutation(s) within a gene that regulates the differentiation and function of osteoblasts (OBs) or osteoclasts (OCs). Nevertheless, the molecular basis is unknown for approximately one-fifth of such entities. NF-κB signaling is a key regulator of bone remodeling and acts by enhancing OC survival while impairing OB maturation and function. The NF-κB transcription complex comprises five subunits. In mice, deletion of the p50 and p52 subunits together causes osteopetrosis (OPT). In humans, however, mutations within the genes that encode the NF-κB complex, including the Rela/p65 subunit, have not been reported. We describe a neonate who died suddenly and unexpectedly and was found at postmortem to have HBM documented radiographically and by skeletal histopathology. Serum was not available for study. Radiographic changes resembled malignant OPT, but histopathological investigation showed morphologically normal OCs and evidence of intact bone resorption excluding OPT. Furthermore, mutation analysis was negative for eight genes associated with OPT or HBM. Instead, accelerated bone formation appeared to account for the HBM. Subsequently, trio-based whole exome sequencing revealed a heterozygous de novo missense mutation (c.1534_1535delinsAG, p.Asp512Ser) in exon 11 of RELA encoding Rela/p65. The mutation was then verified using bidirectional Sanger sequencing. Lipopolysaccharide stimulation of patient fibroblasts elicited impaired NF-κB responses compared with healthy control fibroblasts. Five unrelated patients with unexplained HBM did not show a RELA defect. Ours is apparently the first report of a mutation within the NF-κB complex in humans. The missense change is associated with neonatal osteosclerosis from in utero increased OB function rather than failed OC action. These findings demonstrate the importance of the Rela/p65 subunit within the NF-κB pathway for human

  6. Managing voluntary turnover through challenging assignments

    NARCIS (Netherlands)

    Preenen, P.T.Y.; de Pater, I.E.; van Vianen, A.E.M.; Keijzer, L.

    2011-01-01

    This study examines employees’ challenging assignments as manageable means to reduce turnover intentions, job search behaviors, and voluntary turnover. Results indicate that challenging assignments are negatively related to turnover intentions and job search behaviors and that these relationships

  7. Managing voluntary turnover through challenging assignments

    NARCIS (Netherlands)

    Preenen, P.T.Y.; Pater, I.E. de; Vianen, A.E.M. van; Keijzer, L.

    2011-01-01

    This study examines employees' challenging assignments as manageable means to reduce turnover intentions, job search behaviors, and voluntary turnover. Results indicate that challenging assignments are negatively related to turnover intentions and job search behaviors and that these relationships

  8. Introducing "optimal challenges" in resident training

    DEFF Research Database (Denmark)

    Sørensen, Anette Bagger; Christensen, Mette Krogh

    Background: Residents are often caught between two interests: the resident’s desire to participate in challenging learning situations and the department’s work planning. However, these interests may clash if they are not coordinated by the senior doctors, and challenging learning situations risk...... that the residents benefit from the intervention because they experienced more optimal challenges than before the intervention. However, the matching of resident and case seems to work against the established culture in the department: The daily work has for many years been organized so that senior doctors have...... their “own” patients and they do not “share” patients with residents. Thus the patients were accustomed to have their “own” specialist doctor. Conclusion: The intervention generated optimal challenges, but revealed the need for more team-based organization of senior doctors and residents’ working...

  9. Cultural challenges to the psychiatric enterprise.

    Science.gov (United States)

    Fabrega, H

    1995-01-01

    Two challenges to psychiatry emanating from the study of cultural differences in mental illness are reviewed. The first challenge, conducted under the banner of cultural relativism, appeared to undermine the validity of psychiatric disorders. The misconceptions of this challenge, as embodied in the excesses of the labeling theory of sociology, were associated with the writings of antipsychiatrists and rejection of the community mental health movement. The result of all this was a devaluation of insights inherent in the cultural perspective. The second challenge draws emphasis to the pervasive role played by cultural differences in every facet of the psychiatric enterprise. Its relevance and contributions are briefly summarized. The study of the cultural sciences as they pertain to psychiatry offers a necessary corrective to the increasing impersonality and reductionism that is coming to characterize the neurobiologic approach.

  10. Reflections of a Faraday Challenge Day Leader

    Science.gov (United States)

    Sewell, Keira

    2014-01-01

    Keira Sewell has just finished her second year as a Challenge Leader for the Faraday Challenge, a STEM-based scheme run by the Institution of Engineering and Technology. Aimed at 12-13 year-old students, its purpose is to engage students in future careers in engineering. Each year, a new challenge is held in over sixty schools and universities…

  11. Challenges and Opportunities for Libraries in Pakistan

    OpenAIRE

    Shafiq UR, Rehman; Pervaiz, Ahmad

    2007-01-01

    Abstract: This paper, based on review of literature, observation, and informal conversations, discusses various challenges regarding finance, collection development, ICTs, human resources, library education, library association and research & development faced by library profession in Pakistan. The opportunities to meet these challenges have also been explored. Keywords: Library challenges and opportunities (Pakistan); Librarianship (Pakistan); Library issues; Library profession in Pa...

  12. Maasai Mara - the Challenges of a World Unique Ecosystem

    DEFF Research Database (Denmark)

    The report describes the complex challenges of the Maasai Mara in Kenya. The report is based on stakeholder and research inputs from the Maasai Mara Science and Development Summit in April 2015 at the Maasai Mara University, arranged by the Maasai Mara Science and Development Initiative. The emer....... The emerging challenges are categorized into: (1) land use and climate challenges: (2) ecosystem challenges; (3) political and economic challenges; (4) human and cultural challenges....

  13. Urban mental health: Challenges and perspectives

    DEFF Research Database (Denmark)

    Okkels, Niels

    2018-01-01

    Purpose of review: To provide an update on urban mental health and highlight the challenges that require urgent attention. Recent findings: The majority of the world's population live in towns and urbanization is expected to increase in all areas of the world. Challenges to mental health in urban...... services. Fast and unstructured urbanization, such as that seen in many developing countries, further exacerbates these challenges. There are promising initiatives emerging including initiatives to end homelessness, to improve access to green areas in urban environments, to provide emergency psychiatric...

  14. Cultural Challenges of Social-Economic Innovation

    DEFF Research Database (Denmark)

    Bajde, Domen; Ottlewski, Lydia

    2016-01-01

    Purpose We introduce the concept of social-economic innovation (SEI) and point to cultural challenges involved in instituting SEI. In the second part of the paper, we delve into the alternative exchange system of “Housing for help” (HFH) to explore the challenging negotiation of roles and relations...... of the cultural processes and challenges involved in instituting unconventional social-economic systems. The paucity of existent research and the preliminary nature of our study call for further investigation. Practical implications The study informs individual and institutional efforts to negotiate...

  15. Challenges, opportunities and trends in engineering education

    International Nuclear Information System (INIS)

    Rosen, M.A.

    2005-01-01

    Many challenges and opportunities face the engineering profession and engineering education. The engineering profession advances best if challenges are properly addressed, opportunities beneficially exploited and reasoned speculation made on future trends. In this article, the author presents his views on some of the challenges and opportunities facing the engineering education, and possible future trends, with the objective of fostering continued discussion of and action on these issues. This topic is of great importance because the development of engineering education is strongly influenced by the challenges and opportunities it faces and how it responds, and by anticipated future trends. (author)

  16. The Cross-Cultural Knowledge Sharing Challenge

    DEFF Research Database (Denmark)

    Persson, John Stouby

    2013-01-01

    Cross-cultural offshoring in software development challenges effective knowledge sharing. While research has suggested temporarily co-locating participants to address this challenge, few studies are available on what knowledge sharing practices emerge over time when co-locating cross-cultural sof...

  17. Small finance banks: Challenges

    Directory of Open Access Journals (Sweden)

    Jayadev M

    2017-12-01

    Full Text Available A recent innovation in the Indian banking structure has been the formation of a new banking institution—small finance banks (SFBs. These banks are expected to penetrate into financial inclusion by providing basic banking and credit services with a differentiated banking model to the larger population. In this context the new SFBs have multiple challenges in coming out with a new, differentiated business model. The challenges include building low cost liability portfolio, technology management, and balancing the regulatory compliances. This paper also presents the top of mind views of three senior executives of new small finance banks.

  18. Environmental challenge

    International Nuclear Information System (INIS)

    Conable, B.; Warford, J.; Partow, Z.; Lutz, E.; Munasinghe, M.

    1991-09-01

    The contents include the following: Development and the Environment: A Global Balance; Evolution of the World Bank's Environmental Policy; Accounting for the Environment; Public Policy and the Environment; Managing Drylands; Environmental Action Plans in Africa; Agroforestry in Sub-Saharan Africa; Irrigation and the Environmental Challenge; Curbing Pollution in Developing Countries; Global Warming and the Developing World; and The Global Environment Facility

  19. Training Staff to Manage Challenging Behaviour

    NARCIS (Netherlands)

    Oorsouw, W.M.W.J. van; Embregts, P.J.C.M.; Bosman, A.M.T.; Jahoda, A.

    2010-01-01

    Background - A training package for staff working with clients presenting challenging behaviour was developed to (1) increase their knowledge regarding challenging behaviour, and (2) to improve the quality of physical intervention techniques. The latter aim was intended to reduce staff anxiety about

  20. Inequality and Development Challenges | IDRC - International ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    2013-08-30

    Inequality and Development Challenges. Couverture du livre Inequality and Development Challenges. Editor(s):. Maria Clara Couto Soares, Mario Scerri et Rasigan Maharajh. Publisher(s):. Routledge, CRDI. August 30, 2013. ISBN: 9780415710329. 372 pages. e-ISBN: 9781552505571. Download PDF · Read the e-book.

  1. Challenges and opportunities

    International Nuclear Information System (INIS)

    Morgan, G.

    1998-01-01

    Challenges and opportunities facing the Canadian natural gas industry were discussed. The greatest opportunity is that the industry will become part of a fully functioning continental gas market for the first time in history. The challenge will be to ensure that the access to continental markets, which the Alliance project would provide, moves forward in a timely way, especially if the proposed merger between Canada's two dominant natural gas pipelines occurs. The second challenge is to find ways to deal with global warming in a more sensible and knowledgeable way. In the view of this author, the implications of the Kyoto greenhouse gas emission protocol could be potentially devastating to the competitiveness of the North American economy. According to the author, the emission stabilization policy will save the Earth only 0.05 degree C of warming in 2025 based on projected planetary temperature rise from 1990 to 2050. By 2050, the stabilization of emissions will have resulted in savings of only 0.10 degrees C, still a negligible amount. The impact of the Canadian Kyoto obligation was analyzed using federal Department of the Environment data. It was noted that in order for Canada to meet its commitment of reducing greenhouse gas emissions to 1990 levels by 6 per cent by 2008-2012, actual annual reduction in emission would have to amount to 20-25 per cent. To achieve that would require unimaginably drastic measures. 1 tab., 1 fig

  2. Anomalies of tooth formation in hypohidrotic ectodermal dysplasia

    DEFF Research Database (Denmark)

    Lexner, Michala O; Bardow, Allan; Hertz, Jens Michael

    2007-01-01

    OBJECTIVE: The X-linked hypohidrotic ectodermal dysplasia (HED) is the most common type of ectodermal dysplasia. The clinical identification of possible heterozygous females can be difficult because of the varying degrees of clinical signs caused by X-chromosome inactivation. This study is the fi......OBJECTIVE: The X-linked hypohidrotic ectodermal dysplasia (HED) is the most common type of ectodermal dysplasia. The clinical identification of possible heterozygous females can be difficult because of the varying degrees of clinical signs caused by X-chromosome inactivation. This study...... affected males had multiple missing permanent teeth and tooth malformations. The heterozygous females had a significantly higher frequency of agenesis of permanent teeth compared to normative data. The heterozygous females had an increased prevalence of tooth malformations and reduced tooth size...

  3. Limited importance of the dominant-negative effect of TP53 missense mutations

    International Nuclear Information System (INIS)

    Stoczynska-Fidelus, Ewelina; Liberski, Pawel P; Rieske, Piotr; Szybka, Malgorzata; Piaskowski, Sylwester; Bienkowski, Michal; Hulas-Bigoszewska, Krystyna; Banaszczyk, Mateusz; Zawlik, Izabela; Jesionek-Kupnicka, Dorota; Kordek, Radzislaw

    2011-01-01

    Heterozygosity of TP53 missense mutations is related to the phenomenon of the dominant-negative effect (DNE). To estimate the importance of the DNE of TP53 mutations, we analysed the percentage of cancer cases showing a single heterozygous mutation of TP53 and searched for a cell line with a single heterozygous mutation of this gene. This approach was based on the knowledge that genes with evident DNE, such as EGFR and IDH1, represent nearly 100% of single heterozygous mutations in tumour specimens and cell lines. Genetic analyses (LOH and sequencing) performed for early and late passages of several cell lines originally described as showing single heterozygous TP53 mutations (H-318, G-16, PF-382, MOLT-13, ST-486 and LS-123). Statistical analysis of IARC TP53 and SANGER databases. Genetic analyses of N-RAS, FBXW7, PTEN and STR markers to test cross-contamination and cell line identity. Cell cloning, fluorescence-activated cell sorting and SSCP performed for the PF-382 cell line. A database study revealed TP53 single heterozygous mutations in 35% of in vivo (surgical and biopsy) samples and only 10% of cultured cells (in vitro), although those numbers appeared to be overestimated. We deem that published in vivo TP53 mutation analyses are not as rigorous as studies in vitro, and we did not find any cell line showing a stable, single heterozygous mutation. G16, PF-382 and MOLT-13 cells harboured single heterozygous mutations temporarily. ST-486, H-318 and LS-123 cell lines were misclassified. Specific mutations, such as R175H, R273H, R273L or R273P, which are reported in the literature to exert a DNE, showed the lowest percentage of single heterozygous mutations in vitro (about 5%). We suggest that the currently reported percentage of TP53 single heterozygous mutations in tumour samples and cancer cell lines is overestimated. Thus, the magnitude of the DNE of TP53 mutations is questionable. This scepticism is supported by database investigations showing that retention

  4. 50 top IT project management challenges

    CERN Document Server

    Doraiswamy, Premanand

    2012-01-01

    This book offers a focused and concise summary of 50 challenges facing today's IT project manager. The authors draw on years of practical experience (rather than classroom theory) to outline these challenges and offer useful tips and advice on how to deal with them.

  5. DuraChem trademark - challenges and solutions

    International Nuclear Information System (INIS)

    Howard, I.S.; Bowan, B.W.; Kirshe, M.H.

    1996-01-01

    Vitrification of low-level ion exchange resins represents numerous challenges never before successfully accomplished. These challenges include (1) Feed material preparation and transfer, (2) Melter temperature and volume control, (3) Glass composition, stabilization, and control, and (4) Off-gas treatment and particulate capture. The DuraChem trademark team of Chem-Nuclear Systems, Inc. and GTS Duratek, Inc. began its journey in 1994 and is in the process of starting-up the first centralized vitrification facility for commercial ion-exchange and filtration media. This paper addresses each of the challenges and provides an update of this unique volume-reduction and stabilization technology

  6. THORP and after - challenging state decisions

    International Nuclear Information System (INIS)

    Bowden, P.; Lawrence, J.

    1994-01-01

    This article looks at an increasing trend for European Community law to be used by those seeking to challenge decisions taken at a national level which effect the environment. The debate over the future operation of British Nuclear Fuels Ltd's Thermal Oxide Reprocessing Plant at the Sellafield site (THORP) is used as an example of this trend. The United Kingdom government's energy policy authorised the construction and operation of the THORP plant. The decision to continue with the project has been challenged by Greenpeace and Lancashire County Council acting cooperatively. Their challenge was based on Community law and legislation. (UK)

  7. Practical Challenges for Digital Watermarking Applications

    Directory of Open Access Journals (Sweden)

    Sharma Ravi K

    2002-01-01

    Full Text Available The field of digital watermarking has recently seen numerous articles covering novel techniques, theoretical studies, attacks, and analysis. In this paper, we focus on an emerging application to highlight practical challenges for digital watermarking applications. Challenges include design considerations, requirements analysis, choice of watermarking techniques, speed, robustness, and the tradeoffs involved. We describe common attributes of watermarking systems and discuss the challenges in developing real world applications. Our application uses digital watermarking to connect ordinary toys to the digital world. The application captures important aspects of watermarking systems and illustrates some of the design issues faced.

  8. Homeland Security. Management Challenges Facing Federal Leadership

    Science.gov (United States)

    2002-12-01

    Security Management Challenges Facing Federal Leadership 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT...including attention to management practices and key success factors. HOMELAND SECURITY Management Challenges Facing Federal Leadership www.gao.gov/cgi...significant management and coordination challenges if it is to provide this leadership and be successful in preventing and responding to any future

  9. Safety analysis - current and future regulatory challenges

    Energy Technology Data Exchange (ETDEWEB)

    Jamieson, T., E-mail: Terry.Jamieson@cnsc-ccsn.gc.ca [Canadian Nuclear Safety Commission, Ottawa, ON (Canada)

    2015-07-01

    'Full text:' The current and future regulatory challenges associated with deterministic safety analysis are reviewed, including: 1. The CNSC's and safety control areas. 2. Traditional safety analysis approach. 3. Experience gained and impact. 4. Current analysis and regulatory approaches. 5. Current status. 6. Complexity and challenges In particular, the technical, regulatory and strategic aspects of these challenges are discussed. (author)

  10. Safety analysis - current and future regulatory challenges

    International Nuclear Information System (INIS)

    Jamieson, T.

    2015-01-01

    'Full text:' The current and future regulatory challenges associated with deterministic safety analysis are reviewed, including: 1. The CNSC's and safety control areas. 2. Traditional safety analysis approach. 3. Experience gained and impact. 4. Current analysis and regulatory approaches. 5. Current status. 6. Complexity and challenges In particular, the technical, regulatory and strategic aspects of these challenges are discussed. (author)

  11. Common Breastfeeding Challenges

    Science.gov (United States)

    ... or duplicated without permission of the Office on Women’s Health in the U.S. Department of Health and Human Services. Citation of the source is appreciated. Page last updated: March 02, 2018. Common breastfeeding challenges Breastfeeding can be ...

  12. The boomer challenge.

    Science.gov (United States)

    Barr, Paul

    2014-01-01

    Hospitals and the rest of health care will have to make some major adjustments to meet the needs of the aging baby boom generation. The first article in our year-long series inventories the many challenges that lie ahead.

  13. Data Challenges

    CERN Multimedia

    McCubbin, N A

    Some two years ago we planned a series of Data Challenges starting at the end of 2001. At the time, that seemed to be comfortingly far in the future... Well, as the saying goes, doesn't time fly when you are having fun! ATLAS Computing is now deep in the throes of getting the first Data Challenge (DC0) up and running. One of the main aims of DC0 is to have a software 'release' in which we can generate full physics events, track all particles through the detector, simulate the detector response, reconstruct the event, and study it, with appropriate data storage en route. As all software is "always 95% ready" (!), we have been able to do most of this, more or less, for some time. But DC0 forces us to have everything working, together, at the same time: a reality check. DC0 should finish early next year, and it will be followed almost immediately afterwards by DC1 (DC0 was foreseen as the 'check' for DC1). DC1 will last into the middle of 2002, and has two major goals. The first is generation, simulation, and r...

  14. Nasal mucosal blood flow after intranasal allergen challenge

    International Nuclear Information System (INIS)

    Holmberg, K.; Bake, B.; Pipkorn, U.

    1988-01-01

    The nasal mucosal blood flow in patients with allergic rhinitis was determined at nasal allergen challenges with the 133 Xenon washout method. Determinations were made in 12 subjects before and 15 minutes after challenge with diluent and increasing doses of allergen. The time course was followed in eight subjects by means of repeated measurements during 1 hour after a single allergen dose. Finally, the blood flow was measured after unilateral allergen challenge in the contralateral nasal cavity. A dose-dependent decrease in blood flow was found after nasal challenge with increasing doses of allergens, whereas challenge with diluent alone did not induce any changes. The highest allergen dose, which also induced pronounced nasal symptoms, resulted in a decrease in blood flow of 25% (p less than 0.001). The time-course study demonstrated a maximum decrease in blood flow 10 to 20 minutes after challenge and then a gradual return to baseline. Unilateral allergen challenge resulted in a decrease in blood flow in the contralateral, unchallenged nasal cavity, suggesting that part of the allergen-induced changes in blood flow were reflex mediated

  15. Respiratory challenge MRI: Practical aspects

    Directory of Open Access Journals (Sweden)

    Fiona C. Moreton

    2016-01-01

    Full Text Available Respiratory challenge MRI is the modification of arterial oxygen (PaO2 and/or carbon dioxide (PaCO2 concentration to induce a change in cerebral function or metabolism which is then measured by MRI. Alterations in arterial gas concentrations can lead to profound changes in cerebral haemodynamics which can be studied using a variety of MRI sequences. Whilst such experiments may provide a wealth of information, conducting them can be complex and challenging. In this paper we review the rationale for respiratory challenge MRI including the effects of oxygen and carbon dioxide on the cerebral circulation. We also discuss the planning, equipment, monitoring and techniques that have been used to undertake these experiments. We finally propose some recommendations in this evolving area for conducting these experiments to enhance data quality and comparison between techniques.

  16. LHC luminosity upgrade detector challenges

    CERN Multimedia

    CERN. Geneva; de Roeck, Albert; Bortoletto, Daniela; Wigmans, Richard; Riegler, Werner; Smith, Wesley H

    2006-01-01

    LHC luminosity upgrade: detector challenges The upgrade of the LHC machine towards higher luminosity (1035 cm -2s-1) has been studied over the last few years. These studies have investigated scenarios to achieve the increase in peak luminosity by an order of magnitude, as well as the physics potential of such an upgrade and the impact of a machine upgrade on the LHC DETECTORS. This series of lectures will cover the following topics: • Physics motivation and machine scenarios for an order of magnitude increase in the LHC peak luminosity (lecture 1) • Detector challenges including overview of ideas for R&D programs by the LHC experiments: tracking and calorimetry, other new detector developments (lectures 2-4) • Electronics, trigger and data acquisition challenges (lecture 5) Note: the much more ambitious LHC energy upgrade will not be covered

  17. The Challenge of Prejudice: Counsellors' Talk about Challenging Clients' Prejudices

    Science.gov (United States)

    Spong, Sheila J.

    2012-01-01

    This paper considers the implications for training and practice of counsellors' responses to the notion of challenging clients' prejudices. It explores tensions in counselling discourse between social responsibility, responsibility to the client and responsibility for one's self as counsellor. Three focus groups of counsellors were asked whether a…

  18. The challenges of risk society for impact assessment

    DEFF Research Database (Denmark)

    Larsen, Sanne Vammen

    2017-01-01

    , the challenge of delivering assessments and predictions and the challenge of handling differences of opinion and debate. Through a case example of integration of climate change in strategic environmental assessment, the paper uses empirical evidence from a survey and a series of interviews to carry out......This paper takes its point of departure in Ulrich Beck’s theory of risk society and the aspects that characterise this society. The paper puts forward a hypothe- sis, on which theoretical challenges the characteristics of risk society pose to impact assessment as a decision support tool; namely...... a preliminary discussion of how the theoretical challenges are reflected in practice. The case study results show that the challenge of delivering assessments and predictions in a risk society is reflected in the current state of practice, while the challenge of handling differences of opinion and debate...

  19. Asia's new challenges

    DEFF Research Database (Denmark)

    Brach, Juliana; Vang, Jan

    2012-01-01

    Asian countries are currently undergoing significant changes with respect to their role in and interaction with the international economy. Despite their heterogeneity, Asian countries share the common aim to upgrade capacities, skills and capabilities. This paper aims at unpacking the challenges ...

  20. Visualizing news: obstacles, challenges, and solutions

    NARCIS (Netherlands)

    Dr. Piet Bakker; Gerard Smit; Yael de Haan; Laura Buijs

    2013-01-01

    Depicting news graphically is considered an apt way to deal with challenges of modern journalism: to disclose big data, and present news attractively, visually, and fast to grasp. This study delves into reported obstacles and challenges for the production of news visualizations. It focuses on the

  1. The 24-Hour Mathematical Modeling Challenge

    Science.gov (United States)

    Galluzzo, Benjamin J.; Wendt, Theodore J.

    2015-01-01

    Across the mathematics curriculum there is a renewed emphasis on applications of mathematics and on mathematical modeling. Providing students with modeling experiences beyond the ordinary classroom setting remains a challenge, however. In this article, we describe the 24-hour Mathematical Modeling Challenge, an extracurricular event that exposes…

  2. The Challenge of A Sustainability Change

    DEFF Research Database (Denmark)

    Winkel, Thomas Dyrmann; Poulsen, Søren Bolvig; Rosenstand, Claus Andreas Foss

    2015-01-01

    Changing a company’s role and position in its context towards a more ambitious profile centred on waste minimisation can be challenging due to external factors such as regulations and economic logics, but also internal challenges of transforming visions into supporting activities can hinder the r...

  3. 22 CFR 9.8 - Classification challenges.

    Science.gov (United States)

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Classification challenges. 9.8 Section 9.8 Foreign Relations DEPARTMENT OF STATE GENERAL SECURITY INFORMATION REGULATIONS § 9.8 Classification... classification status is improper are expected and encouraged to challenge the classification status of the...

  4. Multi-scale biomedical systems: measurement challenges

    International Nuclear Information System (INIS)

    Summers, R

    2016-01-01

    Multi-scale biomedical systems are those that represent interactions in materials, sensors, and systems from a holistic perspective. It is possible to view such multi-scale activity using measurement of spatial scale or time scale, though in this paper only the former is considered. The biomedical application paradigm comprises interactions that range from quantum biological phenomena at scales of 10-12 for one individual to epidemiological studies of disease spread in populations that in a pandemic lead to measurement at a scale of 10+7. It is clear that there are measurement challenges at either end of this spatial scale, but those challenges that relate to the use of new technologies that deal with big data and health service delivery at the point of care are also considered. The measurement challenges lead to the use, in many cases, of model-based measurement and the adoption of virtual engineering. It is these measurement challenges that will be uncovered in this paper. (paper)

  5. Ireland’s Competitiveness Challenge 2014

    OpenAIRE

    2014-01-01

    Ireland’s Competitiveness Challenge 2014, which is produced under the Action Plan for Jobs 2014, outlines the National Competitiveness Council’s view of the main competitiveness issues confronting the business sector in Ireland over the medium term, and sets out a series of policy responses required to address these challenges. Building on their earlier benchmarking of Irish competitiveness, the Council focus on six major themes in the 2014 report: addressing cost competitiveness; broadening ...

  6. Systems Challenges for Hypersonic Vehicles

    Science.gov (United States)

    Hunt, James L.; Laruelle, Gerard; Wagner, Alain

    1997-01-01

    This paper examines the system challenges posed by fully reusable hypersonic cruise airplanes and access to space vehicles. Hydrocarbon and hydrogen fueled airplanes are considered with cruise speeds of Mach 5 and 10, respectively. The access to space matrix is examined. Airbreathing and rocket powered, single- and two-stage vehicles are considered. Reference vehicle architectures are presented. Major systems/subsystems challenges are described. Advanced, enhancing systems concepts as well as common system technologies are discussed.

  7. The Challenges of Leadership.

    Science.gov (United States)

    Myrtle, Robert C

    Perhaps in no other period in recent times have the challenges leaders face been so profound. In these times of uncertainty and turbulence, we look to leaders who create a sense of purpose, who generate feelings of trust and optimism, and who tap the passion, talent, and efforts of those so essential to the success of the organization and of the people it serves. Our research suggests that becoming the leader whom people look to and admire requires an active commitment to responding to 5 essential leadership challenges. These are (1) creating a sense of purpose, (2) devising means for aligning the actions of the followers with that sense of purpose, (3) establishing a context that enables others to behave in a way that is consistent with the vision and values of the organization, (4) ensuring that the work that is done provides meaning to those engaging in the work activities, and (5) adding to the sum of everyone's knowledge through learning through reflective actions. In this article, we describe these challenges and offer suggestions that you can take to become a more effective and respected leader.

  8. CHALLENGES OF SOFTWARE QUALITY ASSURANCE AND TESTING

    Directory of Open Access Journals (Sweden)

    Md.Shahadat Hossain

    2018-02-01

    Full Text Available Uncertainty exists in Software Company over the world. Software quality problem is leading issue for the software industry. The issue exists from 40 years or 50 years long. The industry is suffering and closing for this issue. In this circumstance, it is important to address and remove its root cause. Otherwise, day by day industry economic loss will increase. I figure out some vital challenges of software quality assurance and testing which have been facing by software industries. The research focused on several small and medium software companies of the world. This paper represents different category of challenges along with responsible stakeholders. This research finds out that testing tools are available testing elements are available testing process has improved but still software has some testing challenges. My research figured out the bottleneck of challenges and explained in this paper. Here software engineers have scope to improve & overcome those challenges. This paper suggests systematic approach to solve the problem.

  9. Global challenges

    International Nuclear Information System (INIS)

    Blix, H.

    1990-01-01

    A major challenge now facing the world is the supply of energy needed for growth and development in a manner which is not only economically viable but also environmentally acceptable and sustainable in view of the demands of and risks to future generations. The internationally most significant pollutants from energy production through fossil fuels are SO 2 and NO x which cause acid rain, and CO 2 which is the most significant contributor to the greenhouse effect. Nuclear power, now providing about 17% of the world's electricity and 5% of the primary energy already is making a notable contribution to avoiding these emissions. While the industrialized countries will need more energy and especially electricity in the future, the needs of the developing countries are naturally much larger and present a tremendous challenge to the shaping of the world's future energy supply system. The advanced countries will have to accept special responsibilities, as they can most easily use advanced technologies and they have been and remain the main contributors to the environmental problems we now face. Energy conservation and resort to new renewable energy sources, though highly desirable, appear inadequate alone to meet the challenges. The world can hardly afford to do without an increased use of nuclear power, although it is strongly contested in many countries. The objections raised against the nuclear option focus on safety, waste management and disposal problems and the risk for proliferation of nuclear weapons. These issues are not without their problems. The risk of proliferation exists but will not appreciably diminish with lesser global reliance on nuclear power. The waste issue is more of a political than a technical problem. The use of nuclear power, or any other energy source, will never be at zero risk, but the risks are constantly reduced by new techniques and practices. The IAEA sees it as one of its priority tasks to promote such techniques. (author)

  10. The RERS 2017 Challenge and Workshop

    NARCIS (Netherlands)

    Jasper, Marc; Fecke, Maximilian; Steffen, Bernhard; Schordan, Markus; Meijer, Jeroen; Pol, Jaco van de; Howar, Falk; Siegel, Stephen F.

    RERS is an annual verification challenge that focuses on LTL and reachability properties of reactive systems. In 2017, RERS was extended to a one day workshop that in addition to the original challenge program also featured an invited talk about possible future developments. As a satellite of ISSTA

  11. Navigating Transitions: Challenges for Engineering Students

    Science.gov (United States)

    Moore-Russo, Deborah; Wilsey, Jillian N.; Parthum, Michael J., Sr.; Lewis, Kemper

    2017-01-01

    As college students enter engineering, they face challenges when they navigate across various transitions. These challenges impact whether a student can successfully adapt to the rigorous curricular requirements of an engineering degree and to the norms and expectations that are particular to engineering. This article focuses on the transitions…

  12. The challenges of pharmacy education in Yemen.

    Science.gov (United States)

    Al-Worafi, Yaser Mohammed

    2014-10-15

    Pharmacy education in Yemen has faced many challenges since its introduction in the 1980s. Most Yemeni pharmacy schools, especially private ones, are experiencing difficulties in providing the right quality and quantity of clinical educational experiences. Most of these challenges are imbedded in a teaching style and curricula that have failed to respond to the needs of the community and country. The slow shift from traditional drug-dispensing to a patient-centered or focused approach in pharmacy practice requires a fundamental change in the roles and responsibilities of both policymakers and educators. The purpose of this paper is twofold: (1) to discuss the challenges facing the pharmacy education in Yemen; (2) to provided recommendations to overcome challenges.

  13. ASSOCIATION OF SOME BIOCHEMICAL-GENETIC MARKERS WITH THE REPRODUCTION PARAMETERS OF THE BOTOSANI KARAKUL EWES

    Directory of Open Access Journals (Sweden)

    GH. HRINCĂ

    2008-10-01

    Full Text Available The paper describes some associative aspects of various biochemical-genetic markers with the reproduction activity in ewes of the Botosani Karakul breed. The two most important reproduction parameters (fecundity and prolificacy were analyzed according to the genotypes or phenotypes of polymorph systems (haemoglobin, transferrin, albumin and blood potassium of females. The relationship between reproduction data and genetic markers in ewes was quantified both for each genotype (phenotype and for each mating couple type made up depending on the genotype (phenotype of the couple partners (homozygous x homozygous, homozygous x heterozygous or heterozygous x heterozygous. All these associative aspects and their results are discussed for each polymorph genetic system. The ewes which are heterozygous at different genetic marker loci are more fertile and more prolific than the ewes which are homozygous at the levels of these loci. The highest conception and lambing rates resulted from the mating couples in which both partners were heterozygous and the least lambs were obtained from the mating couples in which both partners were homozygous; the fertility and prolificacy had intermediate values in heterogeneous mating couples (heterozygotes x homozygotes but they were nearer to the case in which both mating couple partners were heterozygous. The sheep breeding field can benefit by the contribution of biochemical-genetic markers to optimize the selection criteria with a view to increasing the reproduction capacity of this species.

  14. Hopes and Challenges

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    China tops the medal tally again at the Asian Games but still faces challenges in some events The curtain of the 16th Asian Games has fallen, but the 15 days of exciting competitions will be recorded in the history of the Games.

  15. An Evaluation of ChalleNGe Graduates DOD Employability

    Science.gov (United States)

    2018-01-22

    initial reading and applied math TABE scores are more likely to complete ChalleNGe. In addition, those graduates who begin ChalleNGe with higher TABE...each site is given discretion in how it structures its program. As a result, the academic goals of the ChalleNGe sites vary. Some seek to have...students arrive at ChalleNGe at low levels of reading comprehension, writing, and basic math ; they simply are not ready to acquire a second language

  16. Sustainable Materials Management (SMM) Electronics Challenge Data

    Science.gov (United States)

    On September 22, 2012, EPA launched the SMM Electronics Challenge. The Challenge encourages electronics manufacturers, brand owners and retailers to strive to send 100 percent of the used electronics they collect from the public, businesses and within their own organizations to third-party certified electronics refurbishers and recyclers. The Challenge??s goals are to: 1). Ensure responsible recycling through the use of third-party certified recyclers, 2). Increase transparency and accountability through public posting of electronics collection and recycling data, and 3). Encourage outstanding performance through awards and recognition. By striving to send 100 percent of used electronics collected to certified recyclers and refurbishers, Challenge participants are ensuring that the used electronics they collect will be responsibly managed by recyclers that maximize reuse and recycling, minimize exposure to human health and the environment, ensure the safe management of materials by downstream handlers, and require destruction of all data on used electronics. Electronics Challenge participants are publicly recognized on EPA's website as a registrant, new participant, or active participant. Awards are offered in two categories - tier and champion. Tier awards are given in recognition of achieving all the requirements under a gold, silver or bronze tier. Champion awards are given in two categories - product and non-product. For champion awards, a product is an it

  17. Mathematical olympiad challenges

    CERN Document Server

    Andreescu, Titu

    2000-01-01

    Mathematical Olympiad Challenges is a rich collection of problems put together by two experienced and well-known professors and coaches of the U.S. International Mathematical Olympiad Team. Hundreds of beautiful, challenging, and instructive problems from algebra, geometry, trigonometry, combinatorics, and number theory were selected from numerous mathematical competitions and journals. An important feature of the work is the comprehensive background material provided with each grouping of problems. The problems are clustered by topic into self-contained sections with solutions provided separately. All sections start with an essay discussing basic facts and one or two representative examples. A list of carefully chosen problems follows and the reader is invited to take them on. Additionally, historical insights and asides are presented to stimulate further inquiry. The emphasis throughout is on encouraging readers to move away from routine exercises and memorized algorithms toward creative solutions to open-e...

  18. A reflective teaching challenge to motivate educational innovation.

    Science.gov (United States)

    Edwards, Roger A; Kirwin, Jennifer; Gonyeau, Michael; Matthews, S James; Lancaster, Jason; DiVall, Margarita

    2014-06-17

    To describe a teaching challenge intended to increase faculty use of evidence-based and student-centered instructional strategies in the demanding school of pharmacy context with technology-savvy students. A teaching challenge was created that required faculty members to incorporate a "new-to-you" innovative teaching method in a class, course, or experiential activity. The method was linked to at least 1 of 7 evidence-based principles for effective teaching. Faculty members were exposed to colleagues' teaching strategies via brief voluntary presentations at department meetings. A post-challenge survey provided assessment data about the challenge. Responses to a baseline survey provided additional information about what faculty members were already doing (52% response rate). Eighty-one percent of faculty respondents completed the challenge. A wide array of new strategies (13 categories such as flipped classrooms and social media) was implemented and 75% included the use of technology. Nearly all respondents (96%) thought that participation in the challenge was worth the effort and planned to participate again the following year. All faculty members intended to continue using their new strategy and 56% planned additional modifications with future implementations. The challenge demonstrated how multiple goals of curricular improvement, faculty development, and student-centered instruction could be achieved together. The teaching challenge motivated most of the faculty members to try something new to them. Links between evidence-based principles and day-to-day activities were strengthened. The new-to-you design placed the challenge within reach of faculty members regardless of their background, subject, or experience.

  19. Preservice Teachers' Perceptions of Challenging Behavior

    Science.gov (United States)

    Butler, Anne; Monda-Amaya, Lisa

    2016-01-01

    Challenging behavior can have adverse effects on both students and teachers, and preservice teachers often report feeling ill prepared to manage this behavior. The purpose of this study was to examine (a) preservice teacher perceptions of student and teacher behavior during scenarios of challenging behavior, (b) alternative solutions or strategies…

  20. The Marihuana Dilemma: Challenge to Commanders.

    Science.gov (United States)

    The marihuana dilemma poses a major challenge to commanders in the US Army today. The problem was analyzed as to the characteristics of the drug...available to commanders to meet the challenge. The essay concludes that marihuana should not be legalized; drug users or former drug users should not be