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Sample records for challenged heterozygous watanabe

  1. 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; Poulsen, Morten; Wester, Ingmar; Lütjohann, Dieter; Mortensen, Alicja

    2009-01-01

    Rapeseed oil (RSO) is a novel source of plant sterols, containing the unique brassicasterol in concentrations higher than allowed for plant sterol blends in food products in the European Union. Effects of RSO sterols and stanols on aortic atherosclerosis were studied in cholesterol-fed heterozygous...... brassicasterol were well tolerated. They were hypocholesterolaemic and inhibited experimental atherosclerosis in cholesterol-fed Hh-WHHL rabbits. A significant uptake of plant sterols into the blood and incorporation of campesterol and campestanol into aortic tissue was recorded....

  2. 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

    The spontaneous development of atherosclerotic disease in 38 homozygous and 34 heterozygous Watanabe heritable hyperlipidaemic rabbits was evaluated by qualitative and quantitative light microscopy in aorta, coronary, pulmonary and renal arteries, by naked eye and macroscopic morphometric estimat...... 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....

  3. Watanabe rabbits with heritable hypercholesterolaemia: a model of atherosclerosis

    OpenAIRE

    Aliev, G; Burnstock, G.

    1998-01-01

    Many factors play important roles in the development of atherosclerotic lesions. The leading risk factor for atherosclerosis is familial hypercholesterolaemia (FH). FH is a genetic disease characterized by a deficiency of receptors for low density lipoprotein (LDL) on the plasmalemma of endothelial cells, a high level of serum LDL, and early development of atherosclerosis and skin xanthoma. Watanabe and colleagues have developed a line of rabbits with unprovoke...

  4. Orthology Guided Assembly in highly heterozygous crops

    DEFF Research Database (Denmark)

    Ruttink, Tom; Sterck, Lieven; Rohde, Antje;

    2013-01-01

    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...

  5. DISKRIMINASI GENDER DALAM NOVEL GINKO KARYA JUNICHI WATANABE

    Directory of Open Access Journals (Sweden)

    Linda Unsriana

    2015-04-01

    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 womens 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 Ginkos 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.

  6. Redundans: an assembly pipeline for highly heterozygous genomes.

    Science.gov (United States)

    Pryszcz, Leszek P; Gabaldón, Toni

    2016-07-01

    Many genomes display high levels of heterozygosity (i.e. presence of different alleles at the same loci in homologous chromosomes), being those of hybrid organisms an extreme such case. The assembly of highly heterozygous genomes from short sequencing reads is a challenging task because it is difficult to accurately recover the different haplotypes. When confronted with highly heterozygous genomes, the standard assembly process tends to collapse homozygous regions and reports heterozygous regions in alternative contigs. The boundaries between homozygous and heterozygous regions result in multiple assembly paths that are hard to resolve, which leads to highly fragmented assemblies with a total size larger than expected. This, in turn, causes numerous problems in downstream analyses such as fragmented gene models, wrong gene copy number, or broken synteny. To circumvent these caveats we have developed a pipeline that specifically deals with the assembly of heterozygous genomes by introducing a step to recognise and selectively remove alternative heterozygous contigs. We tested our pipeline on simulated and naturally-occurring heterozygous genomes and compared its accuracy to other existing tools. Our method is freely available at https://github.com/Gabaldonlab/redundans. PMID:27131372

  7. "Applications of the Asymptotic Expansion Approach based on Malliavin-Watanabe Calculus in Financial Problems"

    OpenAIRE

    Naoto Kunitomo; Akihiko Takahashi

    2003-01-01

    This paper reviews the asymptotic expansion approach based on Malliavin-Watanabe Calculus in Mathematical Finance. We give the basic formulation of the asymptotic expansion approach and discuss its power and usefulness to solve important problems arised in nance. As illustrations we use three major problems in nance and give some useful formulae and new results including numerical analyses.

  8. Diarrhea-like condition and intestinal muscosal responses in susceptible homozygous and heterozygous F4R+ pigs challenged with enterotoxigenic Escherichia coli

    DEFF Research Database (Denmark)

    Sugiharto, Sugiharto; Hedemann, Mette Skou; Jensen, Bent Borg;

    2012-01-01

    Enterotoxigenic Escherichia coli (ETEC) F4 is a major cause of diarrhea in both neonatal and young pigs. Indeed, only pigs having F4 receptors are susceptible. Among the susceptible pigs, it is yet unknown if spontaneous E. coli postweaning diarrhea (PWD) occurrence and intestinal mucosal responses...... to ETEC differ between genotypes. This study investigated a diarrhea-like condition and intestinal mucosal responses in F4 homo- and heterozygous susceptible weaner pigs. Sixteen weaned pigs (28 d of age) were used in a 2 × 2 factorial study with genotype (homo- or heterozygous F4R+) and inoculation...

  9. A possible heterozygous advantage in muscular dystrophy.

    Science.gov (United States)

    Emery, A E H

    2016-01-01

    In certain autosomal recessive disorders there is suggestive evidence that heterozygous carriers may have some selective advantage over normal homozygotes. These include, for example, cystic fibrosis, Tay-Sachs disease and phenylketonuria. The best example so far, however, is that of significant heterozygous advantage in sickle-cell anaemia with increased resistance to falciparum malaria. PMID:27245530

  10. 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...... currant anthocyanin studies were performed. Procedures for workup and analyses of urine and plasma samples containing anthocyanins were developed with high recoveries (99 and 81%, respectively) and low limits of quantification (greater than or equal to 6.6 and greater than or equal to 1.1 nM, respectively......). 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...

  11. 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 grape...... skin and seed extract (GSE) on the development of atherosclerosis. WHHL rabbits received either semisynthetic diet (casein based) or semisynthetic diet added GSE over a period of 15 wk. Plasma lipids and aortic cholesterol accumulation were measured. Feeding semisynthetic diet was associated with...... was comparable in the control and GSE-dosed females, but it was significantly reduced in the abdominal part of GSE-dosed male compared to the controls (P <0.05). In conclusion, feeding GSE extract to WHHL rabbits had no significant effects in females but was associated with transient less...

  12. Dissociation of atherogenesis from aortic accumulation of lipid hydro(pero)xides in Watanabe heritable hyperlipidemic rabbits

    OpenAIRE

    Witting, Paul; Pettersson, Knut; Östlund-Lindqvist, Ann-Margret; Westerlund, Christer; Wågberg, Maria; Stocker, Roland

    1999-01-01

    Antioxidants can inhibit atherosclerosis, but it is unclear how inhibition of intimal lipid oxidation relates to atherogenesis. Here we tested the effect of probucol and its metabolite bisphenol on aortic lipid (per)oxidation and atherogenesis in Watanabe heritable hyperlipidemic (WHHL) rabbits. LDL and aortas from rabbits fed probucol contained bisphenol at concentrations comparable to those in bisphenol-treated animals. Bisphenol treatment increased plasma cholesterol slightly, and plasma a...

  13. 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)

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

    International Nuclear Information System (INIS)

    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 13N-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)

  15. Fundus albipunctatus associated with compound heterozygous mutations in RPE65

    DEFF Research Database (Denmark)

    Schatz, Patrik; Preising, Markus; Lorenz, Birgit; Sander, Birgit; Larsen, Michael; Rosenberg, Thomas

    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....

  16. Atm heterozygous deficiency enhances development of mammary carcinomas in p53 heterozygous knockout mice

    International Nuclear Information System (INIS)

    Ataxia-telangiectasia is an autosomal-recessive disease that affects neuro-immunological functions, associated with increased susceptibility to malignancy, chromosomal instability and hypersensitivity to ionizing radiation. Although ataxia-telangiectasia mutated (ATM) heterozygous deficiency has been proposed to increase susceptibility to breast cancer, some studies have not found excess risk. In experimental animals, increased susceptibility to breast cancer is not observed in the Atm heterozygous deficient mice (Atm+/-) carrying a knockout null allele. In order to determine the effect of Atm heterozygous deficiency on mammary tumourigenesis, we generated a series of Atm+/- mice on the p53+/- background with a certain predisposition to spontaneous development of mammary carcinomas, and we examined the development of the tumours after X-irradiation. BALB/cHeA-p53+/- mice were crossed with MSM/Ms-Atm+/- mice, and females of the F1 progeny ([BALB/cHeA × MSM/Ms]F1) with four genotypes were used in the experiments. The mice were exposed to X-rays (5 Gy; 0.5 Gy/min) at age 5 weeks. We tested the effect of haploinsufficiency of the Atm gene on mammary tumourigenesis after X-irradiation in the p53+/- mice of the BALB/cHeA × MSM/Ms background. The singly heterozygous p53+/- mice subjected to X-irradiation developed mammary carcinomas at around 25 weeks of age, and the final incidence of mammary carcinomas at 39 weeks was 31% (19 out of 61). The introduction of the heterozygous Atm knockout alleles into the background of the p53+/- genotype significantly increased the incidence of mammary carcinoma to 58% (32 out of 55) and increased the average number of mammary carcinomas per mouse. However, introduction of Atm alleles did not change the latency of development of mammary carcinoma. Our results indicate a strong enhancement in mammary carcinogenesis by Atm heterozygous deficiency in p53+/- mice. Thus, doubly heterozygous mice represent a useful model system with which to

  17. 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 O.; Mortensen, Alicja; Nilas, Lisbeth;

    2007-01-01

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

  18. 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...

  19. 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 in...

  20. Anthocyanins increase low-density lipoprotein and plasma cholesterol and do not reduce atherosclerosis in Watanabe Heritable Hyperlipidemic rabbits

    DEFF Research Database (Denmark)

    Nielsen, I. L. F.; Rasmussen, S.E.; Mortensen, Alicja;

    2005-01-01

    Anthocyanin-rich beverages have shown beneficial effects on coronary heart disease in epidemiological and intervention studies. In the present study, we investigated the effect of black currant anthocyanins on atherosclerosis. Watanabe Heritable Hyperlipidemic rabbits (n = 61) were fed either a...... purified anthocyanin fraction front black currants, a black currant juice, probucol or control diet for 16 weeks. Purified anthocyanins significantly increased plasma cholesterol and low-density lipoprotein (LDL) cholesterol. Intake of black currant juice had no effect on total plasma cholesterol, but...... lowered very-low-density lipoprotein (VLDL) cholesterol significantly. There were no significant effects of either purified anthocyanins or black currant juice on aortic cholesterol or development of atherosclerosis after 16 weeks. Probucol had no effect on plasma cholesterol but significantly lowered...

  1. 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 in.......7 +/- 1156.1 nmol/g vs. 455.0 +/- 207.8 nmol/g, P <0.01). In contrast, the oxidation of plasma and HDL from probucol treated animals was not statistically significantly increased, implying that probucol mediates a selective oxidation of atherogenic cholesterol-transporting lipoproteins. Quercetin treated...... animals did not show increased oxidation of LDL land VLDL in rabbits) and cholesterol levels were not decreased. Furthermore, no protective antioxidant effect of quercetin was seen. In conclusion, the results suggest that a prooxidant mechanism rather than antioxidative effects influences lipoprotein...

  2. 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

    Foods containing plant sterol or stanol esters can be beneficial in lowering LDL-cholesterol concentration, a major risk factor for CVD. The present study examined whether high dietary intake of rapeseed oil (RSO) derived plant sterol and stanol esters is associated with increased levels of these...... form for 120 d (n 9 for each group). Concentrations of cholesterol, its precursor lathosterol, plant sterols and stanols in brain and additionally in liver and plasma were determined by highly sensitive GC-MS. High-dose intake of RSO derived plant sterols and stanols resulted in increased levels of...... these components in plasma and liver. In brain a limited uptake of plant sterols and stanols was proven, indicating that these compounds passed the blood-brain barrier and may be retained in the brain tissue of Watanabe rabbits. Plant stanol ester feeding lowered plant sterol levels in brain, liver, and...

  3. 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; Lütjohann, Dieter; Mortensen, Alicja

    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...

  4. 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...

  5. Male Men1 heterozygous mice exhibit fasting hyperglycemia in the early stage of MEN1.

    Science.gov (United States)

    Gao, Zhongxiuzi; Zhang, Li; Xie, Wenting; Wang, Siqi; Bao, Xiaorui; Guo, Yuli; Zhang, Houjian; Hu, Qingzhong; Chen, Yi; Wang, Zeen; Xue, Maoqiang; Jin, Guanghui

    2016-09-01

    Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited syndrome characterized by multiple tumors in the parathyroid glands, endocrine pancreas and anterior pituitary. Recent clinical studies have revealed a strong association between MEN1 syndrome and the risk of developing diabetes mellitus; however, the underlying mechanisms remain unknown. In this study, heterozygous Men1 knockout (Men1(+/-)) mice were used as MEN1 models to investigate MEN1-associated glucose metabolic phenotypes and mechanisms. Heterozygous deficiency of Men1 in 12-month-old male mice induced fasting hyperglycemia, along with increased serum insulin levels. However, male Men1(+/-) mice did not show insulin resistance, as evidenced by Akt activation in hepatic tissues and an insulin tolerance test. Increased glucose levels following pyruvate challenge and expression of key gluconeogenic genes suggested increased hepatic glucose output in the male Men1(+/-) mice. This effect could be partly due to higher basal serum glucagon levels, which resulted from pancreatic islet cell proliferation induced by heterozygous loss of Men1 Taken together, our results indicate that fasted male Men1(+/-) mice, in the early stage of development of MEN1, display glucose metabolic disorders. These disorders are caused not by direct induction of insulin resistance, but via increased glucagon secretion and the consequent stimulation of hepatic glucose production. PMID:27432891

  6. Filaggrin compound heterozygous patients carry mutations in trans position

    DEFF Research Database (Denmark)

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

    2013-01-01

    ; 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 to the...... 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/2282......del4 compound heterozygous individuals were found to carry the two mutations in trans position. FLG null mutation compound heterozygous individuals can be considered functionally equivalent to FLG null mutation homozygosity for any of the two mutations....

  7. Interview : Masato Watanabe (JICA)

    OpenAIRE

    Watanabe, Masato

    2013-01-01

    He obtained his B.A. in Law from the University of Tokyo in 1980. Currently, he is the Vice President of Japan International Cooperation Agency (JICA). Before joining JICA in July 2009, he held multiple positions in Diplomatic Services. He served as Minister at the Embassy of Japan in Indonesia (from 2004-2007), and Deputy Director-General of International Cooperation Bureau, Ministry of Foreign Affairs (MOFA) of Japan (from 2007-2009). From his various assignments at the MOFA, he has accumul...

  8. Gene expression patterns in heterozygous Plk4 murine embryonic fibroblasts

    Directory of Open Access Journals (Sweden)

    Nantais Jordan

    2009-07-01

    Full Text Available Abstract Background The polo-like kinases (Plks are a group of serine/threonine kinases which have roles in many aspects of cellular function including the regulation of mitotic activity and cellular stress responses. This study focuses on Plk4, the most divergent member of the Plk family, which is necessary for proper cellular proliferation. More specifically, alterations in Plk4 levels cause significantly adverse mitotic defects including abnormal centrosome duplication and aberrant mitotic spindle formation. We sought to clarify the effect of reduced Plk4 levels on the cell by examining transcript profiles of Plk4 wild-type and heterozygous mouse embryonic fibroblasts (MEFs. Subsequently, the levels of several key proteins involved in the DNA damage response were examined. Results 143 genes were found to be significantly up-regulated in the heterozygous MEFs compared to their wild-type counterparts, while conversely, 9 genes were down-regulated. Numerous genes with increased transcript levels in heterozygous MEFs were identified to be involved in p53-dependent pathways. Furthermore, examination of the promoter regions of all up- and down-regulated genes revealed that the majority contained putative p53 responsive elements. An analysis of transcript levels in MEFs after exposure to either ionizing or ultraviolet radiation revealed a significant change between wild type and heterozygous MEFS for Plk4 transcript levels upon only UV exposure. Furthermore, changes in protein levels of several important cell check-point and apoptosis regulators were examined, including p53, Chk1, Chk2, Cdc25C and p21. In heterozygous MEFs, p53, p21 and Chk2 protein levels were at significantly higher levels. Furthermore, p53 activity was increased 5 fold in the Plk4 heterozygous MEFs. Conclusion Global transcript profiles and levels of key proteins involved in cellular proliferation and DNA damage pathways were examined in wild-type and Plk4 heterozygous MEFs. It

  9. Efficient de novo assembly of highly heterozygous genomes from whole-genome shotgun short reads.

    Science.gov (United States)

    Kajitani, Rei; Toshimoto, Kouta; Noguchi, Hideki; Toyoda, Atsushi; Ogura, Yoshitoshi; Okuno, Miki; Yabana, Mitsuru; Harada, Masayuki; Nagayasu, Eiji; Maruyama, Haruhiko; Kohara, Yuji; Fujiyama, Asao; Hayashi, Tetsuya; Itoh, Takehiko

    2014-08-01

    Although many de novo genome assembly projects have recently been conducted using high-throughput sequencers, assembling highly heterozygous diploid genomes is a substantial challenge due to the increased complexity of the de Bruijn graph structure predominantly used. To address the increasing demand for sequencing of nonmodel and/or wild-type samples, in most cases inbred lines or fosmid-based hierarchical sequencing methods are used to overcome such problems. However, these methods are costly and time consuming, forfeiting the advantages of massive parallel sequencing. Here, we describe a novel de novo assembler, Platanus, that can effectively manage high-throughput data from heterozygous samples. Platanus assembles DNA fragments (reads) into contigs by constructing de Bruijn graphs with automatically optimized k-mer sizes followed by the scaffolding of contigs based on paired-end information. The complicated graph structures that result from the heterozygosity are simplified during not only the contig assembly step but also the scaffolding step. We evaluated the assembly results on eukaryotic samples with various levels of heterozygosity. Compared with other assemblers, Platanus yields assembly results that have a larger scaffold NG50 length without any accompanying loss of accuracy in both simulated and real data. In addition, Platanus recorded the largest scaffold NG50 values for two of the three low-heterozygosity species used in the de novo assembly contest, Assemblathon 2. Platanus therefore provides a novel and efficient approach for the assembly of gigabase-sized highly heterozygous genomes and is an attractive alternative to the existing assemblers designed for genomes of lower heterozygosity. PMID:24755901

  10. Clinically symptomatic heterozygous carnitine palmitoyltransferase II (CPT II) deficiency.

    Science.gov (United States)

    Joshi, Pushpa Raj; Deschauer, Marcus; Zierz, Stephan

    2012-12-01

    Two symptomatic patients with heterozygous carnitine palmitoyltransferase II (CPT II) deficiency are reported. Patient 1, a 21-year-old female professional tennis player, suffered from exercise-induced attacks of muscle pain, burning sensations and proximal weakness. Patient 2, a 30-year-old male amateur marathon runner developed muscle cramps and rhabdomyolysis upon extensive exercise and insolation-induced fever. In both patients, the common p.S113L mutation was found in heterozygote state. No second mutation could be found upon sequencing of all the exons of CPT2 gene including exon-intron boundaries. Biochemically, residual CPT activity in muscle homogenate upon inhibition by malonyl-CoA and Triton-X-100 was intermediate between controls and patients with mutations on both alleles. Although CPT II deficiency is an autosomal recessive disorder, the reported patients indicate that heterozygotes might also have typical attacks of myalgia, pareses or rhabdomyolysis. PMID:23184072

  11. Comparison of the effects of fish oil and olive oil on blood lipids and aortic atherosclerosis in Watanabe heritable hyperlipidaemic rabbits

    DEFF Research Database (Denmark)

    Mortensen, Alicja; Hansen, Birgit Fischer; Hansen, Jørgen Fischer; Frandsen, Henrik; Bartnikowska, Elzbieta; Andersen, Peder Søren; Bertelsen, Lone Skoubo

    1998-01-01

    To compare the effects of fish oil and olive oil on the development of atherosclerosis in Watanabe heritable hyperlipidaemic (WHHL) rabbits, 6-week-old animals were given a daily dose (1.5 ml/kg body weight) of fish oil (n 10) or olive oil (n 10) by oral administration for 16 weeks. Plasma...... treatment, and throughout the study thereafter, blood lipids were significantly (P <0.05) lower in the fish-oil group than in the olive-oil group (cholesterol: 17.0 v. 30.3 mmol/l, triacylglycerols 2.97 v. 6.25 mmol/l, at termination). In the fish-oil group cholesterol was significantly lower in...... intermediate-density lipoproteins (2.69 v. 6.76 mmol/l) and VLDL (3.36 v. 11.51 mmol/l). Triacylglycerol levels of intermediate-density lipoproteins and VLDL in the fish-oil group were also significantly lower when compared with the olive-oil group (0.54 v 1.36 mmol/l and 0.92 v. 2.87 mmol/l respectively). No...

  12. Irradiated HMEC from A-T Heterozygous Breast Tissue

    Science.gov (United States)

    Richmond, Robert; Bors, Karen; Cruz, Angela; Pettengil, Olive; Curreri, Peter A. (Technical Monitor)

    2002-01-01

    Women who are heterozygous for ataxia-telangiectasia (A-T) carry a single defective ATM gene in chromosome 11 q22-23, and have been statistically determined with high significance within a defined database to be approximately 5-fold more susceptible for developing breast cancer than their noma1 counterpart. Breast cancer susceptibility of these A-T heterozygotes has been hypothesized to include consequence of response to damage caused by low levels of ionizing radiation. Prophylactic mastectomy specimens were donated by a 41 year-old obligate A-T heterozygote who was located prior to her elective surgery through an existing pedigree. Harvest of that breast tissue provided an isolate of long-term growth human mammary epithelial cells (HMEC), designated WH612/3. An isolate of presumed normal long-term growth HMEC, designated 48R, was obtained from Dr. Martha Stampfer (Lawrence Berkeley Laboratory, University of California), and the A-T heterozygous HMEC were transformed with E6 and E7 oncogenes of human papilloma virus Type-16 in the laboratory of Dr. Ray White (Hunt- Cancer Institute, University of Utah) for use in this study. The objective of this study is to study the expression of end points that may bear on cancer outcome following irradiation of HMEC. Specific end points are cell survival, cell cycle, p53 expression, and apoptosis. Survival curves, immunostaining, and flow cytometery are used to examine these end points. Radiation-induced cell killing shows less shoulder development in the survival curve for WH61U3 compared to 48R HMEC, suggesting less repair of damage in the former HMEC. Additional information is included in the original extended abstract.

  13. 99mTc-Annexin A5 for noninvasive characterization of atherosclerotic lesions: imaging and histological studies in myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits

    International Nuclear Information System (INIS)

    Apoptosis is commonly observed in advanced atherosclerotic lesions. 99mTc-annexin A5 (99mTc-annexin V) has been proposed as a potential tracer for imaging apoptosis in atherosclerotic plaques. Accordingly, we determined the usefulness of 99mTc-annexin A5 as an atherosclerosis imaging tracer in a rabbit model (myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits; WHHLMI rabbits) of spontaneous atherosclerosis. The WHHLMI and control rabbits were injected intravenously with 99mTc-annexin A5. After in vivo planar imaging, the radioactivity in the aorta was measured. Autoradiography, TUNEL staining, Azan-Mallory staining and immunohistological studies were performed serially throughout the aorta. 99mTc-Annexin A5 accumulation in the aorta of the WHHLMI rabbits was 5.6-fold higher than in that of control rabbits. Autoradiography showed heterogeneous multifocal accumulation of 99mTc-annexin A5 in WHHLMI rabbits. 99mTc-Annexin A5 accumulation was highest in the atheromatous lesions (6.2 ± 2.5, %ID x BW/mm2 x 103), followed in decreasing order by neointimal (4.9 ± 1.3), fibroatheromatous (4.5 ± 1.9), and collagen-rich lesions (3.3 ± 1.4). The regional 99mTc-annexin A5 accumulation was significantly correlated with the TUNEL-positive cell density, macrophage density and ''vulnerability index,'' an index of the morphological destabilized characteristics. The in vivo imaging clearly visualized the atherosclerotic lesions in WHHLMI rabbits. The present study in WHHLMI rabbits showed higher 99mTc-annexin A5 accumulation in grade IV atheroma than in other more stable lesions. 99mTc-Annexin A5 may be useful in identifying atheroma that is at higher risk for rupture and possibly in assessing the response to anti-atherosclerotic therapy. (orig.)

  14. Enhanced learning and memory in GAT1 heterozygous mice

    Institute of Scientific and Technical Information of China (English)

    Jun Shi; Youqing Cai; Guoxiang Liu; Neng Gong; Zhenze Liu; Tianle Xu; Zhugang Wang; Jian Fei

    2012-01-01

    γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system.The termination of GABA transmission is through the action of a family of membrane proteins,called GABA transporters (GAT1-4).It is well established that GABA system is involved in the modulation of memory.Our previous study showed that homozygous GAT1-/- mice exhibited impaired hippocampus-dependent learning and memory.To evaluate the impact of endogenous reduced GABA reuptake on mice cognitive behaviors,the ability of learning and memory of heterozygous GAT1+/- mice was detected by the passive avoidance paradigm and Morris water maze.The hole board paradigm was also used to measure changes in anxiety-related behavior or exploratory behavior in such mice.As one form of synaptic plasticity,longterm potentiation was recorded in the mouse hippocampal CA1 area.We found that GAT1+/- mice displayed increased learning and memory,decreased anxiety-like behaviors,and highest synaptic plasticity compared with wild-type and homozygous GAT1-/- mice.Our results suggest that a moderate reduction in GAT1 activity causes the enhancement of learning and memory in mice.

  15. Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy

    Science.gov (United States)

    Dazzo, Emanuela; Fanciulli, Manuela; Serioli, Elena; Minervini, Giovanni; Pulitano, Patrizia; Binelli, Simona; Di Bonaventura, Carlo; Luisi, Concetta; Pasini, Elena; Striano, Salvatore; Striano, Pasquale; Coppola, Giangennaro; Chiavegato, Angela; Radovic, Slobodanka; Spadotto, Alessandro; Uzzau, Sergio; La Neve, Angela; Giallonardo, Anna Teresa; Mecarelli, Oriano; Tosatto, Silvio C.E.; Ottman, Ruth; Michelucci, Roberto; Nobile, Carlo

    2015-01-01

    Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic epilepsy syndrome clinically characterized by focal seizures with prominent auditory symptoms. ADLTE is genetically heterogeneous, and mutations in LGI1 account for fewer than 50% of affected families. Here, we report the identification of causal mutations in reelin (RELN) in seven ADLTE-affected families without LGI1 mutations. We initially investigated 13 ADLTE-affected families by performing SNP-array linkage analysis and whole-exome sequencing and identified three heterozygous missense mutations co-segregating with the syndrome. Subsequent analysis of 15 small ADLTE-affected families revealed four additional missense mutations. 3D modeling predicted that all mutations have structural effects on protein-domain folding. Overall, RELN mutations occurred in 7/40 (17.5%) ADLTE-affected families. RELN encodes a secreted protein, Reelin, which has important functions in both the developing and adult brain and is also found in the blood serum. We show that ADLTE-related mutations significantly decrease serum levels of Reelin, suggesting an inhibitory effect of mutations on protein secretion. We also show that Reelin and LGI1 co-localize in a subset of rat brain neurons, supporting an involvement of both proteins in a common molecular pathway underlying ADLTE. Homozygous RELN mutations are known to cause lissencephaly with cerebellar hypoplasia. Our findings extend the spectrum of neurological disorders associated with RELN mutations and establish a link between RELN and LGI1, which play key regulatory roles in both the developing and adult brain. PMID:26046367

  16. Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy.

    Science.gov (United States)

    Dazzo, Emanuela; Fanciulli, Manuela; Serioli, Elena; Minervini, Giovanni; Pulitano, Patrizia; Binelli, Simona; Di Bonaventura, Carlo; Luisi, Concetta; Pasini, Elena; Striano, Salvatore; Striano, Pasquale; Coppola, Giangennaro; Chiavegato, Angela; Radovic, Slobodanka; Spadotto, Alessandro; Uzzau, Sergio; La Neve, Angela; Giallonardo, Anna Teresa; Mecarelli, Oriano; Tosatto, Silvio C E; Ottman, Ruth; Michelucci, Roberto; Nobile, Carlo

    2015-06-01

    Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic epilepsy syndrome clinically characterized by focal seizures with prominent auditory symptoms. ADLTE is genetically heterogeneous, and mutations in LGI1 account for fewer than 50% of affected families. Here, we report the identification of causal mutations in reelin (RELN) in seven ADLTE-affected families without LGI1 mutations. We initially investigated 13 ADLTE-affected families by performing SNP-array linkage analysis and whole-exome sequencing and identified three heterozygous missense mutations co-segregating with the syndrome. Subsequent analysis of 15 small ADLTE-affected families revealed four additional missense mutations. 3D modeling predicted that all mutations have structural effects on protein-domain folding. Overall, RELN mutations occurred in 7/40 (17.5%) ADLTE-affected families. RELN encodes a secreted protein, Reelin, which has important functions in both the developing and adult brain and is also found in the blood serum. We show that ADLTE-related mutations significantly decrease serum levels of Reelin, suggesting an inhibitory effect of mutations on protein secretion. We also show that Reelin and LGI1 co-localize in a subset of rat brain neurons, supporting an involvement of both proteins in a common molecular pathway underlying ADLTE. Homozygous RELN mutations are known to cause lissencephaly with cerebellar hypoplasia. Our findings extend the spectrum of neurological disorders associated with RELN mutations and establish a link between RELN and LGI1, which play key regulatory roles in both the developing and adult brain. PMID:26046367

  17. Hidden disease susceptibility and sexual dimorphism in the heterozygous knockout of Cyp51 from cholesterol synthesis.

    Directory of Open Access Journals (Sweden)

    Monika Lewinska

    Full Text Available We examined the genotype-phenotype interactions of Cyp51+/- mice carrying one functional allele of lanosterol 14α-demethylase from cholesterol biosynthesis. No distinct developmental or morphological abnormalities were observed by routine visual inspection of Cyp51+/- and Cyp51+/+ mice and fertility was similar. We further collected a large data-set from female and male Cyp51+/- mice and controls fed for 16 weeks with three diets and applied linear regression modeling. We used 3 predictor variables (genotype, sex, diet, and 39 response variables corresponding to the organ characteristics (7, plasma parameters (7, and hepatic gene expression (25. We observed significant differences between Cyp51+/- and wild-type mice in organ characteristics and blood lipid profile. Hepatomegaly was observed in Cyp51+/- males, together with elevated total and low-density lipoprotein cholesterol. Cyp51+/- females fed high-fat, high-cholesterol diet were leaner and had elevated plasma corticosterone compared to controls. We observed elevated hepatocyte apoptosis, mitosis and lipid infiltration in heterozygous knockouts of both sexes. The Cyp51+/- females had a modified lipid storage homeostasis protecting them from weight-gain when fed high-fat high-cholesterol diet. Malfunction of one Cyp51 allele therefore initiates disease pathways towards cholesterol-linked liver pathologies and sex-dependent response to dietary challenge.

  18. 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

  19. Primary defects in the lens underlie complex anterior segment abnormalities of the Pax6 heterozygous eye

    OpenAIRE

    Collinson, J. Martin; Quinn, Jane C.; Buchanan, Malcolm A.; Kaufman, Matthew H.; Wedden, Sarah E.; West, John D.; Hill, Robert E.

    2001-01-01

    We describe lens defects in heterozygous small eye mice, and autonomous deficiencies of Pax6+/− cells in the developing lens of Pax6+/+ ↔ Pax6+/− chimeras. Two separate defects of the lens were identified by analyzing the distribution of heterozygous cells in chimeras: Pax6+/− cells are less readily incorporated into the lens placode than wild type, and those that are incorporated into the lens are not maintained efficiently in the proliferating lens epithelium...

  20. Novel Compound Heterozygous Mutations in the Cathepsin K Gene in Japanese Female Siblings with Pyknodysostosis

    OpenAIRE

    Matsushita, M.(CNS, The University of Tokyo, RIKEN Campus, Saitama, Wako, 351-0198, Japan); Kitoh, H.; Kaneko, H.; Mishima, K.; Itoh, Y.; Hattori, T; Ishiguro, N

    2012-01-01

    We report on female siblings with pyknodysostosis who showed common clinical and radiographic features including disproportionate short stature, dental abnormalities, increased bone density, open fontanelle, and acroosteolysis. Sequence analysis of the cathepsin K (CTSK) gene demonstrated compound heterozygous mutations (935 C>T, A277V and 489 G>C, R122P) in the affected siblings and a heterozygous mutation in their parents. The former missense mutation has previously been reported in 6 unrel...

  1. 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; Magyari, Melinda; Nielsen, Karen Cecilie; Lucamp; Grønskov, Karen; Brøndum-Nielsen, Karen

    2012-01-01

    , 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...

  2. 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…

  3. Bone Mineral Density in Postmenopausal Women Heterozygous for the C282Y HFE Mutation

    Science.gov (United States)

    Gates, Frances; Fulcher, Greg R.

    2016-01-01

    Mutations in the HFE gene may be associated with increased tissue iron stores reflected in an elevated serum ferritin. With homozygous mutation C282Y, the increase in serum ferritin may be associated with tissue damage in the liver, pancreas, and pituitary and with a reduced bone mineral density. With heterozygous mutation C282Y, the degree of iron retention is less but information relating to how a heterozygous C282Y mutation might impact bone mineral density is uncertain. The present study was undertaken to study the relationships between bone mineral density measured by dual energy X-ray absorptiometry and the serum ferritin and serum iron in postmenopausal women heterozygous for the C282Y mutation. The spinal bone mineral density, L2–4, was significantly less than age matched community controls (P = 0.016). There was no significant change in the femoral neck bone mineral density compared to age matched community controls. The correlation between the spinal bone mineral density, L2–4, the femoral neck bone mineral density, and the serum ferritin was not significant. The serum iron correlated significantly inversely with the femoral neck bone mineral density (P = 0.048). The heterozygous C282Y mutation may be associated with impairment of bone cell function in postmenopausal women when only small increases in the serum iron or serum ferritin have occurred. PMID:27123357

  4. Novel compound heterozygous NMNAT1 variants associated with Leber congenital amaurosis

    DEFF Research Database (Denmark)

    Siemiatkowska, Anna M; van den Born, L Ingeborgh; van Genderen, Maria M; Bertelsen, Mette; Zobor, Ditta; Rohrschneider, Klaus; van Huet, Ramon A C; Nurohmah, Siska; Klevering, B Jeroen; Kohl, Susanne; Faradz, Sultana M H; Rosenberg, Thomas; den Hollander, Anneke I; Collin, Rob W J; Cremers, Frans P M

    2014-01-01

    , were screened in 532 additional patients with retinal dystrophies. This cohort encompassed 108 persons with isolated or autosomal recessive cone-rod dystrophy (CRD), 271 with isolated or autosomal recessive retinitis pigmentosa (RP), and 49 with autosomal dominant RP, as well as 104 persons with LCA in...... whom the causative mutation was previously identified. RESULTS: Compound heterozygous alterations were found in six patients with LCA and in one person with early-onset RP. All except one carried the common p.E257K variant on one allele. Macular atrophy was absent in one patient, who carried this......: Although macular atrophy can occur in LCA and CRD, no NMNAT1 mutations were found in the latter cohort. NMNAT1 variants were also not found in a large group of patients with sporadic or autosomal recessive RP. The enrichment of p.E257K ina heterozygous state in patients with LCA versus controls suggests...

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

    DEFF Research Database (Denmark)

    van Nuenen, BF; Siebner, Hartwig; Weiss, MM; Bloem, BR; Reetz, K; van Eimeren, T; Lohmann, K; Hagenah, J; Pramstaller, PP; Binkofski, F; Klein, C

    2008-01-01

    OBJECTIVE: To use a combined neurogenetic-neuroimaging approach to examine the functional consequences of preclinical dopaminergic nigrostriatal dysfunction in the human motor system. Specifically, we examined how a single heterozygous mutation in different genes associated with recessively......MRI, participants performed simple sequences of three thumb-to-finger opposition movements with their right dominant hand. Since heterozygous Parkin and PINK1 mutations cause a latent dopaminergic nigrostriatal dysfunction, we predicted a compensatory recruitment of those rostral premotor areas that are normally...... 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...

  6. The Characteristics of Heterozygous Protein Truncating Variants in the Human Genome.

    Science.gov (United States)

    Bartha, István; Rausell, Antonio; McLaren, Paul J; Mohammadi, Pejman; Tardaguila, Manuel; Chaturvedi, Nimisha; Fellay, Jacques; Telenti, Amalio

    2015-12-01

    Sequencing projects have identified large numbers of rare stop-gain and frameshift variants in the human genome. As most of these are observed in the heterozygous state, they test a gene's tolerance to haploinsufficiency and dominant loss of function. We analyzed the distribution of truncating variants across 16,260 autosomal protein coding genes in 11,546 individuals. We observed 39,893 truncating variants affecting 12,062 genes, which significantly differed from an expectation of 12,916 genes under a model of neutral de novo mutation (pimpact. The study of protein truncating variants delineates the essential genome and, more generally, identifies rare heterozygous variants as an unexplored source of diversity of phenotypic traits and diseases. PMID:26642228

  7. 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. PMID:26965573

  8. Exposure to low-dose rotenone precipitates synaptic plasticity alterations in PINK1 heterozygous knockout mice.

    Science.gov (United States)

    Martella, G; Madeo, G; Maltese, M; Vanni, V; Puglisi, F; Ferraro, E; Schirinzi, T; Valente, E M; Bonanni, L; Shen, J; Mandolesi, G; Mercuri, N B; Bonsi, P; Pisani, A

    2016-07-01

    Heterozygous mutations in the PINK1 gene are considered a susceptibility factor to develop early-onset Parkinson's disease (PD), as supported by dopamine hypometabolism in asymptomatic mutation carriers and subtle alterations of dopamine-dependent striatal synaptic plasticity in heterozygous PINK1 knockout (PINK1(+/-)) mice. The aim of the present study was to investigate whether exposure to low-dose rotenone of heterozygous PINK1(+/-) mice, compared to their wild-type PINK1(+/+) littermates, could impact on dopamine-dependent striatal synaptic plasticity, in the absence of apparent structural alterations. Mice were exposed to a range of concentrations of rotenone (0.01-1mg/kg). Chronic treatment with concentrations of rotenone up to 0.8mg/kg did not cause manifest neuronal loss or changes in ATP levels both in the striatum or substantia nigra of PINK1(+/-) and PINK1(+/+) mice. Moreover, rotenone (up to 0.8mg/kg) treatment did not induce mislocalization of the mitochondrial membrane protein Tom20 and release of cytochrome c in PINK1(+/-) striata. Accordingly, basic electrophysiological properties of nigral dopaminergic and striatal medium spiny neurons (MSNs) were normal. Despite the lack of gross alterations in neuronal viability in chronically-treated PINK1(+/-), a complete loss of both long-term depression (LTD) and long-term potentiation (LTP) was recorded in MSNs from PINK1(+/-) mice treated with a low rotenone (0.1mg/kg) concentration. Even lower concentrations (0.01mg/kg) blocked LTP induction in heterozygous PINK1(+/-) MSNs compared to PINK1(+/+) mice. Of interest, chronic pretreatment with the antioxidants alpha-tocopherol and Trolox, a water-soluble analog of vitamin E and powerful antioxidant, rescued synaptic plasticity impairment, confirming that, at the doses we utilized, rotenone did not induce irreversible alterations. In this model, chronic exposure to low-doses of rotenone was not sufficient to alter mitochondrial integrity and ATP production, but

  9. Effect of heterozygous β-thalassaemia trait on coronary atherosclerosis via coronary artery disease risk factors: a preliminary study

    OpenAIRE

    Hashemi, M.; Shirzadi, E; Talaei, Z; L. Moghadas; Shaygannia, I; Yavari, M; AMIRI, N.; H. Taheri; H. Montazeri; Shamsolkottabi, H

    2007-01-01

    Summary Background Thalassaemia is considered the most common genetic disorder worldwide. An association between the heterozygous β-thalassaemia trait and myocardial infarction has previously been observed. However, the relationship between heterozygous β-thalassaemia and atherosclerosis, considering other coronary artery disease (CAD) risk factors, has remained unclear. Methods A case-control study was conducted to evaluate the hypothesis that thalassaemia minor affects the likelihood of ath...

  10. Glucose-6-phosphate Dehydrogenase Deficiency and Malaria: Cytochemical Detection of Heterozygous G6PD Deficiency in Women

    OpenAIRE

    Peters, Anna L.; Van Noorden, Cornelis J. F.

    2009-01-01

    Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a X-chromosomally transmitted disorder of the erythrocyte that affects 400 million people worldwide. Diagnosis of heterozygously-deficient women is complicated: as a result of lyonization, these women have a normal and a G6PD-deficient population of erythrocytes. The cytochemical assay is the only reliable assay to discriminate between heterozygously-deficient women and non-deficient women or homozygously-deficient women. G6PD deficiency ...

  11. Comparison of classical and probable heterozygous familial hypercholesterolemia cases with controls

    Directory of Open Access Journals (Sweden)

    Samia Perwaiz Khan

    2012-07-01

    Full Text Available Backgroud: Heterozygous familial hypercholesterolemia are either classical cases with high LDL-C levels, tendon xanthomas and LDL receptor gene mutation or probable cases with hypercholesterolemia without known LDL receptor gene mutations. Aims & Objectives: This study was done to compare the severity of hypercholesterolemia and risk of CVD in classical and probable cases of heterozygous familial hypercholesterolemia in tertiary care hospitals of Karachi. This was a case-series done from June 2008 to July 2010 at Dr Ziauddin Hospital and National Institute of Cardiovascular Diseases, Karachi, Pakistan. Methods: Out of more than 240 patients with dyslipidemia or premature coronary artery diseases 120 patients who had primary hypercholesterolemia and were found to have total cholesterol >230mg/dL and LDL-C >160mg/dL were included in the study. All these cases had premature coronary artery diseases or had a family history of coronary artery diseases. They were grouped as classical or probable cases depending on raised LDL-C, xanthelasmas, xanthoma, premature coronary artery diseases and LDL-R gene mutations. Their blood samples were collected after twelve hours fasting. PCR was done for mutation specific primers for exons 3, 4, 9 and 14. Results: Out of these 120 patients with heterozygous familial hypercholesterolemia, classical cases with LDL-receptor gene mutation were 42(35% and probable cases without LDL-receptor gene mutations were 78(65%. Eleven (27% of these classical cases had severe hypercholesterolemia having total cholesterol (>290mg/dL and LDL-C (>200mg/dL and were found to have xanthelasmas, xanthomas and arcus cornealis. Discussion/Conclusions: Amongst the HeFH patients from the tertiary care hospitals of Karachi, classical cases with tendon xanthomas and LDL receptor gene mutations had severe hypercholesterolemia with greater risk of CVD, they required more aggressive treatment. Probable cases were also at risk of CVD and needed

  12. Genome editing. The mutagenic chain reaction: a method for converting heterozygous to homozygous mutations.

    Science.gov (United States)

    Gantz, Valentino M; Bier, Ethan

    2015-04-24

    An organism with a single recessive loss-of-function allele will typically have a wild-type phenotype, whereas individuals homozygous for two copies of the allele will display a mutant phenotype. We have developed a method called the mutagenic chain reaction (MCR), which is based on the CRISPR/Cas9 genome-editing system for generating autocatalytic mutations, to produce homozygous loss-of-function mutations. In Drosophila, we found that MCR mutations efficiently spread from their chromosome of origin to the homologous chromosome, thereby converting heterozygous mutations to homozygosity in the vast majority of somatic and germline cells. MCR technology should have broad applications in diverse organisms. PMID:25908821

  13. Effect of auditory stress agents on heterozygous German waltzing guinea pigs

    Institute of Scientific and Technical Information of China (English)

    Åsa Skj€onsberg; Maoli Duan; Ann-Christin Johnson; Mats Ulfendahl

    2014-01-01

    The German waltzing guinea pig is a strain of animals expressing deafness and severe balance disorders at birth. The mutation arose spontaneously in a breeding facility in Germany and as the affected animals show a characteristic waltzing behavior, the strain is named the German waltzing guinea pig. The strain is presently bred only at Karolinska Institutet. The hereditary inner ear impairment has a recessive mode of inheritance and the strain thus produces not only affected homozygotes but also symptom-free heterozygotes and fully normal offspring. The outcome depends solely on the genotype of the parents. The heterozygotes, which have obtained the“waltzing”gene from one parent only, have normal hearing and no balance dysfunction. The heterozygous animals appear normal but will, in turn, carry the genetic defect to the next generation. The present thesis is focused on these animals. Noise and ototoxic drugs are well known stress factors that interfere negatively with the hearing organ in both humans and animals, causing hearing impairment. However, the inter-individual variability in susceptibility to auditory stress factors is surprisingly large, most likely due to different genetic predisposition. In this study, heterozygous animals of the German waltzing guinea pig, animals carrying a genetic defect known to cause severe hearing impairment, were used to study how an unexplored gene for deafness interacts with auditory stress agents, i.e. noise exposure and the ototoxic drugs gentamicin and cisplatin. Animals were exposed to both narrowband as well as broadband noise at different ages and hearing thresholds were measured using ABRs. Heterozygotes of the German waltzing guinea pig showed less threshold shifts compared to control strains. Older animals were less affected by the noise trauma than younger animals. To test the hypothesis that the efferent system contributes to protection of the inner ear against noise trauma, measurements using a new method of

  14. Interaction of the heterozygous nude gene with the asplenia trait in mammary tumorigenesis

    OpenAIRE

    1985-01-01

    The BALB/c mouse strain has been shown to contain endogenous mouse mammary tumor virus (MMTV) proviral sequences. However, no exogenous MMTV particles have been detected in their tissues. Female BALB/c mice from our colonies exhibit a very low incidence of spontaneous mammary tumors (SMT); less than 1% at up to 20 mo of age. Immunodeficient BALB/c mice heterozygous for the nude gene (nu/+, +/+), for the dominant hemimelia gene associated with asplenia (+/+, Dh/+), or for both traits (nu/+, Dh...

  15. Impact of heterozygous mutations in BRCA1 and BRCA2. Sensitivity to genotoxic drugs

    International Nuclear Information System (INIS)

    The carriers of heterozygous mutations in BRCA1 / 2 have a high risk of developing breast cancer. The loss of the normal allele with consequent loss of function is frequently observed in tumor level. Since these genes involved in the cellular response to genetic damage, loss of function can determine differences in sensitivity to genotoxic agents. In this study investigated whether heterozygous mutations in BRCA1 / 2 modify the sensitivity to genotoxic drugs using lymphoblastic cell lines developed from individuals who carry no mutation carriers and heterozygous for BRCA1 / 2. Materials and methods. Chemo sensitivity of the cell lines was compared lymphoblastoid GM13709 (mutation in exon 11 of BRCA1 2187delA), GM14622 (level 607stop mutation in exon 11 of BRCA2) and GM 14453 (normal BRCA1 / 2) from exposure to Adriamycin (0.2-2.5 mM) and Cisplatin (0.625- 80mM) through the test of cell viability based on MTT reduction. It determined the inhibitory concentration 50 (IC50) from curves regression dose-response obtained after 24 hours of drug exposure. It 5 independent experiments performed in triplicate. Results. The line GM14622 was significantly (P = 0.003) more sensitive to Adriamycin (IC50: 0.585 mM) than the Control GM14453 (IC50: 1.364 mM) online while GM13709 was similar to the control (IC50: 1.324 mM) response. Turn the line GM14622 was also significantly (P = 0.01) more sensitive cisplatin (IC50: 12.7 mM) than the line GM14453 (IC50: 28.6mm) and GM13709 had the same response as the (IC50: 28.6 mM) control. Discussion and Conclusions. Our results suggest that mutations deleterious heterozygous BRCA2 may confer increased sensitivity to drugs genotoxic, which may have implications in the management of patients carrying or BRCA2 mutations in women with sporadic breast cancer exhibit low expression of BRCA2

  16. Rare case of homozygous epimerase deficiency and heterozygous of duarte 2 variant.

    Science.gov (United States)

    Koliofoti, Eleana Georgia; Gkentzi, Despoina; Varvarigou, Anastasia; Trigka, Maria; Schulpis, Kleopatra

    2014-09-01

    We present a rare case of galactosemia identified by a positive screening test. A 20-day-old female infant was admitted with jaundice and bloody stained diarrhea. There was no history of fever, convulsions, abdominal distention, or bleeding from other sites. Laboratory findings indicated elevated total billirubin, alanine transaminase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase. International normalized ratio (INR), prothrombin time (PT) and activated partial thromboplastin time (aPTT) were prolonged. Total vitamin D was low. Quantitative assay for GALT in hemolysates of RBC: 17 μmol/min/mg protein (normal values: 20-35) (compound heterozygous for D2/N: 16-19). GALE level in RBC hemolysate: 11.5 μmol/h/g Hb (normal values 19-35). Our patient was homozygous for the peripheral form of epimerase deficiency galactosemia, as well as heterozygous for GALT/(D2) deficiency. She was started on galactose restricted diet and vitamin supplementation. At the age of 10 months, the patient appeared normal with no signs of developmental delay or eye-cataract. PMID:24859500

  17. Higher Incidence of Lung Adenocarcinomas Induced by DMBA in Connexin 43 Heterozygous Knockout Mice

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    Krishna Duro de Oliveira

    2013-01-01

    Full Text Available Gap junctions are communicating junctions which are important for tissue homeostasis, and their disruption is involved in carcinogenic processes. This study aimed to verify the influence of deletion of one allele of the Connexin 43 gene on cancer incidence in different organs. The 7, 12-dimethylbenzanthracene (DMBA carcinogenic model, using hebdomadary doses by gavage of 9 mg per animal, was used to induce tumors in Connexin 43 heterozygous or wild-type mice. The experiment began in the eighth week of the mice life, and all of them were euthanized when reaching inadequate physical condition, or at the end of 53 weeks. No statistical differences occurred for weight gain and cancer survival time (P=0.9853 between heterozygous and wild-type mice. Cx43+/− mice presented significantly higher susceptibility to lung cancer (P=0.0200 which was not evidenced for benign neoplasms (P=0.3449. In addition, incidence of ovarian neoplasms was 2.5-fold higher in Cx43+/− mice, although not statistically significant. Other organs showed a very similar cancer occurrence between Cx43 groups. The experiment strengthens the evidence of the relationship between Connexin 43 deficiency and carcinogenesis.

  18. Altered expression of neuropeptides in FoxG1-null heterozygous mutant mice.

    Science.gov (United States)

    Frullanti, Elisa; Amabile, Sonia; Lolli, Maria Grazia; Bartolini, Anna; Livide, Gabriella; Landucci, Elisa; Mari, Francesca; Vaccarino, Flora M; Ariani, Francesca; Massimino, Luca; Renieri, Alessandra; Meloni, Ilaria

    2016-02-01

    Foxg1 gene encodes for a transcription factor essential for telencephalon development in the embryonic mammalian forebrain. Its complete absence is embryonic lethal while Foxg1 heterozygous mice are viable but display microcephaly, altered hippocampal neurogenesis and behavioral and cognitive deficiencies. In order to evaluate the effects of Foxg1 alteration in adult brain, we performed expression profiling in total brains from Foxg1+/- heterozygous mutants and wild-type littermates. We identified statistically significant differences in expression levels for 466 transcripts (Pgenes was found a group of genes expressed in the basal ganglia and involved in the control of movements. A relevant (three to sevenfold changes) and statistically significant increase of expression, confirmed by qRT-PCR, was found in two highly correlated genes with expression restricted to the hypothalamus: Oxytocin (Oxt) and Arginine vasopressin (Avp). These neuropeptides have an important role in maternal and social behavior, and their alteration is associated with impaired social interaction and autistic behavior. In addition, Neuronatin (Nnat) levels appear significantly higher both in Foxg1+/- whole brain and in hippocampal neurons after silencing Foxg1, strongly suggesting that it is directly or indirectly repressed by Foxg1. During fetal and neonatal brain development, Nnat may regulate neuronal excitability, receptor trafficking and calcium-dependent signaling and, in the adult brain, it is predominantly expressed in parvalbumin-positive GABAergic interneurons. Overall, these results implicate the overexpression of a group of neuropeptides in the basal ganglia, hypothalamus, cortex and hippocampus in the pathogenesis FOXG1 behavioral impairments. PMID:25966633

  19. HEK293T Cells Are Heterozygous for CCR5 Delta 32 Mutation

    Science.gov (United States)

    Qi, Chunxia; Jia, Xiaopeng; Lu, Lingling; Ma, Ping; Wei, Min

    2016-01-01

    C-C chemokine receptor 5 (CCR5) is a receptor for chemokines and a co-receptor for HIV-1 entry into the target CD4+ cells. CCR5 delta 32 deletion is a loss-of-function mutation, resistant to HIV-1 infection. We tried to induce the CCR5 delta 32 mutation harnessing the genome editing technique, CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR and CRISPR associated protein 9, Cas9) in the commonly used cell line human embryonic kidney HEK 293T cells. Surprisingly, we found that HEK293T cells are heterozygous for CCR5 delta 32 mutation, in contrast to the wild type CCR5 cells, human acute T cell leukemia cell line Jurkat and human breast adenocarcinoma cell line MDA-MB-231 cells. This finding indicates that at least one human cell line is heterozygous for the CCR5 delta 32 mutation. We also found that in PCR amplification, wild type CCR5 DNA and mutant delta 32 DNA can form mismatched heteroduplex and move slowly in gel electrophoresis. PMID:27042825

  20. Compound heterozygous PKHD1 variants cause a wide spectrum of ductal plate malformations.

    Science.gov (United States)

    Courcet, Jean-Benoît; Minello, Anne; Prieur, Fabienne; Morisse, Laurent; Phelip, Jean-Marc; Beurdeley, Alain; Meynard, Daniel; Massenet, Denis; Lacassin, Flore; Duffourd, Yannis; Gigot, Nadège; St-Onge, Judith; Hillon, Patrick; Vanlemmens, Claire; Mousson, Christiane; Cerceuil, Jean-Pierre; Guiu, Boris; Thevenon, Julien; Thauvin-Robinet, Christel; Jacquemin, Emmanuel; Rivière, Jean-Baptiste; Michel-Calemard, Laurence; Faivre, Laurence

    2015-12-01

    Ductal plate malformations (DPM) present with a wide phenotypic spectrum comprising Von Meyenburg complexes (VMC), Caroli disease (CD), Caroli syndrome (CS), and autosomal recessive polycystic kidney disease (ARPKD). Variants in PKHD1 are responsible for ARPKD and CS with a high inter- and intra-familial phenotypic variability. Rare familial cases of CD had been reported and exceptional cases of CD are associated with PKHD1 variants. In a family of three siblings presenting with a wide spectrum of severity of DPM, we performed whole exome sequencing and identified two PKHD1 compound heterozygous variants (c.10444G>A; p.Arg3482Cys and c.5521C>T; p.Glu1841Lys), segregating with the symptoms. Two compound heterozygous PKHD1 variants, including one hypomorphic variant, were identified in two other familial cases of DPM with at least one patient presenting with CD. This report widens the phenotypic variability of PKHD1 variants to VMC, and others hepatic bile ducts malformations with inconstant renal phenotype in adults and highlights the important intra-familial phenotypic variability. It also showed that PKHD1 might be a major gene for CD. This work adds an example of the contribution of exome sequencing, not only in the discovery of new genes but also in expanding the phenotypic spectrum of well-known disease-associated genes, using reverse phenotyping. © 2015 Wiley Periodicals, Inc. PMID:26385851

  1. 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)

    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 [14C]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 125I-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

  2. Description of the phenotypes of 63 heterozygous, homozygous and compound heterozygous patients carrying the Hb Groene Hart [α119(H2)Pro→Ser; HBA1: c.358C>T] variant.

    Science.gov (United States)

    Joly, Philippe; Lacan, Philippe; Garcia, Caroline; Francina, Alain

    2014-01-01

    We here report the phenotypes and genotypes of 63 patients of North African origin, carriers of Hb Groene Hart [Hb GH, α119(H2)Pro → Ser; HBA1: c.358C>T], an α(+)-thalassemia (α(+)-thal) hemoglobin (Hb) variant. Fifty patients were heterozygous, five were homozygous and eight also carried the common -α(3.7) (rightward) deletion in compound heterozygosity. The expression of the α(GH)-globin chain is increased in the following order: heterozygous, compound heterozygous and homozygous. Parallel significant changes of mean corpuscular Hb (MCH) and mean corpuscular volume (MCV) were also observed. Our large cohort of Hb GH carriers could have been obtained by the systematic realization of globin chain separation by reversed phase liquid chromatography (RP-LC) in our routine Hb testing. PMID:24111644

  3. A hybrid BAC physical map of potato: a framework for sequencing a heterozygous genome

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    de Boer Jan M

    2011-12-01

    Full Text Available Abstract Background Potato is the world's third most important food crop, yet cultivar improvement and genomic research in general remain difficult because of the heterozygous and tetraploid nature of its genome. The development of physical map resources that can facilitate genomic analyses in potato has so far been very limited. Here we present the methods of construction and the general statistics of the first two genome-wide BAC physical maps of potato, which were made from the heterozygous diploid clone RH89-039-16 (RH. Results First, a gel electrophoresis-based physical map was made by AFLP fingerprinting of 64478 BAC clones, which were aligned into 4150 contigs with an estimated total length of 1361 Mb. Screening of BAC pools, followed by the KeyMaps in silico anchoring procedure, identified 1725 AFLP markers in the physical map, and 1252 BAC contigs were anchored the ultradense potato genetic map. A second, sequence-tag-based physical map was constructed from 65919 whole genome profiling (WGP BAC fingerprints and these were aligned into 3601 BAC contigs spanning 1396 Mb. The 39733 BAC clones that overlap between both physical maps provided anchors to 1127 contigs in the WGP physical map, and reduced the number of contigs to around 2800 in each map separately. Both physical maps were 1.64 times longer than the 850 Mb potato genome. Genome heterozygosity and incomplete merging of BAC contigs are two factors that can explain this map inflation. The contig information of both physical maps was united in a single table that describes hybrid potato physical map. Conclusions The AFLP physical map has already been used by the Potato Genome Sequencing Consortium for sequencing 10% of the heterozygous genome of clone RH on a BAC-by-BAC basis. By layering a new WGP physical map on top of the AFLP physical map, a genetically anchored genome-wide framework of 322434 sequence tags has been created. This reference framework can be used for anchoring and

  4. Structural and functional influences of coagulation factor XIII subunit B heterozygous missense mutants.

    Science.gov (United States)

    Thomas, Anne; Biswas, Arijit; Ivaskevicius, Vytautas; Oldenburg, Johannes

    2015-07-01

    The coagulation factor XIII(FXIII) is a plasma circulating heterotetrameric protransglutaminase that acts at the end of the coagulation cascade by covalently cross-linking preformed fibrin clots (to themselves and to fibrinolytic inhibitors) in order to stabilize them against fibrinolysis. It circulates in the plasma as a heterotetramer composed of two homomeric catalytic Factor XIIIA2 (FXIIIA2) and two homomeric protective/carrier Factor XIIIB2 subunit (FXIIIB2). Congenital deficiency of FXIII is of two types: severe homozygous/compound heterozygous FXIII deficiency which results in severe bleeding symptoms and mild heterozygous FXIII deficiency which is associated with mild bleeding (only upon trauma) or an asymptomatic phenotype. Defects in the F13B gene (Factor XIIIB subunit) occur more frequently in mild FXIII deficiency patients than in severe FXIII deficiency. We had recently reported secretion-related defects for seven previously reported F13B missense mutations. In the present study we further analyze the underlying molecular pathological mechanisms as well as the heterozygous expression phenotype for these mutations using a combination of in vitro heterologous expression (in HEK293T cells) and confocal microscopy. In combination with the in vitro work we have also performed an in silico solvated molecular dynamic simulation study on previously reported FXIIIB subunit sushi domain homology models in order to predict the putative structure-functional impact of these mutations. We were able to categorize the mutations into the following functional groups that: (1) affect antigenic stability as well as binding to FXIIIA subunit, that is, Cys5Arg, Cys316Phe, and Pro428Ser (2) affect binding to FXIIIA subunit with little or no influence on antigenic stability, that is, Ile81Asn and Val401Gln c) influence neither aspects and are most likely causality linked polymorphisms or functional polymorphisms, that is, Leu116Phe and Val217Ile. The Cys5Arg mutation was the

  5. Developmental abnormalities induced by X-irradiation in P53 deficient or heterozygous mice

    International Nuclear Information System (INIS)

    Full text: In order to assess the influence of a p53 mutation on radiation-induced developmental effects, males heterozygous for the p53 mutation (mimicking the human Li-Fraumeni syndrome) were crossed with C57BL females. Their heterozygous p53+/- progeny was mated with each other, in order to obtain p53+/- (50%), p53-/- (25 %) and p53+/+ (25 %) embryos. Pregnant females were X-irradiated with 0.5 Gy on days 1 (pre-implantation period), 8 or 11 (organogenesis period) of gestation. Dissection of the pregnant females occurred on day 19 of gestation. P53 genotype was determined by PCR from small pieces of soft foetal tissues. In non-irradiated animals, slightly less p53-/- foetuses were found upon dissection than expected, probably reflecting a predominant elimination of these embryos during gestation. Exencephaly was the only external malformation found in foetuses from non-irradiated females, affecting as much as 5 of the 91 living foetuses of this series. Four of those were p53-/- and one was p53+/-. In animals irradiated on day 1 of pregnancy, prenatal mortality was increased, predominantly affecting the p53-/- embryos. Among the 100 living foetuses obtained in this series, 2 showed exencephaly, both of them being p53-/-. This lower frequency of malformed foetuses compared to non-irradiated animals could be due to an increased elimination of p53-/- foetuses or embryos after irradiation. The proportion of living p53-/- foetuses that were obtained after irradiation on day 8 was also lower than expected, and elimination preferentially affected female foetuses. Malformations were twice as frequent as in the non-irradiated group, and predominantly affected female foetuses (73%). Abnormal foetuses were either p53-/- (6/94) or p53+/- (5/94). Interestingly, in addition to exencephaly, other various external malformations were found in this group, including cephalic oedema, gastroschisis, polydactyly and cleft palate. In foetuses irradiated on day 11 of their development

  6. Haplotype inference from unphased SNP data in heterozygous polyploids based on SAT

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    Achenbach Ute

    2008-07-01

    Full Text Available Abstract Background Haplotype inference based on unphased SNP markers is an important task in population genetics. Although there are different approaches to the inference of haplotypes in diploid species, the existing software is not suitable for inferring haplotypes from unphased SNP data in polyploid species, such as the cultivated potato (Solanum tuberosum. Potato species are tetraploid and highly heterozygous. Results Here we present the software SATlotyper which is able to handle polyploid and polyallelic data. SATlo-typer uses the Boolean satisfiability problem to formulate Haplotype Inference by Pure Parsimony. The software excludes existing haplotype inferences, thus allowing for calculation of alternative inferences. As it is not known which of the multiple haplotype inferences are best supported by the given unphased data set, we use a bootstrapping procedure that allows for scoring of alternative inferences. Finally, by means of the bootstrapping scores, it is possible to optimise the phased genotypes belonging to a given haplotype inference. The program is evaluated with simulated and experimental SNP data generated for heterozygous tetraploid populations of potato. We show that, instead of taking the first haplotype inference reported by the program, we can significantly improve the quality of the final result by applying additional methods that include scoring of the alternative haplotype inferences and genotype optimisation. For a sub-population of nineteen individuals, the predicted results computed by SATlotyper were directly compared with results obtained by experimental haplotype inference via sequencing of cloned amplicons. Prediction and experiment gave similar results regarding the inferred haplotypes and phased genotypes. Conclusion Our results suggest that Haplotype Inference by Pure Parsimony can be solved efficiently by the SAT approach, even for data sets of unphased SNP from heterozygous polyploids. SATlotyper is

  7. 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

    2016-05-01

    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

  8. [Stroke and iridodonesis revealing a homocystinuria caused by a compound heterozygous mutation of cystathionine beta-synthase].

    Science.gov (United States)

    Lefaucheur, R; Triquenot-Bagan, A; Quillard, M; Genevois, O; Hannequin, D

    2008-01-01

    Iridodonesis or tremulous iris is a clinical sign of ectopia lentis which is frequently associated with homocystinuria. We present a forty-two-year-old woman victim of a left middle cerebral artery ischemic stroke. The clinical examination found bilateral iridodonesis and laboratory tests showed an increased level of serum homocysteine and homocystinuria. Homocystinuria was caused by a compound heterozygous I278T and D444N mutation of cystathionine beta-synthase (CBS) gene and also a C667T heterozygous polymorphism of methylene-tetrahydrofolate-reductase gene. This case was atypical because of the incomplete phenotype, development of complications in adulthood and the association of a rare compound heterozygous mutation of the CBS gene. PMID:18805305

  9. 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)

    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 (x2y2) and EII (α2y2) 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 y4 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 y4. Mouse y4 has a high affinity for oxygen, P50 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

  10. The mutagenic chain reaction: a method for converting heterozygous to homozygous mutations

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    Gantz, Valentino M.; Bier, Ethan

    2015-01-01

    An organism with a single recessive loss-of-function allele will typically have a wild-type phenotype while individuals homozygous for two copies of the allele will display a mutant phenotype. Here, we develop a method that we refer to as the mutagenic chain reaction (MCR), which is based on the CRISPR/Cas9 genome editing system for generating autocatalytic mutations to generate homozygous loss-of-function mutations. We demonstrate in Drosophila that MCR mutations efficiently spread from their chromosome of origin to the homologous chromosome thereby converting heterozygous mutations to homozygosity in the vast majority of somatic and germline cells. MCR technology should have broad applications in diverse organisms. PMID:25908821

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

    International Nuclear Information System (INIS)

    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 123I-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 123I-LDL binding by prickly pear in FH-patients in vivo and indicate that prickly pear exerts a significant hypolipidemic action via receptor upregulation. (author)

  12. Lung Adenocarcinoma with Pulmonary Miliary Metastases and Complex Somatic Heterozygous EGFR Mutation

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    Alexandre Schaller

    2014-11-01

    Full Text Available The pretreatment detection of an activating mutation of EGFR is now routinely performed in metastatic nonsquamous non-small cell lung cancer (NSCLC. The therapeutic impact of such a detection is major, as patients with advanced NSCLC exhibiting a mutation of exon 19 or 21 will benefit from EGFR-tyrosine kinase inhibitors (TKI. The presence of an EGFR resistance mutation, such as T790M in EGFR-TKI-naïve patients, is seldom looked for and is related either to a germinal mutation or to somatically mutated subclones. It has a negative predictive impact. We present the case of a patient with a lung papillary adenocarcinoma and miliary intrapulmonary metastases whose tumor displays a somatic complex heterozygous EGFR mutation, combining L858R (exon 21 and a primary resistance mutation T790M (exon 20, both detected by direct sequencing.

  13. Cancer Risk-Assessment of Radiation Damage in Ataxia Telangiectasia Heterozygous Human Breast Epithelial Cell Cultures

    Science.gov (United States)

    Applewhite, Lisa C.

    2002-01-01

    This paper describes the study of the markers of cellular changes that are found during the onset of carcinogenesis. Several of the biological factors are markers of stress response, oncoprotein expression, and differentiation factors. Oxidative stress response agents such as heat shock proteins (HSPs) protect cells from oxidative stresses such as ionizing radiation. The onocoprotein HER-2/neu, a specific breast cancer marker, indicates early onset of cancer. Additional structural and morphogenetic markers of differentiation were considered in order to determine initial cellular changes at the initial onset of cancer. As an additional consideration, all-trans retinoic acid (RA), a differentiation agent, was considered because of its known role in regulating normal differentiation and inhibiting tumor proliferation via specific nuclear receptors. This paper discusses study and results of the preliminary analyses of gamma irradiation of AT heterozygous human breast epithelial cells (WH). Comparisons are also made of the effects various RA concentrations post-irradiation.

  14. A novel heterozygous missense mutation in the UMOD gene responsible for Familial Juvenile Hyperuricemic Nephropathy

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    Clemente Carla

    2005-01-01

    Full Text Available Abstract Background Familial Juvenile Hyperuricemic Nephropathy is an autosomal dominant nephropathy, characterized by decreased urate excretion and progressive interstitial nephritis. Mutations in the uromodulin coding UMOD gene have been found responsible for the disease in some families. Case presentation We here describe a novel heterozygous p.K307T mutation in an affected female with hyperuricemia, renal cysts and renal failure. The proband's only son is also affected and the mutation was found to segregate with the disease. Conclusions This mutation is the fourth reported in exon 5. Initial studies identified a mutation clustering in exon 4 and it has been recommended that sequencing this exon alone should be the first diagnostic test in patients with chronic interstitial nephritis with gout or hyperuricemia. However, regarding the increasing number of mutations being reported in exon 5, we now suggest that sequencing exon 5 should also be performed.

  15. Leprechaunism (Donohue syndrome): a case bearing novel compound heterozygous mutations in the insulin receptor gene.

    Science.gov (United States)

    Kawashima, Yuki; Nishimura, Rei; Utsunomiya, Akari; Kagawa, Reiko; Funata, Hiroaki; Fujimoto, Masanobu; Hanaki, Keiichi; Kanzaki, Susumu

    2013-01-01

    Leprechaunism (Donohue syndrome) is the most severe type of insulin receptor (INSR) gene anomaly with the majority of patients surviving for only 2 years. We report a surviving 2 -year-old male with leprechaunism, bearing novel compound heterozygous mutations in the INSR. The patient is a Japanese boy with acanthosis nigricans, lack of subcutaneous fat, hirsutism, thick lips, gum hypertrophy and extremely high insulin levels (6702 mU/mL). He was as having identified novel compound heterozygous mutations in INSR (p.T910M and p. E1047K). At 24 day-old, recombinant human insulin-like growth factor 1 (rh-IGF1) treatment was started because of poor weight gain. At 2 years old, the patient's serum glucose level and HbA1C value had worsened, and both a bolus of rh-IGF-1 and a subcutaneous injection of a rapid-acting insulin analog after meals, in addition to α-glycosidase inhibitor, were initiated from 2 years onward. Oxygen administration and biphasic positive airway pressure treatment were also initiated from 2 years old due to upper airway obstruction with adenoidal hypertrophy. In the experiments conducted using COS7 cells homozygously transfected with the INSR mutation, T910M INSR failed to process the proreceptor and decreased insulin-stimulated tyrosine phosphorylation. E1047K INSR resulted in a complete absence of insulin-stimulated tyrosine phosphorylation. These findings suggest the near absence of INSR in this patient. We consider that the rhIGF1 treatment contributed to his long survival, but it was not able to prevent his diabetic condition. Our report provides important insights into the function of INSR, and for the treatment of leprechaunism. PMID:22972224

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

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    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. Hippocampal dysfunction in the Euchromatin histone methyltransferase 1 heterozygous knockout mouse model for Kleefstra syndrome.

    Science.gov (United States)

    Balemans, Monique C M; Kasri, Nael Nadif; Kopanitsa, Maksym V; Afinowi, Nurudeen O; Ramakers, Ger; Peters, Theo A; Beynon, Andy J; Janssen, Sanne M; van Summeren, Rik C J; Eeftens, Jorine M; Eikelenboom, Nathalie; Benevento, Marco; Tachibana, Makoto; Shinkai, Yoichi; Kleefstra, Tjitske; van Bokhoven, Hans; Van der Zee, Catharina E E M

    2013-03-01

    Euchromatin histone methyltransferase 1 (EHMT1) is a highly conserved protein that catalyzes mono- and dimethylation of histone H3 lysine 9, thereby epigenetically regulating transcription. Kleefstra syndrome (KS), is caused by haploinsufficiency of the EHMT1 gene, and is an example of an emerging group of intellectual disability (ID) disorders caused by genes encoding epigenetic regulators of neuronal gene activity. Little is known about the mechanisms underlying this disorder, prompting us to study the Euchromatin histone methyltransferase 1 heterozygous knockout (Ehmt1(+/-)) mice as a model for KS. In agreement with the cognitive disturbances observed in patients with KS, we detected deficits in fear extinction learning and both novel and spatial object recognition in Ehmt1(+/-) mice. These learning and memory deficits were associated with a significant reduction in dendritic arborization and the number of mature spines in hippocampal CA1 pyramidal neurons of Ehmt1(+/-) mice. In-depth analysis of the electrophysiological properties of CA3-CA1 synapses revealed no differences in basal synaptic transmission or theta-burst induced long-term potentiation (LTP). However, paired-pulse facilitation (PPF) was significantly increased in Ehmt1(+/-) neurons, pointing to a potential deficiency in presynaptic neurotransmitter release. Accordingly, a reduction in the frequency of miniature excitatory post-synaptic currents (mEPSCs) was observed in Ehmt1(+/-) neurons. These data demonstrate that Ehmt1 haploinsufficiency in mice leads to learning deficits and synaptic dysfunction, providing a possible mechanism for the ID phenotype in patients with KS. PMID:23175442

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

    Directory of Open Access Journals (Sweden)

    Shum David

    2011-02-01

    Full Text Available Abstract Background 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. Methods 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. Results 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. Conclusions These results suggest that aberrant Plk methylation is correlated with the development of HCC in mice.

  19. Impaired Resolution of Inflammation in the Endoglin Heterozygous Mouse Model of Chronic Colitis

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    Madonna R. Peter

    2014-01-01

    Full Text Available Endoglin is a coreceptor of the TGF-β superfamily predominantly expressed on the vascular endothelium and selective subsets of immune cells. We previously demonstrated that Endoglin heterozygous (Eng+/− mice subjected to dextran sulfate sodium (DSS developed persistent gut inflammation and pathological angiogenesis. We now report that colitic Eng+/− mice have low colonic levels of active TGF-β1, which was associated with reduced expression of thrombospondin-1, an angiostatic factor known to activate TGF-β1. We also demonstrate dysregulated expression of BMPER and follistatin, which are extracellular regulators of the TGF-β superfamily that modulate angiogenesis and inflammation. Heightened colonic levels of the neutrophil chemoattractant and proangiogenic factor, CXCL1, were also observed in DSS-treated Eng+/− mice. Interestingly, despite increased macrophage and neutrophil infiltration, a gut-specific reduction in expression of the key phagocytic respiratory burst enzymes, NADPH oxidase 2 (Nox-2 and myeloperoxidase, was seen in Eng+/− mice undergoing persistent inflammation. Taken together, these findings suggest that endoglin is required for TGF-β superfamily mediated resolution of inflammation and fully functional myeloid cells.

  20. Impaired water maze learning performance without altered dopaminergic function in mice heterozygous for the GDNF mutation.

    Science.gov (United States)

    Gerlai, R; McNamara, A; Choi-Lundberg, D L; Armanini, M; Ross, J; Powell-Braxton, L; Phillips, H S

    2001-10-01

    Exogenous glial cell line-derived neurotrophic factor (GDNF) exhibits potent survival-promoting effects on dopaminergic neurons of the nigrostriatal pathway that is implicated in Parkinson's disease and also protects neurons in forebrain ischemia of animal models. However, a role for endogenous GDNF in brain function has not been established. Although mice homozygous for a targeted deletion of the GDNF gene have been generated, these mice die within hours of birth because of deficits in kidney morphogenesis, and, thus, the effect of the absence of GDNF on brain function could not be studied. Herein, we sought to determine whether adult mice, heterozygous for a GDNF mutation on two different genetic backgrounds, demonstrate alterations in the nigrostriatal dopaminergic system or in cognitive function. While both neurochemical and behavioural measures suggested that reduction of GDNF gene expression in the mutant mice does not alter the nigrostriatal dopaminergic system, it led to a significant and selective impairment of performance in the spatial version of the Morris water maze. A standard panel of blood chemistry tests and basic pathological analyses did not reveal alterations in the mutants that could account for the observed performance deficit. These results suggest that endogenous GDNF may not be critical for the development and functioning of the nigrostriatal dopaminergic system but it plays an important role in cognitive abilities. PMID:11683907

  1. A Heterozygous ZMPSTE24 Mutation Associated with Severe Metabolic Syndrome, Ectopic Fat Accumulation, and Dilated Cardiomyopathy.

    Science.gov (United States)

    Galant, Damien; Gaborit, Bénédicte; Desgrouas, Camille; Abdesselam, Ines; Bernard, Monique; Levy, Nicolas; Merono, Françoise; Coirault, Catherine; Roll, Patrice; Lagarde, Arnaud; Bonello-Palot, Nathalie; Bourgeois, Patrice; Dutour, Anne; Badens, Catherine

    2016-01-01

    ZMPSTE24 encodes the only metalloprotease, which transforms prelamin into mature lamin A. Up to now, mutations in ZMPSTE24 have been linked to Restrictive Dermopathy (RD), Progeria or Mandibulo-Acral Dysplasia (MAD). We report here the phenotype of a patient referred for severe metabolic syndrome and cardiomyopathy, carrying a mutation in ZMPSTE24. The patient presented with a partial lipodystrophic syndrome associating hypertriglyceridemia, early onset type 2 diabetes, and android obesity with truncal and abdominal fat accumulation but without subcutaneous lipoatrophy. Other clinical features included acanthosis nigricans, liver steatosis, dilated cardiomyopathy, and high myocardial and hepatic triglycerides content. Mutated fibroblasts from the patient showed increased nuclear shape abnormalities and premature senescence as demonstrated by a decreased Population Doubling Level, an increased beta-galactosidase activity and a decreased BrdU incorporation rate. Reduced prelamin A expression by siRNA targeted toward LMNA transcripts resulted in decreased nuclear anomalies. We show here that a central obesity without subcutaneous lipoatrophy is associated with a laminopathy due to a heterozygous missense mutation in ZMPSTE24. Given the high prevalence of metabolic syndrome and android obesity in the general population, and in the absence of familial study, the causative link between mutation and phenotype cannot be formally established. Nevertheless, altered lamina architecture observed in mutated fibroblasts are responsible for premature cellular senescence and could contribute to the phenotype observed in this patient. PMID:27120622

  2. Generation of heterozygous fibrillin-1 mutant cloned pigs from genome-edited foetal fibroblasts.

    Science.gov (United States)

    Umeyama, Kazuhiro; Watanabe, Kota; Watanabe, Masahito; Horiuchi, Keisuke; Nakano, Kazuaki; Kitashiro, Masateru; Matsunari, Hitomi; Kimura, Tokuhiro; Arima, Yoshimi; Sampetrean, Oltea; Nagaya, Masaki; Saito, Masahiro; Saya, Hideyuki; Kosaki, Kenjiro; Nagashima, Hiroshi; Matsumoto, Morio

    2016-01-01

    Marfan syndrome (MFS) is an autosomal dominant genetic disease caused by abnormal formation of the extracellular matrix with an incidence of 1 in 3, 000 to 5, 000. Patients with Marfan syndrome experience poor quality of life caused by skeletal disorders such as scoliosis, and they are at high risk of sudden death from cardiovascular impairment. Suitable animal models of MFS are essential for conquering this intractable disease. In particular, studies employing pig models will likely provide valuable information that can be extrapolated to humans because of the physiological and anatomical similarities between the two species. Here we describe the generation of heterozygous fibrillin-1 (FBN1) mutant cloned pigs (+/Glu433AsnfsX98) using genome editing and somatic cell nuclear transfer technologies. The FBN1 mutant pigs exhibited phenotypes resembling those of humans with MFS, such as scoliosis, pectus excavatum, delayed mineralization of the epiphysis and disrupted structure of elastic fibres of the aortic medial tissue. These findings indicate the value of FBN1 mutant pigs as a model for understanding the pathogenesis of MFS and for developing treatments. PMID:27074716

  3. 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. PMID:26340513

  4. 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. PMID:18538870

  5. 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.

  6. Generation of heterozygous fibrillin-1 mutant cloned pigs from genome-edited foetal fibroblasts

    Science.gov (United States)

    Umeyama, Kazuhiro; Watanabe, Kota; Watanabe, Masahito; Horiuchi, Keisuke; Nakano, Kazuaki; Kitashiro, Masateru; Matsunari, Hitomi; Kimura, Tokuhiro; Arima, Yoshimi; Sampetrean, Oltea; Nagaya, Masaki; Saito, Masahiro; Saya, Hideyuki; Kosaki, Kenjiro; Nagashima, Hiroshi; Matsumoto, Morio

    2016-01-01

    Marfan syndrome (MFS) is an autosomal dominant genetic disease caused by abnormal formation of the extracellular matrix with an incidence of 1 in 3, 000 to 5, 000. Patients with Marfan syndrome experience poor quality of life caused by skeletal disorders such as scoliosis, and they are at high risk of sudden death from cardiovascular impairment. Suitable animal models of MFS are essential for conquering this intractable disease. In particular, studies employing pig models will likely provide valuable information that can be extrapolated to humans because of the physiological and anatomical similarities between the two species. Here we describe the generation of heterozygous fibrillin-1 (FBN1) mutant cloned pigs (+/Glu433AsnfsX98) using genome editing and somatic cell nuclear transfer technologies. The FBN1 mutant pigs exhibited phenotypes resembling those of humans with MFS, such as scoliosis, pectus excavatum, delayed mineralization of the epiphysis and disrupted structure of elastic fibres of the aortic medial tissue. These findings indicate the value of FBN1 mutant pigs as a model for understanding the pathogenesis of MFS and for developing treatments. PMID:27074716

  7. Radiation Dose-effects on Cell Cycle, Apoptosis, and Marker Expression of Ataxia Telangiectasia-Heterozygous Human Breast Epithelial Cells

    Science.gov (United States)

    Cruz, A.; Bors, K.; Jansen, H.; Richmond, R.

    2003-01-01

    Ataxia-telangiectasia (A-T) is a radiation-sensitive genetic condition. AT-heterozygous human mammary epithelial cells (HMEC) were irradiated using a Cs137 source in order to compare cell cycle, apoptosis, and marker expression responses across 3 radiation doses. No differences in cell cycle and apoptosis were found with any of the radiation doses used (30, 60, and 90 rads) compared with the unirradiated control (0 rad). At the same doses, however, differences were found in marker expression, such as keratin 18 (kl8), keratin 14 (k14), insulin-like growth factor I receptor (IGF-IR), and connexin 43 (cx43). This may indicate that radiation sensitivity in the heterozygous state may be initiated through signal transduction responses.

  8. Hearing Dysfunction in Heterozygous MitfMi-wh/+ Mice, a Model for Waardenburg Syndrome Type 2 and Tietz Syndrome

    OpenAIRE

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

    2012-01-01

    The human deafness-pigmentation syndromes Waardenburg syndrome 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 (MitfMi‐wh/+) mice were studied and hearing function of these mice characterized. MitfMi-wh/+ mice have a profound...

  9. Germline Heterozygous Variants in SEC23B Are Associated with Cowden Syndrome and Enriched in Apparently Sporadic Thyroid Cancer

    Science.gov (United States)

    Yehia, Lamis; Niazi, Farshad; Ni, Ying; Ngeow, Joanne; Sankunny, Madhav; Liu, Zhigang; Wei, Wei; Mester, Jessica L.; Keri, Ruth A.; Zhang, Bin; Eng, Charis

    2015-01-01

    Cancer-predisposing genes associated with inherited cancer syndromes help explain mechanisms of sporadic carcinogenesis and often inform normal development. Cowden syndrome (CS) is an autosomal-dominant disorder characterized by high lifetime risks of epithelial cancers, such that ∼50% of affected individuals are wild-type for known cancer-predisposing genes. Using whole-exome and Sanger sequencing of a multi-generation CS family affected by thyroid and other cancers, we identified a pathogenic missense heterozygous SEC23B variant (c.1781T>G [p.Val594Gly]) that segregates with the phenotype. We also found germline heterozygous SEC23B variants in 3/96 (3%) unrelated mutation-negative CS probands with thyroid cancer and in The Cancer Genome Atlas (TCGA), representing apparently sporadic cancers. We note that the TCGA thyroid cancer dataset is enriched with unique germline deleterious SEC23B variants associated with a significantly younger age of onset. SEC23B encodes Sec23 homolog B (S. cerevisiae), a component of coat protein complex II (COPII), which transports proteins from the endoplasmic reticulum (ER) to the Golgi apparatus. Interestingly, germline homozygous or compound-heterozygous SEC23B mutations cause an unrelated disorder, congenital dyserythropoietic anemia type II, and SEC23B-deficient mice suffer from secretory organ degeneration due to ER-stress-associated apoptosis. By characterizing the p.Val594Gly variant in a normal thyroid cell line, we show that it is a functional alteration that results in ER-stress-mediated cell-colony formation and survival, growth, and invasion, which reflect aspects of a cancer phenotype. Our findings suggest a different role for SEC23B, whereby germline heterozygous variants associate with cancer predisposition potentially mediated by ER stress “addiction.” PMID:26522472

  10. Marked Multiple Tendinitis at the Onset of Rheumatoid Arthritis in a Patient with Heterozygous Familial Hypercholesterolemia: Ultrasonographic Observation

    OpenAIRE

    Takeshi Suzuki; Akiko Okamoto

    2014-01-01

    A 59-year-old woman who had been diagnosed with heterozygous familial hypercholesterolemia developed rheumatoid arthritis (RA). She presented with marked tendinitis of the Achilles tendons, patellar tendons, and finger extensor tendons at the onset of RA. Ultrasonographic examination revealed that tendon lesions were predominantly tendinitis rather than paratenonitis, and that the tendinitis was of the noninsertional variety, rather than the insertional variety. Preexisting tendon xanthomas m...

  11. Marked Multiple Tendinitis at the Onset of Rheumatoid Arthritis in a Patient with Heterozygous Familial Hypercholesterolemia: Ultrasonographic Observation

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    Takeshi Suzuki

    2014-01-01

    Full Text Available A 59-year-old woman who had been diagnosed with heterozygous familial hypercholesterolemia developed rheumatoid arthritis (RA. She presented with marked tendinitis of the Achilles tendons, patellar tendons, and finger extensor tendons at the onset of RA. Ultrasonographic examination revealed that tendon lesions were predominantly tendinitis rather than paratenonitis, and that the tendinitis was of the noninsertional variety, rather than the insertional variety. Preexisting tendon xanthomas might have contributed to the unusually dominant noninsertional tendinitis of multiple tendons.

  12. High Fat Diet Induced Insulin Resistance and Glucose Intolerance is Gender-Specific in IGF-1R Heterozygous Mice

    OpenAIRE

    Garg, Neha; Thakur, Sachin; McMahan, C. Alex; Adamo, Martin L.

    2011-01-01

    Interactions between genes and environment play a critical role in the pathogenesis of Type 2 diabetes. Low birth weight, due to genetic and environmental variables affecting fetal growth, is associated with increased susceptibility to the development of type 2 diabetes and metabolic disorders in adulthood. Clinical studies have shown that polymorphisms in the Insulin-like growth factor 1 (IGF-1) gene or heterozygous mutations in IGF-1 and IGF-1 receptor (IGF-1R) genes, resulting in reduced I...

  13. Region-specific astrogliosis in brains of mice heterozygous for mutations in the neurofibromatosis type 1 (Nf1) tumor suppressor

    OpenAIRE

    Rizvi, Tilat A.; Akunuru, Shailaja; de Courten-Myers, Gabrielle; Switzer, Robert C.; Nordlund, Michael L.; Ratner, Nancy

    1999-01-01

    Brains from human neurofibromatosis type 1 (NF1) patients show increased expression of glial fibrillary acidic protein (GFAP), consistent with activation of astrocytes (M.L. Nordlund, T.A. Rizvi, C.I. Brannan, N. Ratner, Neurofibromin expression and astrogliosis in neurofibromatosis (type 1) brains, J. Neuropathol. Exp. Neurology 54 (1995) 588–600). We analyzed brains from transgenic mice in which the Nf1 gene was targeted by homologous recombination. We show here that, in all heterozygous mi...

  14. Heterozygous mutations in SIX3 and SHH are associated with schizencephaly and further expand the clinical spectrum of holoprosencephaly

    OpenAIRE

    Hehr, Ute; Pineda-Alvarez, Daniel E.; Uyanik, Goekhan; Hu, Ping; Zhou, Nan; Hehr, Andreas; Schell-Apacik, Chayim; Altus, Carola; Daumer-Haas, Cornelia; Meiner, Annechristin; Steuernagel, Peter; Roessler, Erich; Winkler, Juergen; Muenke, Maximilian

    2010-01-01

    Schizencephaly (SCH) is a clinically and etiologically heterogeneous cerebral malformation presenting as unilateral or bilateral hemispheric cleft with direct connection between the inner and outer liquor spaces. The SCH cleft is usually lined by gray matter, which appears polymicrogyric implying an associated impairment of neuronal migration. The majority of SCH patients are sporadic, but familial SCH has been described. An initial report of heterozygous mutations in the homeobox gene EMX2 c...

  15. Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects

    OpenAIRE

    Wessels, Marja W.; Herkert, Johanna C; Frohn-Mulder, Ingrid M.; Dalinghaus, Michiel; van den Wijngaard, Arthur; Ronald R de Krijger; Michels, Michelle; de Coo, Irenaeus FM; Hoedemaekers, Yvonne M; Dooijes, Dennis

    2014-01-01

    Familial hypertrophic cardiomyopathy (HCM) is usually caused by autosomal dominant pathogenic mutations in genes encoding sarcomeric or sarcomere-associated cardiac muscle proteins. The disease mainly affects adults, although young children with severe HCM have also been reported. We describe four unrelated neonates with lethal cardiomyopathy, and performed molecular studies to identify the genetic defect. We also present a literature overview of reported patients with compound heterozygous o...

  16. Heterozygous alleles restore male fertility to cytoplasmic male-sterile radish (Raphanus sativus L.): a case of overdominance

    OpenAIRE

    Wang, Zhi Wei; Wang, Chuan; Gao, Lei; Mei, Shi Yong; Zhou, Yuan; Xiang, Chang Ping; Wang, Ting

    2013-01-01

    The practice of hybridization has greatly contributed to the increase in crop productivity. A major component that exploits heterosis in crops is the cytoplasmic male sterility (CMS)/nucleus-controlled fertility restoration (Rf) system. Through positional cloning, it is shown that heterozygous alleles (RsRf3-1/RsRf3-2) encoding pentatricopeptide repeat (PPR) proteins are responsible for restoring fertility to cytoplasmic male-sterile radish (Raphanus sativus L.). Furthermore, it was found tha...

  17. Mipomersen: evidence-based review of its potential in the treatment of homozygous and severe heterozygous familial hypercholesterolemia

    Directory of Open Access Journals (Sweden)

    Parhofer KG

    2012-05-01

    Full Text Available Klaus G ParhoferMedical Department II, Grosshadern, University Munich, Munich, GermanyAbstract: Familial hypercholesterolemia (FH is an autosomal-dominant inherited disease with a prevalence of one in 500 (heterozygous to one in 1,000,000 (homozygous. Mutations of the low-density lipoprotein (LDL receptor gene, the apolipoprotein B100 gene, or the PCSK9 gene may be responsible for the disease. The resulting LDL hypercholesterolemia results in premature atherosclerosis as early as childhood (homozygous FH or in adulthood (heterozygous FH. Current treatment modalities include lifestyle modification, combination drug therapy (statin-based, and apheresis. Mipomersen is an antisense oligonucleotide which inhibits apolipoprotein B production independent of LDL receptor function and thus works in homozygous FH, heterozygous FH, and other forms of hypercholesterolemia. Mipomersen is given 200 mg/week subcutaneously. Phase III studies indicate that the LDL cholesterol concentration can be reduced by 25%–47%, lipoprotein(a levels by 20%–40%, and triglyceride concentrations by approximately 10%. In general, mipomersen has no effect on high-density lipoprotein cholesterol concentrations. Although there is considerable interindividual variability, the observed lipid effects are largely independent of age, gender, concomitant statin therapy, and underlying dyslipoproteinemia. The most common side effects are injection site reactions (70%–100%, flu-like symptoms (29%–46%, and elevated transaminases associated with an increased liver fat content (6%–15%. Mipomersen may be an interesting addon drug in patients with heterozygous or homozygous FH not reaching treatment goals, either because baseline values are very high or because high-dose statins are not tolerated.Keywords: antisense oligonucleotide, statin intolerance, apolipoprotein B

  18. Variability in clinical phenotypes of heterozygous and homozygous cases of Parkin-related Parkinson’s disease

    OpenAIRE

    Thompson, Amanda J.; Sonja W. Scholz; Singleton, Andrew B.; Hardwick, Angela; McFarland, Nikolaus R.; Okun, Michael S.

    2013-01-01

    Parkin mutations are a common cause of early-onset Parkinson’s disease. To study the clinical features and treatment responses of patients with homozygous or heterozygous Parkin mutations, we performed a retrospective chart review in six early-onset parkinsonism patients with pathogenic Parkin mutations. The clinical phenotypes observed in this cohort, all drawn from different families, were variable. All patients had a slowly progressive form of parkinsonism that responded well to dopaminerg...

  19. Osteogenesis imperfecta IIC caused by a novel heterozygous mutation in the C-propeptide region of COL1A1

    OpenAIRE

    Takagi, Masaki; Matsushita, Mitsuru; Nishimura, Gen; Hasegawa, Tomonobu

    2014-01-01

    Osteogenesis imperfecta IIC (OI IIC), which is a rare variant of lethal OI that has been considered to be an autosomal recessive trait, is characterized by twisted, slender long bones with dense metaphyseal margins. Here, we report a typical case of OI IIC caused by a novel heterozygous mutation in the C-propeptide region of COL1A1. OI IIC seems to be caused by a dominant mutation of COL1A1.

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

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    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.

  1. Phenotypic variability of hyperandrogenemia in females heterozygous for CYP21A2 mutations

    Directory of Open Access Journals (Sweden)

    Vassos Neocleous

    2014-01-01

    Full Text Available Objectives: The objective was to seek evidence on the prevalence and consequences of heterozygous CYP21A2 mutations in girls, adolescent, and adult females with clinical manifestation of androgen excess. Patients and Methods: The study included 64 girls diagnosed with premature adrenarche (PA in childhood and 141 females with clinical hyperandrogenemia manifested in adolescence or adulthood. Direct DNA sequencing and multiplex ligation-dependent probe amplification analysis were used to identify mutations in the CYP21A2 gene. Results: (1 Thirty-four patients were diagnosed with nonclassical-congenital adrenal hyperplasia (NC-CAH based on the 17-hydroxyprogesterone (17-OHP levels and the presence of two mutations in CYP21A2 and therefore were excluded from the study, 66 were found to be heterozygotes and finally 105 had no identifiable mutations. The most frequent mutations among the carriers were the mild p.Val281 Leu and p.Qln318stop. Higher levels of mean stimulated 17-OHP were found in the carriers of the p.Val281 Leu. (2 A notable increased allelic frequency for the known p.Asn493 Ser polymorphism was observed in the pool of females with hyperandrogenemia in whom no mutation was identified. (3 In girls, who presented early with PA, 26.6% were diagnosed with NC-CAH and carried two mutations, 28.7% were identified as heterozygotes 43.7% had no identifiable genetic defect in the translated region of the CYP21A2 gene. On the contrary, in the group of 141 females with late onset hyperandrogenemia, the presence of 2 mutations was detected in 12%, 1 mutation in 33.4% and no mutation in 54.6%. Conclusions: The carrier status for 21-OHD, may be an important factor in the variable phenotype of hyperandrogenism and may be a contributing factor for the early manifestation of the disease.

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

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    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.

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

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    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. PMID:26059812

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

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    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.

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

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    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.

  6. Case Report: Paroxysmal nocturnal hemoglobinuria in a woman heterozygous for G6PD A-.

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    Perdigones, Nieves; Morales, Mariela; Mason, Philip; Bessler, Monica

    2014-01-01

    We describe a case of paroxysmal nocturnal hemoglobinuria (PNH) in a woman who is heterozygous for the glucose-6-phosphate dehydrogenase A-   ( G6PDA-) allele. PNH is associated with one or more clones of cells that lack complement inhibition due to loss of function somatic mutations in the PIGA gene.  PIGA encodes the enzyme phosphatidylinositol glycan anchor biosynthesis, class A, which catalyses the first step of glycosylphosphatidylinisotol ( GPI)  anchor synthesis. Two GPI anchored red cell surface antigens regulate complement lysis. G6PD catalyses the first step of the pentose phosphate pathway and enzyme variants, frequent in some populations have been selected because they confer resistance to malaria, are associated with hemolysis in the presence of oxidizing agents including several drugs. The patient had suffered a hemolytic attack after taking co-trimoxazole, a drug that precipitates hemolysis in G6PD deficient individuals. Since both G6PD and PIGA are X-linked we hypothesized that the PIGA mutation was on the X-chromosome carrying the G6PDA- allele. Investigations showed that in fact the PIGA mutation was on the X-chromosome carrying the normal G6PD B allele. We speculate that complement activation on G6PD A- red cells exposed to Bactrim might have triggered complement activation inducing the lysis of G6PD B PNH Type II red blood cells or that the patient may have had a PNH clone expressing G6PDA- at the time of the hemolytic episode. PMID:25713697

  7. Effects of tacrolimus on infection of Friend murine leukemia virus to Fv-4 gene heterozygous mice

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    Feng-min ZHANG; Bao-feng YANG; Hong-xi GU; Xiao-bei CHEN; Zhao-hua ZHONG; Zhi CHENG

    2004-01-01

    AIM: To investigate the effect of tacrolimus (FK506) on the infection of Friend murine leukemia virus (Friend MuLV) in vivo. METHODS: Three kinds of mice were used including Friend MuLV-sensitive BALB/c mice, Friend MuLV-resistant Fv-4 gene-homozygous mice (Fv-4 mice), and Friend MuLV-resistant Fv-4 gene-heterozygous mice (Fl mice). Tacrolimus was administrated ip to those mice in every 2 d. Those treated mice were inoculated ip with Friend MuLV once on d 3. The symptoms and viral proliferations in those mice were observed to recognize the Friend MuLV infection. The expression and genotype of Fv-4 gene that resistant against the infection of Friend MuLV were analyzed to confirm the genomic background and related mechanism of the resistance. RESULTS:BALB/c mice and Fl mice, but not Fv-4 mice, appeared obvious early death, spleenomegaly, and viral proliferation after both treatments of viral inoculation and tacrolimus administration, whereas the expression and genotype of Fv-4 gene was not changed in F1 mice and Fv-4 mice with treatment of tacrolimus. Compared to the virusinoculated control, the Friend MuLV-sensitivity of tacrolimus-treated BALB/c mice and the Friend MuLV-resistance of tacrolimus-treated Fv-4 mice were the same as the controls, but only Fl mice became the symptoms and viral proliferation after both treatments. It suggested the Friend MuLV-resistant Fl mice could be converted to be Friend MuLV-sensitive by treatment of tacrolimus, and this conversion was not depended on the expression and genotype of Fv-4 gene. CONCLUSION: Tacrolimus could not inhibit the infection of Friend MuLV in all mice, furthermore,it could enhance the infection of Friend MuLV in F1 mice. The enhancement may be related to the immunosuppressive effect of tacrolimus.

  8. Compound heterozygous SCN5A gene mutations in asymptomatic Brugada syndrome child

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    Elena Sommariva

    2012-09-01

    Full Text Available Loss-of-function mutations in the SCN5A gene, encoding the cardiac Nav1.5 sodium channel, have been previously associated with Brugada syndrome (BrS. Despite the low prevalence of the disease, we identified a patient carrying two SCN5A mutations. We aimed at establishing a correlation between genotype, clinical phenotype and in vitro sodium current. A 3-year-old boy presented with right bundle branch block and ST-segment elevation. Genetic analysis and electrophysiology studies in transfected HEK293 cells were performed to identify possibly disease-causing variants and assess their effect on sodium channel function. Two SCN5A variants were identified: a new frameshift deletion causing premature truncation of the putative protein (c.3258_3261del4 and a missense substitution (p.F1293S. In vitro studies revealed that the truncated mutant did not produce functional channels and decreased total sodium current when co-expressed with p.F1293S channels compared to p.F1293S alone. In addition, p.F1293S channels presented with a steep slope of steady-state activation voltagedependency, which was shifted towards more positive potentials by the co-expression with the truncated channel. p.F1293S channels also showed shift towards more positive potentials of the steady-state inactivation both alone and co-expressed with the deletion mutant. Our data identified a severe reduction of sodium channel current associated with two distinct SCN5A changes. However, all mutation carriers were asymptomatic and BrS electrocardiogram was observed only transiently in the compound heterozygous subject. These observations underline the difficulty of genotype/ phenotype correlations in BrS patients and support the idea of a polygenic disorder, where different mutations and variants can contribute to the clinical phenotype.

  9. Heterozygous inactivation of the Nf1 gene in myeloid cells enhances neointima formation via a rosuvastatin-sensitive cellular pathway.

    Science.gov (United States)

    Stansfield, Brian K; Bessler, Waylan K; Mali, Raghuveer; Mund, Julie A; Downing, Brandon; Li, Fang; Sarchet, Kara N; DiStasi, Matthew R; Conway, Simon J; Kapur, Reuben; Ingram, David A

    2013-03-01

    Mutations in the NF1 tumor suppressor gene cause Neurofibromatosis type 1 (NF1). Neurofibromin, the protein product of NF1, functions as a negative regulator of Ras activity. Some NF1 patients develop cardiovascular disease, which represents an underrecognized disease complication and contributes to excess morbidity and mortality. Specifically, NF1 patients develop arterial occlusion resulting in tissue ischemia and sudden death. Murine studies demonstrate that heterozygous inactivation of Nf1 (Nf1(+/-)) in bone marrow cells enhances neointima formation following arterial injury. Macrophages infiltrate Nf1(+/-) neointimas, and NF1 patients have increased circulating inflammatory monocytes in their peripheral blood. Therefore, we tested the hypothesis that heterozygous inactivation of Nf1 in myeloid cells is sufficient for neointima formation. Specific ablation of a single copy of the Nf1 gene in myeloid cells alone mobilizes a discrete pro-inflammatory murine monocyte population via a cell autonomous and gene-dosage dependent mechanism. Furthermore, lineage-restricted heterozygous inactivation of Nf1 in myeloid cells is sufficient to reproduce the enhanced neointima formation observed in Nf1(+/-) mice when compared with wild-type controls, and homozygous inactivation of Nf1 in myeloid cells amplified the degree of arterial stenosis after arterial injury. Treatment of Nf1(+/-) mice with rosuvastatin, a stain with anti-inflammatory properties, significantly reduced neointima formation when compared with control. These studies identify neurofibromin-deficient myeloid cells as critical cellular effectors of Nf1(+/-) neointima formation and propose a potential therapeutic for NF1 cardiovascular disease. PMID:23197650

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

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    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.

  11. Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects

    Science.gov (United States)

    Wessels, Marja W; Herkert, Johanna C; Frohn-Mulder, Ingrid M; Dalinghaus, Michiel; van den Wijngaard, Arthur; de Krijger, Ronald R; Michels, Michelle; de Coo, Irenaeus FM; Hoedemaekers, Yvonne M; Dooijes, Dennis

    2015-01-01

    Familial hypertrophic cardiomyopathy (HCM) is usually caused by autosomal dominant pathogenic mutations in genes encoding sarcomeric or sarcomere-associated cardiac muscle proteins. The disease mainly affects adults, although young children with severe HCM have also been reported. We describe four unrelated neonates with lethal cardiomyopathy, and performed molecular studies to identify the genetic defect. We also present a literature overview of reported patients with compound heterozygous or homozygous pathogenic MYBPC3 mutations and describe their clinical characteristics. All four children presented with feeding difficulties, failure to thrive, and dyspnea. They died from cardiac failure before age 13 weeks. Features of left ventricular noncompaction were diagnosed in three patients. In the fourth, hypertrabeculation was not a clear feature, but could not be excluded. All of them had septal defects. Two patients were compound heterozygotes for the pathogenic c.2373dup p.(Trp792fs) and c.2827C>T p.(Arg943*) mutations, and two were homozygous for the c.2373dup and c.2827C>T mutations. All patients with biallelic truncating pathogenic mutations in MYBPC3 reported so far (n=21) were diagnosed with severe cardiomyopathy and/or died within the first few months of life. In 62% (13/21), septal defects or a patent ductus arteriosus accompanied cardiomyopathy. In contrast to heterozygous pathogenic mutations, homozygous or compound heterozygous truncating pathogenic MYBPC3 mutations cause severe neonatal cardiomyopathy with features of left ventricular noncompaction and septal defects in approximately 60% of patients. PMID:25335496

  12. Pedigree analysis of Mexican families with Fabry disease as a powerful tool for identification of heterozygous females.

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    Gutiérrez-Amavizca, B E; Orozco-Castellanos, R; R Padilla-Gutiérrez, J; Valle, Y; Figuera, L E

    2014-01-01

    Fabry disease (FD) is an X-linked lysosomal storage disease caused by α-galactosidase A deficiency; in contrast to other X-linked diseases, heterozygous females can be as affected as men. The construction and analysis of a family pedigree is a powerful tool to aid clinicians in diagnosis, establishment of inheritance pattern, and early detection of potentially affected relatives. The present study highlights the importance of pedigree analysis in families with FD for identifying other possibly affected relatives and investigating the clinical manifestations. This clinical report included 12 Mexican index cases with confirmed FD diagnosis. We constructed and analyzed their pedigree, and diagnosed FD in 24 affected relatives. Clinical features were similar to those reported for other populations. Pedigree analysis further identified an additional 30 women as possible carriers. We conclude that pedigree construction and analysis is a useful tool to help physicians detect and diagnose relatives at risk for FD, particularly heterozygous females, so that they can receive genetic counseling and early treatment. Mexican families with FD were similar to other populations reported in the literature, and our findings confirmed that heterozygous females can have signs and symptoms ranging from subtle manifestations to the classical severe presentation described in males. PMID:25177955

  13. Deletion of a Yci1 Domain Protein of Candida albicans Allows Homothallic Mating in MTL Heterozygous Cells

    Science.gov (United States)

    Sun, Yuan; Gadoury, Christine; Hirakawa, Matthew P.; Bennett, Richard J.; Harcus, Doreen; Marcil, Anne

    2016-01-01

    ABSTRACT It has been proposed that the ancestral fungus was mating competent and homothallic. However, many mating-competent fungi were initially classified as asexual because their mating capacity was hidden behind layers of regulation. For efficient in vitro mating, the essentially obligate diploid ascomycete pathogen Candida albicans has to change its mating type locus from heterozygous MTLa/α to homozygous MTLa/a or MTLα/α and then undergo an environmentally controlled epigenetic switch to the mating-competent opaque form. These requirements greatly reduce the potential for C. albicans mating. Deletion of the Yci1 domain gene OFR1 bypasses the need for C. albicans cells to change the mating type locus from heterozygous to homozygous prior to switching to the opaque form and mating and allows homothallic mating of MTL heterozygous strains. This bypass is carbon source dependent and does not occur when cells are grown on glucose. Transcriptional profiling of ofr1 mutant cells shows that in addition to regulating cell type and mating circuitry, Ofr1 is needed for proper regulation of histone and chitin biosynthesis gene expression. It appears that OFR1 is a key regulator in C. albicans and functions in part to maintain the cryptic mating phenotype of the pathogen. PMID:27118591

  14. The two mutations, Q204X and nt821, of the myostatin gene affect carcass and meat quality in young heterozygous bulls of French beef breeds.

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    Allais, S; Levéziel, H; Payet-Duprat, N; Hocquette, J F; Lepetit, J; Rousset, S; Denoyelle, C; Bernard-Capel, C; Journaux, L; Bonnot, A; Renand, G

    2010-02-01

    The availability of genetic tests to detect different mutations in the myostatin gene allows the identification of heterozygous animals and would warrant the superiority of these animals for slaughter performance if this superiority is confirmed. Thus, 2 mutations of this gene, Q204X and nt821, were studied in 3 French beef breeds in the program Qualvigène. This work was done with 1,114 Charolais, 1,254 Limousin, and 981 Blonde d'Aquitaine young bulls from, respectively, 48, 36, and 30 sires and slaughtered from 2004 to 2006. In addition to the usual carcass traits recorded at slaughter (e.g., carcass yield, muscle score), carcass composition was estimated by weighing internal fat and dissecting the 6th rib. The muscle characteristic traits analyzed were lipid and collagen contents, muscle fiber section area, and pH. Regarding meat quality, sensory qualities of meat samples were evaluated by a taste panel, and Warner-Bratzler shear force was measured. Deoxyribonucleic acid was extracted from the blood samples of all calves, the blood samples of 78% of the dams, and the blood or semen samples of all the sires. Genotypes were determined for 2 disruptive mutations, Q204X and nt821. Analyses were conducted by breed. The superiority of carcass traits of calves carrying one copy of the mutated allele (Q204X or nt821) over noncarrier animals was approximately +1 SD in the Charolais and Limousin breeds but was not significant in the Blonde d'Aquitaine. In the Charolais breed, for which the frequency was the greatest (7%), young bulls carrying the Q204X mutation presented a carcass with less fat, less intramuscular fat and collagen contents, and a clearer and more tender meat than those of homozygous-normal cattle. The meat of these animals also had slightly less flavor. Also in the Charolais breed, 13 of 48 sires were heterozygous. For each sire, the substitution effect of the wild allele by the mutant allele was approximately +1 SD for carcass conformation and yield

  15. Long-term effects of high-fat or high-carbohydrate diets on glucose tolerance in mice with heterozygous carnitine palmitoyltransferase-1a deficiency

    Science.gov (United States)

    Nyman, L R; Tian, L; Hamm, D A; Schoeb, T R; Gower, B A; Nagy, T R; Wood, P A

    2011-01-01

    Background: Abnormal fatty acid metabolism is an important feature in the mechanisms of insulin resistance and β-cell dysfunction. Carnitine palmitoyltransferase-1a (CPT-1a, liver isoform) has a pivotal role in the regulation of mitochondrial fatty acid oxidation. We investigated the role of CPT-1a in the development of impaired glucose tolerance using a mouse model for CPT-1a deficiency when challenged by either a high-carbohydrate (HCD) or a high-fat diet (HFD) for a total duration of up to 46 weeks. Methods: Insulin sensitivity and glucose tolerance were assessed in heterozygous CPT-1a-deficient (CPT-1a+/−) male mice after being fed either a HCD or a HFD for durations of 28 weeks and 46 weeks. Both glucose and insulin tolerance tests were used to investigate β-cell function and insulin sensitivity. Differences in islet insulin content and hepatic steatosis were evaluated by morphological analysis. Results: CPT-1a+/− mice were more insulin-sensitive than CPT-1a+/+ mice when fed either HCD or HFD. The increased insulin sensitivity was associated with an increased expression of Cpt-1b (muscle isoform) in liver, as well as increased microvesicular hepatic steatosis compared with CPT-1a+/+ mice. CPT-1a+/− mice were more glucose tolerant than CPT-1a+/+ mice when fed the HCD, but there was no significant difference when fed HFD. Moreover, CPT-1a+/− mice fed HFD or HCD had fewer and smaller pancreatic islets than CPT-1a+/+ mice. Conclusions: CPT-1a deficiency preserved insulin sensitivity when challenged by long-term feeding of either diet. Furthermore, CPT-1a-deficient mice had distinct phenotypes dependent on the diet fed demonstrating that both diet and genetics collectively have a role in the development of impaired glucose tolerance. PMID:22229081

  16. Hypothyroidism caused by the combination of two heterozygous mutations: one in the TSH receptor gene the other in the DUOX2 gene.

    Science.gov (United States)

    Satoh, Mari; Aso, Keiko; Ogikubo, Sayaka; Yoshizawa-Ogasawara, Atsuko; Saji, Tsutomu

    2015-05-01

    Subjects who are heterozygous for thyroid stimulating hormone receptor (TSHR) gene mutations present various phenotypes that range from euthyroid to hyperthyrotropinemia. Similarly, heterozygous dual oxidase 2 (DUOX2) gene mutations result in variable phenotypes, such as transient congenital hypothyroidism, subclinical hyperthyrotropinemia, and euthyroid in children. Here, we describe an 8-year-old boy who had normal newborn screening results, but who developed nonautoimmune hypothyroidism at the age of 1 year and 8 months of age. He was heterozygous for previously reported R450H-TSHR mutation and heterozygous for a novel double mutant allele A1323T-DUOX2 and L1343F-DUOX2. He needed levothyroxine (l-T4) replacement therapy to keep serum TSH levels within normal limits; l-T4 dose of 2.01-2.65 μg/kg/day corresponded to the dose taken by children homozygous for R450H-TSHR and by children with permanent congenital hypothyroidism. Therefore, the coexistence of a heterozygous TSHR mutation and a heterozygous DUOX2 mutation may have affected the severity of his hypothyroid condition. PMID:25928756

  17. X-linked G6PD deficiency protects hemizygous males but not heterozygous females against severe malaria.

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    Aldiouma Guindo

    2007-03-01

    Full Text Available BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD is important in the control of oxidant stress in erythrocytes, the host cells for Plasmodium falciparum. Mutations in this enzyme produce X-linked deficiency states associated with protection against malaria, notably in Africa where the A- form of G6PD deficiency is widespread. Some reports have proposed that heterozygous females with mosaic populations of normal and deficient erythrocytes (due to random X chromosome inactivation have malaria resistance similar to or greater than hemizygous males with populations of uniformly deficient erythrocytes. These proposals are paradoxical, and they are not consistent with currently hypothesized mechanisms of protection. METHODS AND FINDINGS: We conducted large case-control studies of the A- form of G6PD deficiency in cases of severe or uncomplicated malaria among two ethnic populations of rural Mali, West Africa, where malaria is hyperendemic. Our results indicate that the uniform state of G6PD deficiency in hemizygous male children conferred significant protection against severe, life-threatening malaria, and that it may have likewise protected homozygous female children. No such protection was evident from the mosaic state of G6PD deficiency in heterozygous females. We also found no significant differences in the parasite densities of males and females with differences in G6PD status. Pooled odds ratios from meta-analysis of our data and data from a previous study confirmed highly significant protection against severe malaria in hemizygous males but not in heterozygous females. Among the different forms of severe malaria, protection was principally evident against cerebral malaria, the most frequent form of life-threatening malaria in these studies. CONCLUSIONS: The A- form of G6PD deficiency in Africa is under strong natural selection from the preferential protection it provides to hemizygous males against life-threatening malaria. Little or no such

  18. Aged Tgfβ2/Gdnf double-heterozygous mice show no morphological and functional alterations in the nigrostriatal system

    OpenAIRE

    Heermann, Stephan; Opazo, Felipe; Falkenburger, Björn; Krieglstein, Kerstin; Spittau, Björn

    2010-01-01

    Loss of dopaminergic neurons in the substantia nigra pars compacta and the resulting decrease in striatal dopamine levels are the hallmarks of Parkinson’s disease. Tgfβ and Gdnf have been identified as neurotrophic factors for dopaminergic midbrain neurons in vivo and in vitro. Haploinsufficiency for either Tgfβ or Gdnf led to dopaminergic deficits. In this study we therefore analyzed the nigrostriatal system of aged Tgfβ2 +/−/Gdnf +/− double-heterozygous mice. Unexpectedly, we found no morph...

  19. Transient congenital hypothyroidism caused by compound heterozygous mutations affecting the NADPH-oxidase domain of DUOX2.

    Science.gov (United States)

    Yoshizawa-Ogasawara, Atsuko; Abe, Kiyomi; Ogikubo, Sayaka; Narumi, Satoshi; Hasegawa, Tomonobu; Satoh, Mari

    2016-03-01

    Here, we describe three cases of loss-of-function mutations in the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase (NOX) domain of dual oxidase 2 (DUOX2) occurring along with concurrent missense mutations in thyroid peroxidase (TPO), leading to transient congenital hypothyroidism (CH). Three Japanese boys with nonconsanguineous parents were diagnosed with CH during their neonatal screenings. All patients presented with moderate-to-severe neonatal hypothyroidism and were diagnosed with transient CH after re-evaluation of thyroid function. Two siblings were compound heterozygous for p.[R1110Q]+[Y1180X] in DUOX2; one of them was also heterozygous for p.[R361L] in TPO. The third patient was compound heterozygous for p.[L1160del]+[R1334W] in DUOX2 and heterozygous for p.[P883S] in TPO. This is the first report of a de novo L1160del mutation affecting the DUOX2 gene and of the novel mutations Y1180X in DUOX2 and R361L in TPO. R1110Q and L1160del were found to reduce H2O2 production (5%-9%, p<0.01), while Y1180X, which introduces a premature stop codon, did not confer detectable H2O2 production (-0.7%±0.6%, p<0.01). Moreover, R1334W, a missense mutation possibly affecting electron transfer, led to reduced H2O2 production (24%±0.9%, p<0.01) in vitro, and R1110Q and R1334W resulted in reduced protein expression. Y1180X was detected in a 120 kDa truncated form, whereas L1160del expression was maintained. Further, R361L, a novel missense mutation in TPO, caused partial reduction in peroxidase activity (20.6%±0.8%, p=0.01), whereas P883S, a missense variant, increased it (133.7%±2.8%, p=0.02). The protein expression levels in the case of R361L and P883S were maintained. In conclusion, we provide clinical and in vitro demonstrations of different functional defects and phenotypic heterogeneity in the same thyroid hormonogenesis pathway. PMID:26565538

  20. A mouse model of human congenital heart disease: high incidence of diverse cardiac anomalies and ventricular noncompaction produced by heterozygous Nkx2-5 homeodomain missense mutation

    Science.gov (United States)

    Chang, Eileen I.; Terada, Ryota; Ryan, Nicole J.; Briggs, Laura E.; Chowdhury, Rajib; Zárate, Miguel A.; Sugi, Yukiko; Nam, Hyun-Joo; Benson, D. Woodrow; Anderson, Robert H.; Kasahara, Hideko

    2014-01-01

    Background Heterozygous human mutations of NKX2-5 are highly penetrant and associated with varied congenital heart defects. The heterozygous knockout of murine Nkx2-5, in contrast, manifests less profound cardiac malformations, with low disease penetrance. We sought to study this apparent discrepancy between human and mouse genetics. Since missense mutations in the NKX2-5 homeodomain (DNA binding domain) are the most frequently reported type of human mutation, we replicated this genetic defect in a murine knock-in model. Methods and Results We generated a murine model in a 129/Sv genetic background by knocking-in an Nkx2-5 homeodomain missense mutation previously identified in humans. The mutation was located at homeodomain position 52Arg→Gly (R52G). All the heterozygous neonatal Nkx2-5+/R52G mice demonstrated a prominent trabecular layer in the ventricular wall, so called noncompaction, along with diverse cardiac anomalies, including atrioventricular septal defects, Ebstein’s malformation of the tricuspid valve, and perimembranous and/or muscular ventricular septal defects. In addition, P10 Nkx2-5+/R52G mice demonstrated atrial septal anomalies, with significant increase in the size of the inter-atrial communication and fossa ovalis, and decrease in the length of the flap valve compared to control Nkx2-5+/+ or Nkx2-5+/− mice. Conclusion The results of our study demonstrate that heterozygous missense mutation in the murine Nkx2-5 homeodomain (R52G) are highly penetrant, and result in pleiotropic cardiac effects. Thus, in contrast to heterozygous Nkx2-5 knockout mice, the effects of the heterozygous knock-in mimic findings in humans with heterozygous missense mutation in NKX2-5 homeodomain. PMID:25028484

  1. Heterozygous mutants of TIRAP (S180L) polymorphism protect adult patients with Plasmodium falciparum infection against severe disease and mortality.

    Science.gov (United States)

    Panda, Aditya K; Das, Bidyut K; Panda, Abhinash; Tripathy, Rina; Pattnaik, Sarit S; Mahto, Harishankar; Pied, Sylviane; Pathak, Sulabha; Sharma, Shobhona; Ravindran, Balachandran

    2016-09-01

    Toll-interleukin-1 receptor domain containing adapter protein (TIRAP) plays a crucial role in TLR2 and TLR4 signaling pathways. Glycosylphospatidylinositol (GPI), considered a toxin molecule of Plasmodium falciparum, interacts with TLR2 and 4 to induce an immune inflammatory response. A single nucleotide polymorphism at coding region of TIRAP (S180L) has been reported to influence TLRs signaling. In the present study, we investigated the association of TIRAP (S180L) polymorphism with susceptibility/resistance to severe P. falciparum malaria in a cohort of adult patients from India. TIRAP S180L polymorphism was typed in 347 cases of severe malaria (SM), 232 uncomplicated malaria and 150 healthy controls. Plasma levels of TNF-α was quantified by ELISA. Heterozygous mutation (S/L) conferred significant protection against MOD (multi organ dysfunction), NCSM (non-cerebral severe malaria) as well as mortality. Interestingly, homozygous mutants (L/L) had 16 fold higher susceptibility to death. TIRAP mutants (S/L and L/L) were associated with significantly higher plasma TNF-α levels compared to wild type (S/S). The results of the present study demonstrate that TIRAP S180L heterozygous mutation may protect patients against severe malaria and mortality. PMID:27166096

  2. 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.

  3. Permanent Neonatal Diabetes Mellitus Due to a C96Y Heterozygous Mutation in the Insulin Gene. A Case Report

    Directory of Open Access Journals (Sweden)

    Anish Ahamed

    2008-11-01

    Full Text Available Context Neonatal diabetes is a rare disorder with an incidence of 1 in 215,000-500,000 live births with 50% of them having permanent neonatal diabetes mellitus. Case report We present a case of permanent neonatal diabetes mellitus due to a C96Y (c.287G>A; p.Cys96Tyr heterozygous mutation in the insulin (INS gene. Both the patient and his father (who had childhoodonset insulin-requiring diabetes were found to be carriers of a heterozygous missense mutation C96Y in exon 3 of the INS gene. It has been hypothesized that these mutations disrupt the folding of the proinsulin molecule and result in a misfolded protein or retention of the protein in the endoplasmic reticulum, resulting in endoplasmic reticulum stress and beta cell apoptosis. Subjects with this form of diabetes will need lifelong insulin therapy. Conclusion Insulin gene mutations appear to be an important cause of neonatal diabetes worldwide. This is the first report of a case from the Indian subcontinent. It is important to carry out genetic tests for mutations linked to pancreatic beta cell dysfunction in all patients with persistent neonatal diabetes mellitus in order to decide on therapy

  4. Homozygous and heterozygous deletions of the von Willebrand factor gene in patients and carriers of sever von Willebrand disease

    International Nuclear Information System (INIS)

    Severe von Willebrand disease is characterized by undetectable or trace quantities of von Willebrand factor in plasma and tissue stores. The authors have studied the genomic DNA of 10 affected individuals from six families with this disorder using probes from the 5' and 3' ends of the vWF cDNA and with a probe extending from the 5' end into the central region. Southern blots of restriction endonuclease digest and gene dosage analysis measurements carried out with quantitative slot blots of undigested genomic DNA separated these patients into three groups. The first group consisted of a family with complete homozygous deletions of the vWF gene in the four probands. The second group was comprised of a family in which there was a complete heterozygous deletion of the vWF gene in the proband and one asymptomatic parent, suggesting that a different type of genetic abnormality was inherited from the other parent. Thus, the patient appeared to be doubly heterozygous for interacting genetic abnormalities affecting vWF expression. In the third group, no gene deletions could be detected. Alloantibodies developed only in the kindred with homozygous deletions. These techniques should prove useful in identifying carriers of severe von Willebrand disease and also in defining patients predictably at risk of developing alloantibodes to vWF

  5. Heterozygous mutations in SIX3 and SHH are associated with schizencephaly and further expand the clinical spectrum of holoprosencephaly.

    Science.gov (United States)

    Hehr, Ute; Pineda-Alvarez, Daniel E; Uyanik, Goekhan; Hu, Ping; Zhou, Nan; Hehr, Andreas; Schell-Apacik, Chayim; Altus, Carola; Daumer-Haas, Cornelia; Meiner, Annechristin; Steuernagel, Peter; Roessler, Erich; Winkler, Juergen; Muenke, Maximilian

    2010-03-01

    Schizencephaly (SCH) is a clinically and etiologically heterogeneous cerebral malformation presenting as unilateral or bilateral hemispheric cleft with direct connection between the inner and outer liquor spaces. The SCH cleft is usually lined by gray matter, which appears polymicrogyric implying an associated impairment of neuronal migration. The majority of SCH patients are sporadic, but familial SCH has been described. An initial report of heterozygous mutations in the homeobox gene EMX2 could not be confirmed in 52 patients investigated in this study in agreement with two independent SCH patient cohorts published previously. SCH frequently occurs with additional cerebral malformations like hypoplasia or aplasia of the septum pellucidum or optic nerve, suggesting the involvement of genes important for the establishment of midline forebrain structures. We therefore considered holoprosencephaly (HPE)-associated genes as potential SCH candidates and report for the first time heterozygous mutations in SIX3 and SHH in a total of three unrelated patients and one fetus with SCH; one of them without obvious associated malformations of midline forebrain structures. Three of these mutations have previously been reported in independent patients with HPE. SIX3 acts directly upstream of SHH, and the SHH pathway is a key regulator of ventral forebrain patterning. Our data indicate that in a subset of patients SCH may develop as one aspect of a more complex malformation of the ventral forebrain, directly result from mutations in the SHH pathway and hence be considered as yet another feature of the broad phenotypic spectrum of holoprosencephaly. PMID:20157829

  6. The "Goldilocks Effect" in Cystic Fibrosis: identification of a lung phenotype in the cftr knockout and heterozygous mouse

    Directory of Open Access Journals (Sweden)

    Bates Jason HT

    2004-07-01

    Full Text Available Abstract Background Cystic Fibrosis is a pleiotropic disease in humans with primary morbidity and mortality associated with a lung disease phenotype. However, knockout in the mouse of cftr, the gene whose mutant alleles are responsible for cystic fibrosis, has previously failed to produce a readily, quantifiable lung phenotype. Results Using measurements of pulmonary mechanics, a definitive lung phenotype was demonstrated in the cftr-/- mouse. Lungs showed decreased compliance and increased airway resistance in young animals as compared to cftr+/+ littermates. These changes were noted in animals less than 60 days old, prior to any long term inflammatory effects that might occur, and are consistent with structural differences in the cftr-/- lungs. Surprisingly, the cftr+/- animals exhibited a lung phenotype distinct from either the homozygous normal or knockout genotypes. The heterozygous mice showed increased lung compliance and decreased airway resistance when compared to either homozygous phenotype, suggesting a heterozygous advantage that might explain the high frequency of this mutation in certain populations. Conclusions In the mouse the gene dosage of cftr results in distinct differences in pulmonary mechanics of the adult. Distinct phenotypes were demonstrated in each genotype, cftr-/-, cftr +/-, and cftr+/+. These results are consistent with a developmental role for CFTR in the lung.

  7. Novel Compound Heterozygous Spatacsin Mutations in a Greek Kindred with Hereditary Spastic Paraplegia SPG11 and Dementia.

    Science.gov (United States)

    Fraidakis, Matthew J; Brunetti, Maura; Blackstone, Craig; Filippi, Massimo; Chiò, Adriano

    2016-01-01

    SPG11 belongs to the autosomal recessive hereditary spastic paraplegias (HSP) and presents during childhood or puberty with a complex clinical phenotype encompassing learning difficulties, ataxia, peripheral neuropathy, amyotrophy, and mental retardation. We hereby present the case of a 30-year-old female patient with complex autosomal recessive HSP with thinning of the corpus callosum (TCC) and dementia that was compound heterozygous with two novel mutations in the SPG11 gene. Sequence analysis of the SPG11 gene revealed two novel mutations in a compound heterozygous state in the index patient (c.2431C>T/p.Gln811Ter and c.6755_6756insT/p.Glu2252Aspfs*88). MRI showed abnormal TCC, white matter (WM) hyperintensities periventricularly, and the 'ears of the lynx' sign. Diffusion tensor imaging showed a mild-to-moderate decrease in fractional anisotropy and an increase in mean diffusivity in WM compared to age-matched controls, while magnetic resonance spectroscopy showed abnormal findings in affected WM with a decrease in N-acetyl-aspartate in WM regions of interest. This is the first SPG11 kindred from the Greek population to be reported in the medical literature. PMID:27318863

  8. Ex vivo SIV-specific CD8 T cell responses in heterozygous animals are primarily directed against peptides presented by a single MHC haplotype.

    Directory of Open Access Journals (Sweden)

    Justin M Greene

    Full Text Available The presence of certain MHC class I alleles is correlated with remarkable control of HIV and SIV, indicating that specific CD8 T cell responses can effectively reduce viral replication. It remains unclear whether epitopic breadth is an important feature of this control. Previous studies have suggested that individuals heterozygous at the MHC class I loci survive longer and/or progress more slowly than those who are homozygous at these loci, perhaps due to increased breadth of the CD8 T cell response. We used Mauritian cynomolgus macaques with defined MHC haplotypes and viral inhibition assays to directly compare CD8 T cell efficacy in MHC-heterozygous and homozygous individuals. Surprisingly, we found that cells from heterozygotes suppress viral replication most effectively on target cells from animals homozygous for only one of two potential haplotypes. The same heterozygous effector cells did not effectively inhibit viral replication as effectively on the target cells homozygous for the other haplotype. These results indicate that the greater potential breadth of CD8 T cell responses present in heterozygous animals does not necessarily lead to greater antiviral efficacy and suggest that SIV-specific CD8 T cell responses in heterozygous animals have a skewed focus toward epitopes restricted by a single haplotype.

  9. Two mutations in the same low-density lipoprotein receptor allele act in synergy to reduce receptor function in heterozygous familial hypercholesterolemia

    DEFF Research Database (Denmark)

    Jensen, H K; Jensen, T G; Faergeman, O;

    1997-01-01

    present study of two families with familial hypercholesterolemia in the heterozygous form, we found two mutations in the same allele of the low-density lipoprotein (LDL) receptor gene: a missense Asn543. His mutation (N543H) in exon 11, and an in-frame 9-bp deletion (2393del9) in exon 17. The two...... mutations were identified in heterozygous FH index patients in whom no other pathogenic mutations were detected by SSCP analysis of the remaining 16 exons and the promoter region. Both mutations cosegregated with hypercholesterolemia within the families. Each of these mutations had little or no effect on...

  10. 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 situ...... receptors to become insulin-dependently activated. The mother carries a point mutation at the last base pair in exon 17 which, due to abnormal alternative splicing, could lead to normally transcribed receptor or truncated receptor lacking the kinase region. Kinase activation was normal in the mother...... receptors in the mother's skeletal muscle are transcribed almost exclusively from the non-mutated allele. The mutation in exon 17 could lead to reduced transcription or rapid degradation of a predominantly transcribed truncated gene product or both....

  11. 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

    Dilated cardiomyopathy (DCM) associates left ventricular (LV) dilatation and systolic dysfunction and is a major cause of heart failure and cardiac transplantation. LMNA gene encodes lamins A/C, proteins of the nuclear envelope. LMNA mutations cause DCM with conduction and/or rhythm defects. 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...

  12. Impaired ventilatory and thermoregulatory responses to hypoxic stress in newborn Phox2b heterozygous knockout mice

    Directory of Open Access Journals (Sweden)

    Nelina eRamanantsoa

    2011-09-01

    Full Text Available The Phox2b gene is necessary for the development of the autonomic nervous system, and especially, of respiratory neuronal circuits. In the present study, we examined the role of Phox2b in ventilatory and thermoregulatory responses to hypoxic stress, which are closely related in the postnatal period. Hypoxic stress was generated by strong thermal stimulus, combined or not with reduced inspired O2. To this end, we exposed 6-day-old Phox2b+/- pups and their wild-type littermates (Phox2b+/+ to hypoxia (10% O2 or hypercapnia (8% CO2 under thermoneutral (33°C or cold (26°C conditions. We found that Phox2b+/- pups showed less normoxic ventilation (VE in the cold than Phox2b+/+ pups. Phox2b+/- pups also showed lower oxygen consumption (VO2 in the cold, reflecting reduced thermogenesis and a lower body temperature. Furthermore, while the cold depressed ventilatory responses to hypoxia and hypercapnia in both genotype groups, this effect was less pronounced in Phox2b+/- pups. Finally, because serotonin (5-HT neurons are pivotal to respiratory and thermoregulatory circuits and depend on Phox2b for their differentiation, we studied 5-HT metabolism using high-pressure liquid chromatography, and found that it was altered in Phox2b+/- pups. We conclude that Phox2b haploinsufficiency alters the ability of newborns to cope with metabolic challenges, possibly due to 5-HT signaling impairments.

  13. Generation of a heterozygous knockout human embryonic stem cell line for the OCIAD1 locus using CRISPR/CAS9 mediated targeting: BJNhem20-OCIAD1-CRISPR-39

    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-39. The line was generated using CRISPR-Cas9D10A double nickase knockout strategy (Mali et al., 2013.

  14. 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.

  15. 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. PMID:27354540

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

    OpenAIRE

    Deeti K. Shetty; Inamdar, Maneesha S.

    2016-01-01

    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).

  17. Generation of a heterozygous knockout human embryonic stem cell line for the OCIAD1 locus using CRISPR/CAS9 mediated targeting: BJNhem20-OCIAD1-CRISPR-39

    OpenAIRE

    Deeti K. Shetty; Inamdar, Maneesha S.

    2016-01-01

    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-39. The line was generated using CRISPR-Cas9D10A double nickase knockout strategy (Mali et al., 2013).

  18. Novel Compound Heterozygous Mutations in the CYP27B1 Gene Lead to Pseudovitamin D-Deficient Rickets.

    Science.gov (United States)

    Koek, W Nadia H; Zillikens, M Carola; van der Eerden, Bram C J; van Leeuwen, Johannes P T M

    2016-09-01

    Pseudovitamin D deficiency is the consequence of a genetic defect in the CYP27B1 gene resulting in diminished or absent conversion of 25-hydroxyvitamin D3 (25-(OH)D3) into 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) and leads to growth retardation and rickets, usually in the first 2 years of life. DNA obtained from human leucocytes from a patient suspected of pseudovitamin D deficiency and her healthy parents was sequenced for a genetic defect in the CYP27B1 gene. In silico analyses on the mutations were performed using online available software. The 1α-hydroxylase activity of the patient, her parents, and a sample derived from a mixed buffy coat of healthy blood donors was measured by culturing peripheral blood mononuclear cells with 25-(OH)D3 and measuring 1,25-(OH)2D3 production. DNA sequencing of the patient suspected of pseudovitamin D deficiency revealed compound heterozygosity in the CYP27B1 gene for a (c413G>T) mutation in exon 3 (R138L) and a (c1232G>A) mutation in exon 8 (C411Y). In silico analyses confirmed that mutations at these positions are probably damaging for the protein since the amino acids are situated in a highly conserved region. In vitro analyses showed a nearly absent 1α-hydroxylase activity in the patient compared to the healthy blood donors. Her healthy parents each of whom carried one of the mutations also had compromised conversion of 25-(OH)D3 into 1,25-(OH)2D3 in peripheral blood mononuclear cells, being only marginally higher than in the patient. We discovered novel compound heterozygous mutations in the CYP27B1 gene in a young girl presenting with pseudovitamin D-deficient rickets, leading to severely decreased 1,25-(OH)2D3 production. Furthermore, both heterozygous parents showed a diminished 1α-hydroxylase activity. PMID:27364341

  19. Featherweight Challenge

    Science.gov (United States)

    Love, Tyler S.; Ryan, Larry

    2012-01-01

    As science, technology education, and engineering programs suffer budget cuts, educators continue to seek cost-effective activities that engage students and reinforce standards. The featherweight challenge is a hands-on activity that challenges students to continually refine their design while not breaking the budget. This activity uses one of the…

  20. New Codanin-1 Gene Mutations in a Italian Patient with Congenital Dyserythropoietic Anemia Type I and Heterozygous Beta-Thalassemia.

    Science.gov (United States)

    D'Alcamo, Elena; Agrigento, V; Pitrolo, L; Sclafani, S; Barone, R; Calvaruso, G; Buffa, V; Maggio, A

    2016-06-01

    Congenital dyserythropoietic anemia type I is an autosomal recessive disorder associated with macrocytic anemia, ineffective erythropoiesis, iron overloading and characterized by abnormal chromatin ultrastructure in erythroblasts such as internuclear chromatin bridges, spongy heterochromatin and invagination of the nuclear membrane. A 58-year-old Causasian man with chronic hemolytic anemia, heterozygous for β (+) -globin IVS1, nt110 G>A mutation (causing abnormal alpha:beta globin chain ratio) showed clinical, laboratory and hematological features suggesting diagnosis of CDA1. Sequence analysis of CDA-related genes revealed compound heterozygosity for two novel mutations in the CDAN1 gene: a frameshift mutation 3367 del 4 (TTAG) in exon 25 and a missense mutation c.1811 G>T in exon 11 causing an aminoacid change from glycine to valine at codon 565 (G565V). One of the propositus' brothers showed the same gene mutations. As the CDA1 can mimic thalassemia, a frequent misdiagnosis is possible especially in countries where the prevalence of thalassemia is high. A strong clinical suspicion in patients who do not reveal a clear genetic basis for presumed thalassemia may help clinch the correct diagnosis. PMID:27408412

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

    International Nuclear Information System (INIS)

    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

  2. Two heterozygous Cav3.2 channel mutations in a pediatric chronic pain patient: recording condition-dependent biophysical effects.

    Science.gov (United States)

    Souza, Ivana A; Gandini, Maria A; Wan, Miranda M; Zamponi, Gerald W

    2016-04-01

    We report expression system-dependent effects of heterozygous mutations (P769L and A1059S) in the Cav3.2 CACNA1H gene identified in a pediatric patient with chronic pain and absence seizures. The mutations were introduced individually into recombinant channels and then analyzed by means of electrophysiology. When both mutants were co-expressed in tsA-201 cells, we observed a loss of channel function, with significantly smaller current densities across a wide range of voltages (-40 to +20 mV). In addition, when both mutant channels were co-expressed, the channels opened at a more depolarizing potential with a ~5-mV right shift in the half-activation potential, with no changes in half-inactivation potential and the rate of recovery from inactivation. Interestingly, when both mutants were co-expressed in the neuronal-derived CAD cells in a different extracellular milieu, the effect was remarkably different. Although not statistically significant (p replacement of extracellular sodium and potassium with tetraethylammonium chloride. Our results show that experimental conditions can be a confounding factor in the biophysical effects of T-type calcium channel mutations found in certain neurological disorders. PMID:26706850

  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. PMID:23020089

  4. The proportion of hybrid heterodimers in homozygous or doubly heterozygous beta chain variant hemoglobinopathies associated with alpha chain hemoglobin variants.

    Science.gov (United States)

    Krauss, J S

    2000-10-01

    Four alpha genes exist on chromosome 16, but one or more of these genes can be deleted in association with Hemoglobin (Hb)G-Philadelphia in cis to alpha-thalassemia-2 in African-Americans. Therefore, the proportion of HbG-Philadelphia in HbG heterozygotes is trimodal at about 25% for alphaGalpha/alpha alpha, 33% for alphaG-/alpha alpha, and 50% for alphaG-/alpha alpha in patients with HbA. Those who are homozygous or doubly heterozygous for beta chain variants (betaX2 or betaXbetaY) have neither HbA nor the alpha chain variant (alphaX2 betaA2), but have hybrid heterodimers (alphaX2 betaX2). The proportion of hybrid heterodimers here should also be trimodal mirroring alpha gene status. Eleven patients were identified: 4 with Hb SSG, 3 with Hb SCG, and 1 each with Hb OCG, HbSSMontgomery, HbSSChicago, and HbSSBourmedes. Heterodimer proportions were: 43.3 +/- 1.5, 33.5 +/- 2.3, and 15.8 +/- 1.1% for 2, 3, and 4 respective alpha genes which had been studied in 8/11 of the patients (r = 0.98), implying that the prime determinant of the proportion of hybrid heterodimers in this patient group is the number of functional alpha genes. PMID:11045763

  5. Masked deficit of vitamin B12 in the patient with heterozygous beta-thalassemia and spastic paraparesis.

    Science.gov (United States)

    Bilic, Ernest; Bilic, Ervina; Zagar, Marija; Juric, Stjepan

    2004-12-01

    The spinal cord, brain, optic nerves and peripheral nerves may be affected by vitamin B12 (cobalamin) deficiency. Deficiency of vitamin B12 also causes megaloblastic anaemia, meaning that the red blood cells are usually larger than normal. In this paper we report a 16-year old girl who was referred to us for the evaluation of mild paraparesis and paresthesias marked by tingling "pins and needles" feelings and general weakness. The patient, her parents and sisters were on a strict vegan diet, which made us believe that vitamin B12 deficiency may be the possible cause of the neurologic clinical manifestations. The serum level of vitamin B12 was low, but there was no macrocytosis in the routine blood examination. The electrophoresis of haemoglobin was pathologic, there was 3.7% of HbA2 and 11.6% of HbF (heterozygous form of beta-thalassaemia). When megaloblastic anaemia occurs in combination with a condition that gives rise to microcytic anaemia, many megaloblastic features may be masked. Instead of being macrocytic, the anaemia could be normocytic or even microcytic. Vitamin B12 deficiency is a diagnosis that must not be overlooked. This case report turns the light on the fact that increased MCV is a hallmark in vitamin B12 deficiency, but it is not an obligatory sign. PMID:15742609

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

    International Nuclear Information System (INIS)

    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. Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing

    Science.gov (United States)

    Merico, Daniele; Roifman, Maian; Braunschweig, Ulrich; Yuen, Ryan K. C.; Alexandrova, Roumiana; Bates, Andrea; Reid, Brenda; Nalpathamkalam, Thomas; Wang, Zhuozhi; Thiruvahindrapuram, Bhooma; Gray, Paul; Kakakios, Alyson; Peake, Jane; Hogarth, Stephanie; Manson, David; Buncic, Raymond; Pereira, Sergio L.; Herbrick, Jo-Anne; Blencowe, Benjamin J.; Roifman, Chaim M.; Scherer, Stephen W.

    2015-01-01

    Roifman Syndrome is a rare congenital disorder characterized by growth retardation, cognitive delay, spondyloepiphyseal dysplasia and antibody deficiency. Here we utilize whole-genome sequencing of Roifman Syndrome patients to reveal compound heterozygous rare variants that disrupt highly conserved positions of the RNU4ATAC small nuclear RNA gene, a minor spliceosome component that is essential for minor intron splicing. Targeted sequencing confirms allele segregation in six cases from four unrelated families. RNU4ATAC rare variants have been recently reported to cause microcephalic osteodysplastic primordial dwarfism, type I (MOPD1), whose phenotype is distinct from Roifman Syndrome. Strikingly, all six of the Roifman Syndrome cases have one variant that overlaps MOPD1-implicated structural elements, while the other variant overlaps a highly conserved structural element not previously implicated in disease. RNA-seq analysis confirms extensive and specific defects of minor intron splicing. Available allele frequency data suggest that recessive genetic disorders caused by RNU4ATAC rare variants may be more prevalent than previously reported. PMID:26522830

  8. Heterozygous Mutations in MAP3K7, Encoding TGF-β-Activated Kinase 1, Cause Cardiospondylocarpofacial Syndrome.

    Science.gov (United States)

    Le Goff, Carine; Rogers, Curtis; Le Goff, Wilfried; Pinto, Graziella; Bonnet, Damien; Chrabieh, Maya; Alibeu, Olivier; Nistchke, Patrick; Munnich, Arnold; Picard, Capucine; Cormier-Daire, Valérie

    2016-08-01

    Cardiospondylocarpofacial (CSCF) syndrome is characterized by growth retardation, dysmorphic facial features, brachydactyly with carpal-tarsal fusion and extensive posterior cervical vertebral synostosis, cardiac septal defects with valve dysplasia, and deafness with inner ear malformations. Whole-exome sequencing identified heterozygous MAP3K7 mutations in six distinct CSCF-affected individuals from four families and ranging in age from 5 to 37 years. MAP3K7 encodes transforming growth factor β (TGF-β)-activated kinase 1 (TAK1), which is involved in the mitogen-activated protein kinase (MAPK)-p38 signaling pathway. MAPK-p38 signaling was markedly altered when expression of non-canonical TGF-β-driven target genes was impaired. These findings support the loss of transcriptional control of the TGF-β-MAPK-p38 pathway in fibroblasts obtained from affected individuals. Surprisingly, although TAK1 is located at the crossroad of inflammation, immunity, and cancer, this study reports MAP3K7 mutations in a developmental disorder affecting mainly cartilage, bone, and heart. PMID:27426734

  9. Radio-induced apoptosis is impaired in individuals homozygous and heterozygous for the ataxia-telangiectasia gene(s)

    International Nuclear Information System (INIS)

    Ataxia-telangiectasia is a progressive recessive disease featuring neuro degeneration, immunodeficiency, chromosomal instability, radiation hypersensitivity and increased predisposition to cancer. Impaired induction of the tumor suppressor protein p53 after γ-irradiation was recently reported. All together these characteristics may be compatible with an inability to correctly regulate the apoptotic pathway of cell death in this syndrome. We show here that lymphocyte cultures from AT patients are characterized by a 3 times more elevated spontaneous level of apoptotic cells compared to normal ones. In spite of this, 24 h after exposure to γ-irradiation (5 to 10 Gy), AT lymphocytes show a dramatically reduced capacity to undergo apoptosis compared to normal cells. We obtained similar results on EBV-transformed lymphoblasts. Interestingly, lymphoblasts from obligate heterozygous for the AT mutation(s) show the same features as AT lymphoblasts, i.e. an elevated frequency of spontaneous and a reduced level of radio-induced apoptotic figures in comparison to normal cultured cells. In conclusion, we show here, for the first time, that mutation(s) in AT gene(s) results in an impaired ability to correctly regulate the apoptotic pathway of cell death. (author). 26 refs., 4 figs., 2 tabs

  10. [Silencing of Dominant Genes in Heterozygous Genotypes of Interspecific Hybrids Fagopyrum esculentum Moench. x C2026 F. homotropicum Ohnishi].

    Science.gov (United States)

    Fesenko, N N; Fesenko, I N

    2016-04-01

    Fagopyrum homotropicum Ohnishi is a very polymorphic self-pollinating species with homostylous flowers, which morphologically different lineages are differ also in ability to hybridize with F. esculentum Moench. (closely related outcrosser with heterostyly). A lineage C2026 F. homotropicum diverged from F. esculentum with forming noticeable pre-zygotic and post-zygotic barriers: the most successful interspecific crossing F esculentum x C2026 resulted wrinkled hybrid seeds germinated in Petri dishes. These interspecific hybrids and backcrosses F. esculentum x F₁, being heterozygous at loci DET/det, SHT/sht and homostyly gene of F. homotropicum, in our experiments often formed phenotype like a recessive homozygote for at least one of these genes, i.e. dominant alleles were silenced. Apparently, these effects can be caused by disorders of epigenetic regulation associated with the divergence of hybridized species. Such disorders, especially those that occur at the stage of seed development, represent one of the main experimentally confirmed mechanisms of pre-zygotic isolation between species. Apparently, F. esculentum and the lineage C2026 of F. homotropicum represent an example of intermediate stage of post-zygotic isolation development process which based on epigenetic deregulation of gene expression in the hybrids. Sometimes it may be revealed not only at the stage of seed development, but also at later stages of ontogenesis. PMID:27529977

  11. 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.

  12. Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC: Compound heterozygous mutation in the claudin 16 (CLDN16 gene

    Directory of Open Access Journals (Sweden)

    Konrad Martin A

    2008-09-01

    Full Text Available Abstract Background Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC is an autosomal recessive disorder of renal calcium and magnesium wasting frequently complicated by progressive chronic renal failure in childhood or adolescence. Methods A 7 year old boy was investigated following the findings of marked renal insufficiency and nephrocalcinosis in his 18-month old sister. He too was found to have extensive nephrocalcinosis with increased fractional excretion of magnesium: 12.4% ( Results Mutation analysis revealed 2 heterozygous mutations in the claudin 16 gene (CLDN16 in both affected siblings; one missense mutation in exon 4: C646T which results in an amino acid change Arg216Cys in the second extracellular loop of CLDN16 and loss of function of the protein and a donor splice site mutation which changes intron 4 consensus splice site from 'GT' to 'TT' resulting in decreased splice efficiency and the formation of a truncated protein with loss of 64 amino acids in the second extracellular loop. Conclusion The mutations in CLDN16 in this kindred affect the second extra-cellular loop of claudin 16. The clinical course and molecular findings suggest complete loss of function of the protein in the 2 affected cases and highlight the case for molecular diagnosis in individuals with FHHNC.

  13. 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.

  14. Cornelia de Lange syndrome caused by heterozygous deletions of chromosome 8q24: comments on the article by Pereza et al. [2012].

    Science.gov (United States)

    Pereza, Nina; Severinski, Srećko; Ostojić, Saša; Volk, Marija; Maver, Aleš; Dekanić, Kristina Baraba; Kapović, Miljenko; Peterlin, Borut

    2015-06-01

    In the March issue of the Journal in 2012, we reported on a girl with Langer-Giedion syndrome (LGS) phenotype and a 7.5 Mb interstitial deletion at 8q23.3q24.13, encompassing the EXT1, but not the TRPS1 gene. Recent discoveries have shown that heterozygous intragenic mutations or contiguous gene deletions including the RAD21 gene, which is located downstream of the TRPS1 gene, are the cause of Cornelia de Lange syndrome-4. Considering that the interstitial deletion in our patient included the RAD21 and 30 other RefSeq genes, we would like to suggest a revision of the diagnosis reported in our previous paper and compare our patient to other reported patients with Cornelia de Lange syndrome-4 caused by heterozygous deletions of chromosome 8q24. © 2015 Wiley Periodicals, Inc. PMID:25899858

  15. Collagen Content and Electrophoretic Analysis of Type I Collagen in Breast Skin of Heterozygous Naked Neck and Normally Feathered Commercial Broilers

    OpenAIRE

    BİLGEN, Güldehen

    1999-01-01

    This study was conducted to evaluate the breast skin collagen content and electrophoretic analyses of type I collagen in heterozygous naked neck and normally feathered commercial chicks. A total of 72 birds from each genotype were randomly selected at 7 weeks and slaughtered. Breast skin was separated from each carcass and was analysed for collagen content and gel electrophopresis of type I collagen was performed. Males had significantly higher level of skin collagen content than females i...

  16. Aorta of young and middle-aged heterozygous familial hypercholesterolemia patients shows no functional or morphological impairment assessed by MRI

    Directory of Open Access Journals (Sweden)

    Sami Soljanlahti

    2008-09-01

    Full Text Available Sami Soljanlahti1, Taina Autti1, Alpo F Vuorio2, Pekka Keto1, Hannu Turtola3, Kirsi Lauerma11Helsinki Medical Imaging Center, Helsinki University Central Hospital, Helsinki, Finland; 2Division of Internal Medicine, Department of Medicine, University of Helsinki, Helsinki, Finland; 3Department of Internal Medicine, North Karelia Central Hospital, Joensuu, FinlandAbstract: In familial hypercholesterolemia (FH the level of LDL cholesterol is 2–3 times that of the normal population and leads to accelerated atherosclerosis. Improved care for risk factors has decreased cardiovascular mortality of these patients. We studied subclinical atherosclerotic changes with morphologic and functional aortic magnetic resonance imaging (MRI in FH patients under the age of 50. 39 DNA test-verified heterozygous FH-North Karelia patients, aged 6–48, 28 of them treated with statins, and 25 healthy controls, aged 12 to 50, underwent aortic MRI, carotid ultrasound (US, and risk-factor assessment. No differences in any of the morphologic or functional aortic parameters appeared between patients and controls. Age and gender were independent predictors of the majority of the morphologic and functional measures. Carotid intima-media thickness assessed by US was greater in patients (0.57 mm ± 0.13 vs 0.48 ± 0.13 mm, p = 0.005 as was cholesterol-years score (243 ± 122 vs 137 ± 74, p < 0.001. Patients had thicker intima-media of the common carotid artery and higher cholesterol burden as indicated by their cholesterol-years score. Despite this, no differences existed in morphologic or functional aortic parameters assessed with MRI. The improved care of cardiovascular risk factors, especially statin treatment, may protect the aorta of FH patients. However, larger confirmatory studies are needed.Keywords: MRI, ultrasound, atherosclerosis, aorta, familial hypercholesterolemia

  17. 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.

  18. 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. PMID:24904333

  19. 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.

  20. Two novel compound heterozygous mutations in OPA3 in two siblings with OPA3-related 3-methylglutaconic aciduria

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    Christina Lam

    2014-01-01

    Full Text Available OPA3-related 3-methylglutaconic aciduria, or Costeff Optic Atrophy syndrome, is a neuro-ophthalmologic syndrome of early-onset bilateral optic atrophy and later-onset spasticity, and extrapyramidal dysfunction. Urinary excretion of 3-methylglutaconic acid and of 3-methylglutaric acid is markedly increased. OPA3-related 3-methylglutaconic aciduria is due to mutations in the OPA3 gene located at 19q13.2–13.3. Here we describe two siblings with novel compound heterozygous variants in OPA3: c.1A>G (p.1M>V in the translation initiation codon in exon 1 and a second variant, c.142+5G>C in intron 1. On cDNA sequencing the c.1A>G appeared homozygous, indicating that the allele without the c.1A>G variant is degraded. This is likely due to an intronic variant; possibly the IVS1+5 splice site variant. The older female sibling initially presented with motor developmental delay and vertical nystagmus during her first year of life and was diagnosed subsequently with optic atrophy. Her brother presented with mildly increased hip muscle tone followed by vertical nystagmus within the first 6 months of life, and was found to have elevated urinary excretion of 3-methylglutaconic acid and 3-methylglutaric acid, and optic atrophy by 1.5 years of age. Currently, ages 16 and 7, both children exhibit ataxic gaits and dysarthric speech. Immunofluorescence studies on patient's cells showed fragmented mitochondrial morphology. Thus, though the exact function of OPA3 remains unknown, our experimental results and clinical summary provide evidence for the pathogenicity of the identified OPA3 variants and provide further evidence for a mitochondrial pathology in this disease.

  1. 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.

  2. 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.

  3. Logistical challenges

    Directory of Open Access Journals (Sweden)

    Steve Matthews

    2005-07-01

    Full Text Available The impact of the Asian tsunami was unprecedented and the logistical challenges of meeting the needs of those affected were enormous. Had the tsunami happened even five years ago, World Vision would not have been able to respond nearly as effectively as it did.

  4. 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 th...

  5. Ethical Challenges

    Science.gov (United States)

    Morris, Michael

    2004-01-01

    All evaluators face the challenge of striving to adhere to the highest possible standards of ethical conduct. Translating the AEA's Guiding Principles and the Joint Committee's Program Evaluation Standards into everyday practice, however, can be a complex, uncertain, and frustrating endeavor. Moreover, acting in an ethical fashion can require…

  6. Editorial Challenges

    OpenAIRE

    Budin, Wendy C.

    2008-01-01

    In this column, the editor of The Journal of Perinatal Education (JPE) discusses some of the challenges involved in becoming the new editor of JPE. The editor also describes the contents of this issue, which offer a broad range of resources, research, and inspiration for childbirth educators in their efforts to promote normal birth.

  7. Archiving challenges

    OpenAIRE

    Ringersma, J.

    2010-01-01

    Teaching slides on: What is a digital archive? Parties involved in digital archiving Archiving challenges organization of data coherence and persistency access and safety Language archiving software Different users, different needs For: Saami Language Documentation and Revitalization. Winter school, Bodø, Norway

  8. CHALLENGES IN BRONCHIAL CHALLENGE TESTING

    NARCIS (Netherlands)

    Lexmond, A. J.; Hagedoorn, P.; Frijlink, H. W.; de Boer, A. H.

    2013-01-01

    Background: In the adenosine 5'-monophosphate (AMP) bronchial challenge test, AMP is usually administered according to dosing protocols developed for histamine/methacholine. It has never been thoroughly investigated whether these protocols are suitable for AMP as well. Methods: The setup of the two-

  9. Homozygous and heterozygous GH transgenesis alters fatty acid composition and content in the liver of Amago salmon (Oncorhynchus masou ishikawae

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    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. Long term effects of high fat or high carbohydrate diets on glucose tolerance in mice with heterozygous carnitine palmitoyltransferase-1a (CPT-1a) deficiency: Diet influences on CPT1a deficient mice.

    Science.gov (United States)

    Nyman, Lara R; Tian, Liqun; Hamm, Doug A; Schoeb, Trenton R; Gower, Barbara A; Nagy, Tim R; Wood, Philip A

    2011-08-22

    BACKGROUND: Abnormal fatty acid metabolism is an important feature in the mechanisms of insulin resistance and beta-cell dysfunction. Carnitine palmitoyltransferase-1a (CPT-1a, liver isoform) plays a pivotal role in the regulation of mitochondrial fatty acid oxidation. We investigated the role of CPT-1a in the development of impaired glucose tolerance using a mouse model for CPT-1a deficiency when challenged by either a high-carbohydrate (HCD) or a high-fat diet (HFD) for a total duration of up to 46 weeks. METHODS: Insulin sensitivity and glucose tolerance were assessed in heterozygous CPT-1a deficient (CPT-1a+/-) male mice after being fed either a HCD or a HFD for durations of 28 weeks and 46 weeks. Both glucose and insulin tolerance tests were used to investigate beta-cell function and insulin sensitivity. Differences in islet insulin content and hepatic steatosis were evaluated by morphological analysis. RESULTS: CPT-1a+/- mice were more insulin sensitive than CPT-1a+/+ mice when fed either HCD or HFD. The increased insulin sensitivity was associated with an increased expression of Cpt-1b (muscle isoform) in liver, as well as increased microvesicular hepatic steatosis compared to CPT-1a+/+ mice. CPT-1a+/- mice were more glucose tolerant than CPT-1a+/+ mice when fed the HCD, but there was no significant difference when fed HFD. Moreover, CPT-1a+/- mice fed HFD or HCD had fewer and smaller pancreatic islets than CPT-1a+/+ mice. CONCLUSIONS: CPT-1a deficiency preserved insulin sensitivity when challenged by long term feeding of either diet. Furthermore, CPT-1a deficient mice had distinct phenotypes dependent on the diet fed demonstrating that both diet and genetics collectively play a role in the development of impaired glucose tolerance. PMID:22229081

  11. Global challenges

    International Nuclear Information System (INIS)

    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 SO2 and NOx which cause acid rain, and CO2 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)

  12. 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...

  13. (-)-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 group...

  14. 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...

  15. Retention of wild-type p53 in tumors from p53 heterozygous mice: reduction of p53 dosage can promote cancer formation.

    OpenAIRE

    Venkatachalam, S; Shi, Y P; Jones, S N; Vogel, H.; Bradley, A.; Pinkel, D; Donehower, L A

    1998-01-01

    Tumor suppressor genes are generally viewed as being recessive at the cellular level, so that mutation or loss of both tumor suppressor alleles is a prerequisite for tumor formation. The tumor suppressor gene, p53, is mutated in approximately 50% of human sporadic cancers and in an inherited cancer predisposition (Li-Fraumeni syndrome). We have analyzed the status of the wild-type p53 allele in tumors taken from p53-deficient heterozygous (p53+/-) mice. These mice inherit a single null p53 al...

  16. The two mutations, Q204X and nt821, of the myostatin gene affect carcass and meat quality in young heterozygous bulls of French beef breeds

    OpenAIRE

    Levéziel, Hubert; Payet-Duprat, Nathalie; Hocquette, Jean-François; Lepetit, Jacques; Rousset, Sylvie; Denoyelle, Christophe; Bernard-Capel, Carine; Journaux, L.; Bonnot, Aline; Renand, Gilles

    2010-01-01

    The availability of genetic tests to detect different mutations in the myostatin gene allows the identification of heterozygous animals and would warrant the superiority of these animals for slaughter performance if this superiority is confirmed. Thus, 2 mutations of this gene, Q204X and nt821, were studied in 3 French beef breeds in the program Qualvigène. This work was done with 1,114 Charolais, 1,254 Limousin, and 981 Blonde d’Aquitaine young bulls from, respectively, 48, 36, and 30 sires ...

  17. Hepatocytes from wild-type or heterozygous donors are equally effective in achieving successful therapeutic liver repopulation in murine phenylketonuria (PKU).

    Science.gov (United States)

    Hamman, Kelly J; Winn, Shelley R; Harding, Cary O

    2011-11-01

    Successful restoration of phenylalanine (Phe) clearance following liver-directed gene therapy in murine phenylketonuria (PKU) is likely dependent upon both the number of cells successfully transduced and the amount of phenylalanine hydroxylase (PAH) activity expressed per cell. At low levels of transduction, Phe clearance could be limited by the low absolute number of PAH-expressing cells rather than the total amount of PAH activity produced in the liver. We have evaluated the interrelationship between the number of PAH positive cells, the amount of PAH activity produced and Phe clearance through experiments with hepatocyte-mediated therapeutic liver repopulation in the Pah(enu2) mouse, a model of PKU. We compared the therapeutic efficacy of transplantation with either wild-type hepatocytes or hepatocytes from heterozygous Pah(enu2/+) donors into PAH deficient, hyperphenylalaninemic Pah(enu2)/Pah(enu2) mice. The recipient mice were also homozygous for fumarylacetoacetate hydrolase (FAH) deficiency. In this model system, FAH positive donor hepatocytes enjoy a selective growth advantage in the FAH-deficient recipient. If Phe clearance is governed predominantly by the total PAH activity, then more heterozygous cells, which express lower PAH activity than wild-type cells, should be required to correct Phe clearance. If the absolute donor cell number is more important, then wild-type hepatocytes should have no advantage over heterozygous cells. We successfully carried out therapeutic liver repopulation with heterozygous donor cells in fifteen mice and an additional thirteen transplants with wild-type cells. Blood Phe was successfully reduced in both transplant groups, and the relationship between the final blood Phe level and the extent of liver repopulation with donor cells did not differ between the two donor groups. Regardless of the type of donor cell, liver repopulation of approximately 3-10% was sufficient to at least partially reduce blood phenylalanine, and

  18. Characterization of a disease-causing Glu119-Lys mutation in the low-density lipoprotein receptor gene in two Danish families with heterozygous familial hypercholesterolemia

    DEFF Research Database (Denmark)

    Jensen, H K; Jensen, T G; Jensen, L G;

    1994-01-01

    employing genomic DNA amplification and bidirectional solid-phase sequencing. Two subjects were found to be heterozygous for a guanine to adenine base substitution at nucleotide position 418 of the LDL receptor cDNA. This point mutation results in an amino acid change from glutamic acid to lysine at amino...... acid residue 119 in the third repeat of the cysteine-rich ligand binding domain of the mature LDL receptor. Disruption of LDL receptor function by the Glu119-Lys mutation was confirmed by site-directed mutagenesis and expression in COS-7 cells. By Western blotting the mutation was found to affect the...

  19. SPS Challenges

    CERN Document Server

    Chapochnikova, Elena

    2008-01-01

    In future the SPS should be able to transfer to the LHC the beam produced by a completely new pre-injector chain and required by the LHC for different upgrade scenarios. The issues related to this extremely challenging task are presented together with some possible ways of overcoming the problems that arise. Besides an increase in injection energy provided by PS2, these measures can include both an SPS vacuum chamber upgrade against the e-cloud and operation with larger longitudinal emittance for beam stability. As a result the power plant of the SPS RF system must be doubled. The SPS upgrade will also need the improvement or replacement of many other machine elements.

  20. Identification of a novel frameshift heterozygous deletion in exon 8 of the PAX6 gene in a pedigree with aniridia.

    Science.gov (United States)

    Giray Bozkaya, Ozlem; Ataman, Esra; Aksel Kilicarslan, Ozge; Cankaya, Tufan; Ulgenalp, Ayfer

    2016-09-01

    Aniridia is a congenital, panocular abnormality which is characterized by partial or complete absence of iris and various degrees of iris hypoplasia. Mutations in the PAX6 gene are found in ~90% of cases with aniridia. The human PAX6 gene is located at chromosome 11p13 and encodes a transcriptional regulator that has crucial roles in the development of the eyes, central nervous system and pancreatic islets. The present study performed a clinical and genomic analysis of two families containing multiple cases of aniridia. All exons of the PAX6 gene of the probands were sequenced using the Sanger sequencing technique. A heterozygous non‑stop mutation in exon 14 was identified in the first family, which has been previously reported for a different ophthalmological pathology. This mutation causes on‑going translation of the mRNA into the 3'‑untranslated region. In the second family, a novel frameshift heterozygous deletion in exon 8 was identified. PMID:27431685

  1. 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.

  2. Scrapheap Challenge

    CERN Multimedia

    2004-01-01

    Three British guys at CERN recently took a break from work to try their hand at Scrapheap Challenge. Shown on Channel 4 in the UK, it is a show where two teams must construct a machine for a specific task using only the junk they can scavenge from the scrap yard around them. And they have just 10 hours to build their contraption before it is put to the test. The first round, aired 19 September, pitted a team of three women, from the British Army's Royal Electrical and Mechanical Engineers, against the CERN guys - the Up 'n Atoms: Ali Day, David McFarlane and James Ridewood. Each team, with the help of an appointed expert, had the task of making a giant, 3-metre self-propelled "bowling ball", to roll down a 50 metre bowling alley at skittles 4 metres high. The Up 'n Atoms' contraption featured a small car with a huge wheel on its back. Once up to speed, slamming on the brakes caused the wheel to roll over and take the car with it. On their very last run they managed to take out seven pins. Luckily, though, ...

  3. Energetic challenges

    International Nuclear Information System (INIS)

    Full text: Connecting the 2 billion people who have no access to commercial energy is the most important energy challenge facing the world community. Women and children, primarily in developing countries, spend their days collecting wood or cow dung for fuel for cooking and heating their homes in very inefficient stoves: this both harms the environment and directly threatens the health of their families. Outmoded boilers linked to central heating systems in most of the cities of Eastern Europe and the former Soviet Union pose another challenge. They are inefficient; they lack modern pollution control; and the end use of the heat is not metered, leading to more inefficiency and waste. Both of these problems cry out to the world for investment. Investing in energy solutions in these countries can bring about significant and immediate local environmental improvements, achieve greatly improved energy efficiency, and substantially reduce greenhouse gas emissions. But, energy and environmental policy tends to direct investment towards industrial countries, even though it would have a greater impact on the environment - not to mention the human condition in general - in the developing countries and transition economies. We need a new direction in energy policy. The World Energy Council has studied the needs and we believe a number of our proposed policy recommendations would lead towards greater investment in the countries where it is most needed. The political risk of key energy project investments must be addressed both by the countries seeking outside investment and by the global community at large. The countries must create an investor-friendly climate, which includes the rule of law and recognizes private property rights. The global community can contribute by developing new political risk insurance schemes rewarding the countries that create this climate. Energy must be priced to cover costs and ensure payment. In too many countries, blanket subsidies for energy

  4. Regulatory challenges

    International Nuclear Information System (INIS)

    The problem for policy makers wanting to liberalize natural gas markets is that its concentrated structure may also be the socially most efficient one. Because of scale economies, more firms operating in the market may incur higher transportation costs unless the market grows sufficiently in each geographic segment. This argument goes for product extension through vertical (or horizontal) integration and the exploitation of economies of scope as well. Thus, the challenge for governments is to intervene in a way that preserves a market structure that has the potential to minimize cost, and at the same lime change its behavior in order to avoid possible lax cost control and exploitation of market power. The existence of scope advantages indicates that liberalization of the market should open for the possibility to bundle services in competition with provision of unbundled services. If operations are unbundled and there exist economies of scope, the gain from increased competition should be weighed against the losses of less efficient operations of each firm. Thus, with the growth in the European market, gradually more arguments support the idea of unbundling. The significant scale economy in trunk pipelines, sunk investments and capital immobility, possible economies of scope in vertical integration and companies' bundling of services influences vertical and horizontal ownership relations and contractual terms in the European gas market. In specific segments of the markets, these relationships may promote efficient investments and pricing without public interference, but the strong concentration of market power indicates that this is rather the exception than the rule. In order to design an efficient and welfare maximizing way of regulating the market one needs a closer identification of the actual goal of the regulation. Microeconomic theory is often used for this purpose. The author discusses the alternatives of laissez-faire, nationalization or regulation for the

  5. Energy challenges

    International Nuclear Information System (INIS)

    Satisfying the world's insatiable appetite for fuel without destroying the environment is the biggest challenge facing the energy industry. World energy consumption is expected to soar by 50% to a staggering 180 000 GW h per year by 2020, with the developing world demanding an ever-increasing share. Although oil and natural-gas reserves will last for several more decades, environmental concerns are increasingly dominating the agenda. Last year 178 countries agreed to a watered-down version of the original Kyoto protocol, which was designed to reduce the emissions of greenhouse gases from industrialized countries by an average of 5.2% below 1990 levels. Under the new agreement, dubbed 'Kyoto lite' by environmentalists, emissions will be cut by just 2%. The relaxed targets are still not enough to convince the US, the world's biggest polluter, to sign the Kyoto treaty. Renewable technologies still make up less than 1% of the world's commercial energy. Distributed power is also likely to emerge from the development of fuel cells - devices that convert the chemical energy of hydrogen and oxygen directly into electricity, with only water as a by-product. The move away from carbon-based fossil fuels to hydrogen is also driving the hydrogen economy. A longer-term possibility is nuclear fusion. Despite the enormous progress in the performance of experiments over the past 30 years, nuclear fusion is still decades away from generating electricity. Advocates of fusion power claim that it could be a safe and sustainable source of energy that does not produce any greenhouse gases or long-lived nuclear waste. However, physicists have still to demonstrate that the energy produced by the fusion of deuterium and tritium can be sustained. Advances in physics and engineering are making energy from renewable sources increasingly affordable. But political will - as well as scientific progress - is just as crucial for safeguarding the environment for generations to come

  6. 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)

    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

  7. Heterozygous PALB2 c.1592delT mutation channels DNA double-strand break repair into error-prone pathways in breast cancer patients.

    Science.gov (United States)

    Obermeier, K; Sachsenweger, J; Friedl, T W P; Pospiech, H; Winqvist, R; Wiesmüller, L

    2016-07-21

    Hereditary heterozygous mutations in a variety of DNA double-strand break (DSB) repair genes have been associated with increased breast cancer risk. In the Finnish population, PALB2 (partner and localizer of BRCA2) represents a major susceptibility gene for female breast cancer, and so far, only one mutation has been described, c.1592delT, which leads to a sixfold increased disease risk. PALB2 is thought to participate in homologous recombination (HR). However, the effect of the Finnish founder mutation on DSB repair has not been investigated. In the current study, we used a panel of lymphoblastoid cell lines (LCLs) derived from seven heterozygous female PALB2 c.1592delT mutation carriers with variable health status and six wild-type matched controls. The results of our DSB repair analysis showed that the PALB2 mutation causes specific changes in pathway usage, namely increases in error-prone single-strand annealing (SSA) and microhomology-mediated end-joining (MMEJ) compared with wild-type LCLs. These data indicated haploinsufficiency regarding the suppression of error-prone DSB repair in PALB2 mutation carriers. To the contrary, neither reduced HR activities, nor impaired RAD51 filament assembly, nor sensitization to PARP inhibition were consistently observed. Expression of truncated mutant versus wild-type PALB2 verified a causal role of PALB2 c.1592delT in the shift to error-prone repair. Discrimination between healthy and malignancy-presenting PALB2 mutation carriers revealed a pathway shift particularly in the breast cancer patients, suggesting interaction of PALB2 c.1592delT with additional genomic lesions. Interestingly, the studied PALB2 mutation was associated with 53BP1 accumulation in the healthy mutation carriers but not the patients, and 53BP1 was limiting for error-prone MMEJ in patients but not in healthy carriers. Our study identified a rise in error-prone DSB repair as a potential threat to genomic integrity in heterozygous PALB2 mutation carriers

  8. Postnatal microcephaly and pain insensitivity due to a de novo heterozygous DNM1L mutation causing impaired mitochondrial fission and function.

    Science.gov (United States)

    Sheffer, Ruth; Douiev, Liza; Edvardson, Simon; Shaag, Avraham; Tamimi, Khaled; Soiferman, Devorah; Meiner, Vardiella; Saada, Ann

    2016-06-01

    An emerging class of mitochondrial disorders is caused by mutations in nuclear genes affecting mitochondrial dynamics and function. One of these is the DNM1L gene encoding the dynamin-related protein 1 (DRP1), which is pivotal in the mitochondrial fission process. Here, we describe a patient with a novel dominant-negative, de novo DNM1L mutation, which expands the clinical spectrum. The patient reported here exhibits a chronic neurological disorder, characterized by postnatal microcephaly, developmental delay, and pain insensitivity. Muscle biopsy disclosed decreased respiratory chain complex IV activity. Exome sequencing showed a de novo heterozygous c.1084G>A (p.G362S) mutation. Subsequent studies of patient skin fibroblasts showed markedly impaired mitochondrial fission and a partial respiratory chain defect while peroxisomal morphology remained intact. Human foreskin fibroblasts over-expressing the mutant DNM1L gene displayed aberrant mitochondrial morphology. © 2016 Wiley Periodicals, Inc. PMID:26992161

  9. Ataxia-telangiectasia homo- and heterozygous cells show a normal repair and fixation response to anisotonic NaCl treatment after irradiation

    International Nuclear Information System (INIS)

    The effect of anisotonic NaCl treatment on fixation and repair of radiation-induced potentially lethal damage (PLD) was tested in normal human cells and in three homozygous ataxia-telangiectasia (A-T) and two heterozygous A-T cells strains. This effect was observed in both plateau-phase and exponentially growing normal and A-T cells. When an incubation period at 370C was introduced between irradiation and the subsequent anisotonic treatment, recovery was observed in both normal and A-T cells strains. These data show that A-T cells are as proficient as normal cells in repairing PLD that is sensitive to anisotonic NaCl treament. It is proposed that two PLD repair systems may exist, one that is expressed after irradiation in proliferatively arrested cells and another that occurs in plateau-phase as well as exponentially growing cells

  10. Low dose, radiation-induced adaptive response against cancer in high-dose-exposed, cancer-prone, Trp53 heterozygous mice

    International Nuclear Information System (INIS)

    Full text: Mice that are heterozygous for Trp53 are both cancer-prone and sensitive to high radiation doses. Groups of 7-8-week-old female Trp53 heterozygous mice were exposed to 4 Gy of 60Co-gamma radiation at either high (0.5 Gy/min) or low (0.5 mGy/min) dose rate. Other groups received a 10-mGy or 100-mGy dose, given at low dose rate (0.5 mGy/min) 24 h prior to the 4 Gy dose. Tumor frequency and latency were measured over the lifespan of the animals. Compared to animals receiving only 4 Gy at high dose rate, mice receiving a prior 10-mGy adapting exposure had significantly extended lifespan and increased latency for all malignant tumors taken together. However, the latency responses were tumor type specific. The prior 10-mGy exposure increased latency for lymphomas and hemangiosarcomas, but decreased latency for spinal osteosarcomas. Increasing the adapting dose to 100 mGy eliminated the tumor latency increase and significantly reduced lifespan. A 10-mGy adapting dose given prior to a 4 Gy exposure at low dose rate generally showed either a reduced effect or no effect. Adapting exposures had no significant effect on tumor frequency. We conclude that adaptive responses are induced by low doses of radiation in radiation sensitive, cancer prone Trp53 +/ - mice, and that these responses are expressed as an increase in tumor latency that reduces the carcinogenic effects of a subsequent large exposure. The dose at which protective effects give way to detrimental effects is tumor type specific

  11. 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.

  12. 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.

  13. Novel heterozygous C243Y A20/TNFAIP3 gene mutation is responsible for chronic inflammation in autosomal-dominant Behçet's disease

    Science.gov (United States)

    Shigemura, Tomonari; Kaneko, Naoe; Kobayashi, Norimoto; Kobayashi, Keiko; Takeuchi, Yusuke; Nakano, Naoko; Masumoto, Junya; Agematsu, Kazunaga

    2016-01-01

    Objective Although Behçet's disease (BD) is a chronic inflammatory disorder of uncertain aetiology, the existence of familial BD with autosomal-dominant traits suggests that a responsibility gene (or genes) exists. We investigated a Japanese family with a history of BD to search for pathogenic mutations underlying the biological mechanisms of BD. Methods 6 patients over 4 generations who had suffered from frequent oral ulcers, genital ulcers and erythaema nodosum-like lesions in the skin were assessed. Whole-exome sequencing was performed on genomic DNA, and cytokine production was determined from stimulated mononuclear cells. Inflammatory cytokine secretion and Nod2-mediated NF-κB activation were analysed using the transfected cells. Results By whole-exome sequencing, we identified a common heterozygous missense mutation in A20/TNFAIP3, a gene known to regulate NF-κB signalling, for which all affected family members carried a heterozygous C243Y mutation in the ovarian tumour domain. Mononuclear cells obtained from the proband and his mother produced large amounts of interleukin 1β, IL-6 and tumour necrosis factor α (TNF-a) on stimulation as compared with those from normal controls. Although inflammatory cytokine secretion was suppressed by wild-type transfected cells, it was suppressed to a much lesser extent by mutated C243Y A20/TNFAIP3-transfected cells. In addition, impaired suppression of Nod2-mediated NF-κB activation by C243Y A20/TNFAIP3 was observed. Conclusions A C243Y mutation in A20/TNFAIP3 was likely responsible for increased production of human inflammatory cytokines by reduced suppression of NF-κB activation, and may have accounted for the autosomal-dominant Mendelian mode of BD transmission in this family. PMID:27175295

  14. 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.

  15. 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

  16. 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,...

  17. National Drug IQ Challenge

    Science.gov (United States)

    ... Drug & Alcohol IQ Challenge 2016 National Drug & Alcohol IQ Challenge Get Started! Correct/Total Questions: Score: Other ... accessible version of the 2016 National Drug & Alcohol IQ Challenge , [PDF, 637KB]. Download an accessible version of ...

  18. Genotype-specific effects of Mecp2 loss-of-function on morphology of Layer V pyramidal neurons in heterozygous female Rett Syndrome model mice

    Directory of Open Access Journals (Sweden)

    David P Stuss

    2015-04-01

    Full Text Available Rett Syndrome (RTT is a progressive neurological disorder primarily caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2. The heterozygous female brain consists of mosaic of neurons containing both wildtype MeCP2 (MeCP2+ and mutant MeCP2 (MeCP2-. 3-dimensional morphological analysis was performed on individually genotyped layer V pyramidal neurons in the primary motor cortex of heterozygous (Mecp2+/- and wild-type (Mecp2+/+ female mice (>6 mo. from the Mecp2tm1.1Jae line. Comparing basal dendrite morphology, soma and nuclear size of MeCP2+ to MeCP2- neurons reveals a significant cell autonomous, genotype specific effect of Mecp2. MeCP2- neurons have 15% less total basal dendritic length, predominantly in the region 70-130 μm from the cell body and on average 3 fewer branch points, specifically loss in the 2nd and 3rd branch orders. Soma and nuclear areas of neurons of mice were analyzed across a range of ages (5-21 mo. and X-chromosome inactivation (XCI ratios (12-56%. On average, MeCP2- somata and nuclei were 15% and 13% smaller than MeCP2+ neurons respectively. In most respects branching morphology of neurons in wild-type brains (MeCP2 WT was not distinguishable from MeCP2+ but somata and nuclei of MeCP2 WT neurons were larger than those of MeCP2+ neurons. These data reveal cell autonomous effects of Mecp2 mutation on dendritic morphology, but also suggest non-cell autonomous effects with respect to cell size. MeCP2+ and MeCP2- neuron sizes were not correlated with age, but were correlated with XCI ratio. Unexpectedly the MeCP2- neurons were smallest in brains where the XCI ratio was highly skewed towards MeCP2+, i.e. wild-type. This raises the possibility of cell non-autonomous effects that act through mechanisms other than globally secreted factors; perhaps competition for synaptic connections influences cell size and morphology in the genotypically mosaic brain of RTT model mice.

  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)

    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. Developing a Watershed Challenge

    Science.gov (United States)

    Roman, Harry T.

    2010-01-01

    This article presents a watershed challenge that gives students an opportunity to investigate the challenge of using a watershed area as a site for development, examining the many aspects of this multifaceted problem. This design challenge could work well in a team-based format, with students taking on specific aspects of the challenges and…

  1. Exome sequencing reveals a heterozygous DLX5 mutation in a Chinese family with autosomal-dominant split-hand/foot malformation.

    Science.gov (United States)

    Wang, Xue; Xin, Qian; Li, Lin; Li, Jiangxia; Zhang, Changwu; Qiu, Rongfang; Qian, Chenmin; Zhao, Hailing; Liu, Yongchao; Shan, Shan; Dang, Jie; Bian, Xianli; Shao, Changshun; Gong, Yaoqin; Liu, Qiji

    2014-09-01

    Split-hand/foot malformation (SHFM) is a congenital limb deformity due to the absence or dysplasia of central rays of the autopod. Six SHFM loci have already been identified. Here we describe a Chinese family with autosomal-dominant SHFM1 that has previously been mapped to 7q21.2-21.3. The two affected family members, mother and son, showed deep median clefts between toes, ectrodactyly and syndactyly; the mother also showed triphalangeal thumbs. Exome sequencing and variant screening of candidate genes in the six loci known to be responsible for SHFM revealed a novel heterozygous mutation, c.558G>T (p.(Gln186His)), in distal-less homeobox 5 (DLX5). As DLX5 encodes a transcription factor capable of transactivating MYC, we also tested whether the mutation could affect DLX5 transcription acitivity. Results from luciferase reporter assay revealed that a mutation in DLX5 compromised its transcriptional activity. This is the first report of a mutation in DLX5 leading to autosomal-dominant SHFM1. PMID:24496061

  2. Effects of long term exposure to the mycotoxin fumonisin B1 in p53 heterozygous and p53 homozygous transgenic mice.

    Science.gov (United States)

    Bondy, Genevieve; Mehta, Rekha; Caldwell, Don; Coady, Laurie; Armstrong, Cheryl; Savard, Marc; Miller, J David; Chomyshyn, Emily; Bronson, Roni; Zitomer, Nicholas; Riley, Ronald T

    2012-10-01

    The fungal toxin fumonisin B1 (FB1) is a potential human carcinogen based on evidence of renal carcinogenicity in rats and hepatocarcinogenicity in mice. The toxicity and carcinogenicity of FB1 is linked to ceramide synthase inhibition. Based on this mechanism of action and on lack of evidence of genotoxicity, FB1 is considered a non-genotoxic carcinogen. The p53 heterozygous (p53+/-) mouse is a cancer-prone model used for carcinogenesis. The effects of chronic dietary FB1 exposure were characterized in p53+/- mice to confirm non-genotoxicity using a model which is more sensitive to genotoxic than non-genotoxic carcinogens and to clarify the relationship between p53 expression, altered sphingolipid metabolism, and FB1-induced carcinogenesis. Responses to FB1 were similar in p53+/- and p53+/+ mice after 26 weeks exposure to 0, 5, 50 or 150 mg FB1/kg diet, supporting a non-genotoxic mechanism of action. Hepatic adenomas and cholangiomas were observed in mice exposed to 150 mg/kg FB1. For a 10% increase in hepatic megalocytosis, the estimated 95% lower confidence limit of the benchmark dose (BMDL10) ranged from 0.15 and 1.11 mg FB1/kg bw/day. Based on similar responses in p53+/- and p53+/+ mice, p53 and related pathways play a secondary role in responses to FB1 toxicity and carcinogenesis. PMID:22841953

  3. Genotypes and phenotypes of a family with a deaf child carrying combined heterozygous mutations in SLC26A4 and GJB3 genes.

    Science.gov (United States)

    Li, Yunlong; Zhu, Baosheng

    2016-07-01

    Mutations in the SLC26A4 gene have been shown to cause a type of deafness referred to as large vestibular aqueduct syndrome (LVAS), whereas mutations in the GJB3 gene have been associated with nonsyndromic deafness. However, the clinical phenotypes of these mutations vary and remain to be fully elucidated. The present study performed genetic analysis of a Chinese family, in which the child was deaf and the parents were healthy. Sanger sequencing demonstrated that the affected individual harbored three heterogeneous mutations in the SLC26A4 and GJB3 genes, as follows: SLC26A4 IVS-2 A>G, SLC26A4 c.2168 A>G and GJB3 c.538 C>T. The affected individual exhibited hearing loss and was diagnosed with LVAS by computed tomography scan. The mother and father of the affected individual harbored the heterogeneous mutations of SLC26A4 IVS-2 A>G and GJB3 c.538 C>T, and the heterozygous mutation of SLC26A4 c.2168 A>G, respectively. Neither parents exhibited any hearing loss. The results obtained from the deaf patient provided genetic and clinical evidence that carrying combined heterogeneous mutations in the GJB3 and SLC26A4 genes may be involved in the etiology of severe hearing loss, of which the mechanism requires further examination. PMID:27176802

  4. Mitotic recombination and compound-heterozygous mutations are predominant NF1-inactivating mechanisms in children with juvenile myelomonocytic leukemia and neurofibromatosis type 1.

    Science.gov (United States)

    Steinemann, Doris; Arning, Larissa; Praulich, Inka; Stuhrmann, Manfred; Hasle, Henrik; Stary, Jan; Schlegelberger, Brigitte; Niemeyer, Charlotte M; Flotho, Christian

    2010-02-01

    Children with neurofibromatosis type 1 (NF-1), being constitutionally deficient for one allele of the NF1 gene, are at greatly increased risk of juvenile myelomonocytic leukemia (JMML). NF1 is a negative regulator of RAS pathway activity, which has a central role in JMML. To further clarify the role of biallelic NF1 gene inactivation in the pathogenesis of JMML, we investigated the somatic NF1 lesion in 10 samples from children with JMML/NF-1. We report that two-thirds of somatic events involved loss of heterozygosity (LOH) at the NF1 locus, predominantly caused by segmental uniparental disomy of large parts of chromosome arm 17q. One-third of leukemias showed compound-heterozygous NF1-inactivating mutations. A minority of cases exhibited somatic interstitial deletions. The findings reinforce the emerging role of somatic mitotic recombination as a leukemogenic mechanism. In addition, they support the concept that biallelic NF1 inactivation in hematopoietic progenitor cells is required for transformation to JMML in children with NF-1. PMID:20015894

  5. Heterozygous deletion of a 2-Mb region including the dystroglycan gene in a patient with mild myopathy, facial hypotonia, oral-motor dyspraxia and white matter abnormalities.

    Science.gov (United States)

    Frost, Amy R; Böhm, Sabrina V; Sewduth, Raj N; Josifova, Dragana; Ogilvie, Caroline Mackie; Izatt, Louise; Roberts, Roland G

    2010-07-01

    Dystroglycan is a protein which binds directly to two proteins defective in muscular dystrophies (dystrophin and laminin alpha2) and whose own aberrant post-translational modification is the common aetiological route of neuromuscular diseases associated with mutations in genes encoding at least six other proteins (POMT1, POMT2, POMGnT1, LARGE, FKTN and FKRP). It is surprising, therefore, that to our knowledge no mutations of the human dystroglycan gene itself have yet been reported. In this study, we describe a patient with a heterozygous de novo deletion of a approximately 2-Mb region of chromosome 3, which includes the dystroglycan gene (DAG1). The patient is a 16-year-old female with learning difficulties, white matter abnormalities, elevated serum creatine kinase, oral-motor dyspraxia and facial hypotonia but minimal clinically significant involvement of other muscles. As these symptoms are a subset of those observed in disorders of dystroglycan glycosylation (muscle-eye-brain disease and Warker-Warburg syndrome), we assess the likely contribution to her phenotype of her heterogosity for a null mutation of DAG1. We also show that the transcriptional compensation observed in the Dag1(+/-) mouse is not observed in the patient. Although we cannot show that haploinsufficiency of DAG1 is the sole cause of this patient's myopathy and white matter changes, this case serves to constrain our ideas of the severity of the phenotypic consequences of heterozygosity for null DAG1 mutations. PMID:20234391

  6. Heterozygous deletion of CHL1 gene: detailed array-CGH and clinical characterization of a new case and review of the literature.

    Science.gov (United States)

    Tassano, Elisa; Biancheri, Roberta; Denegri, Laura; Porta, Simona; Novara, Francesca; Zuffardi, Orsetta; Gimelli, Giorgio; Cuoco, Cristina

    2014-01-01

    CHL1 gene maps at 3p26.3 and encodes a cell adhesion molecule of the immunoglobulin superfamily highly expressed in the brain. CHL1 regulates neuronal migration and neurite overgrowth in the developing brain, while in mature neurons it accumulates in the axonal membrane and regulates synapse function via the clathrin-dependent pathways. To our knowledge, to date only three familial cases presenting heterozygous deletion of chromosome 3 at band p26.3, including only the CHL1 gene, have been reported. All the patients presented cognitive impairment characterized by learning and language difficulties. Here, we describe a six-year-old boy in which array-CGH analysis disclosed a terminal 3p26.3 deletion. The deletion was transmitted from his normal mother and included only the CHL1 gene. Our patient presented microcephaly, short stature, mild mental retardation, learning and language delay, and strabismus. In our study we compare the phenotypic and molecular cytogenetic features of CHL1 gene deletion cases. Verbal function developmental delay seems to be a common key finding. The concomitance of the genetic and phenotypic alterations could be a good evidence of a new emerging syndrome associated with the deletion of CHL1 gene alone, although the identification of new cases is required. PMID:25451713

  7. Materials challenges and testing for supply of energy and resources

    Energy Technology Data Exchange (ETDEWEB)

    Boellinghaus, Thomas; Lexow, Juergen (eds.) [Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin (Germany); Kishi, Teruo [National Inst. for Materials Science, Tsukuba, Ibaraki (Japan); Kitagawa, Masaki [Isobe Mihamaku, Chiba (Japan)

    2012-07-01

    One major goal of the World Materials Research Institute Forum - WMRIF is to promote young scientists in the field of materials science and engineering. To enhance the international knowledge exchange between young postdoctoral scientists all over the world, WMRIF meanwhile regularly organizes joint workshops among the member institutes. These workshops also represent an increasingly appreciated platform to get known to each other and to build co-operations. For such workshops, various topics are selected, pointing to future perspectives and challenges in the field of materials science and engineering. This book contains the following contributions: I. Materials challenges for nuclear fission and fusion - Examination of Dust Particles from Present-Day Controlled Fusion Devices (Elzbieta Fortuna-Zalesna); Quantitative microstructural investigation of neutron-irradiated RAFM steel for nuclear fusion applications (Oliver J. Weiss), Controlling Welding Residual Stresses by means of Alloy Design (Arne Kromm); Degradation Mechanism of Creep Strength Enhanced Ferritic Steels for Power Plants (Kota Sawada); Electrochemical studies on pitting corrosion on Cr13 steel exposed to CO{sub 2} and artificial brine with high chloride concentration (Oleksandra Yevtushenko); Development of {sup 10}B{sub 2}O{sub 3} processing for use as a neutron conversion materials (Lars F. Voss). II. Materials challenges for water supply Water overlayers on Cu(110) studied by van der Waals density Functional (Sheng Meng). III. Challenges in conclusive, realistic and system oriented materials testing - Employment of high Resolution RBS to characterize ultrathin transparent electrode in high efficiency GaN based Light Emitting Diode (Grace Huiqi Wang); A possible route to the quantification of piezoresponse force microscopy through correlation with electron backscatter diffraction (Tim L. Burnett); High Resolution Analysis of Tungsten Doped Amorphous Carbon thin Films (Marcin Rasinski); Electron

  8. Materials challenges and testing for supply of energy and resources

    International Nuclear Information System (INIS)

    One major goal of the World Materials Research Institute Forum - WMRIF is to promote young scientists in the field of materials science and engineering. To enhance the international knowledge exchange between young postdoctoral scientists all over the world, WMRIF meanwhile regularly organizes joint workshops among the member institutes. These workshops also represent an increasingly appreciated platform to get known to each other and to build co-operations. For such workshops, various topics are selected, pointing to future perspectives and challenges in the field of materials science and engineering. This book contains the following contributions: I. Materials challenges for nuclear fission and fusion - Examination of Dust Particles from Present-Day Controlled Fusion Devices (Elzbieta Fortuna-Zalesna); Quantitative microstructural investigation of neutron-irradiated RAFM steel for nuclear fusion applications (Oliver J. Weiss), Controlling Welding Residual Stresses by means of Alloy Design (Arne Kromm); Degradation Mechanism of Creep Strength Enhanced Ferritic Steels for Power Plants (Kota Sawada); Electrochemical studies on pitting corrosion on Cr13 steel exposed to CO2 and artificial brine with high chloride concentration (Oleksandra Yevtushenko); Development of 10B2O3 processing for use as a neutron conversion materials (Lars F. Voss). II. Materials challenges for water supply Water overlayers on Cu(110) studied by van der Waals density Functional (Sheng Meng). III. Challenges in conclusive, realistic and system oriented materials testing - Employment of high Resolution RBS to characterize ultrathin transparent electrode in high efficiency GaN based Light Emitting Diode (Grace Huiqi Wang); A possible route to the quantification of piezoresponse force microscopy through correlation with electron backscatter diffraction (Tim L. Burnett); High Resolution Analysis of Tungsten Doped Amorphous Carbon thin Films (Marcin Rasinski); Electron Microscopy Studies on Oxide

  9. A novel heterozygous mutation in the ATP6V0A4 gene encoding the V-ATPase a4 subunit in an adult patient with incomplete distal renal tubular acidosis.

    Science.gov (United States)

    Imai, Eri; Kaneko, Shuzo; Mori, Takayasu; Okado, Tomokazu; Uchida, Shinichi; Tsukamoto, Yusuke

    2016-06-01

    A 40-year-old Japanese man who had a medical history of hypokalemic periodic paralysis 4 months prior was hospitalized to undergo a cholecystectomy. Hypokalemia, nephrocalcinosis and alkaluria suggesting distal renal tubular acidosis (dRTA) were detected, but metabolic acidosis was not evident. An ammonium chloride/furosemide-fludrocortisone/bicarbonate loading test demonstrated a remarkable disability in urinary H(+) excretion. A novel heterozygous mutation in the ATP6V0A4 gene encoding the vacuolar H(+)-ATPase (V-ATPase) a4 subunit p.S544L was detected. Among cases of V-ATPase a4 mutations, this is the first case in which a heterozygous mutation developed to an incomplete or latent form of dRTA. PMID:27274828

  10. 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.

  11. 78 FR 49296 - Centennial Challenges 2014 Sample Return Robot Challenge

    Science.gov (United States)

    2013-08-13

    ... SPACE ADMINISTRATION Centennial Challenges 2014 Sample Return Robot Challenge AGENCY: National Aeronautics and Space Administration (NASA). ACTION: Notice of Centennial Challenges 2014 Sample Return Robot... Robot Challenge is scheduled and teams that wish to compete may register. Centennial Challenges is...

  12. Low doses of radiation increase the latency of spontaneous lymphomas and spinal osteosarcomas in cancer-prone, radiation-sensitive Trp53 heterozygous mice

    International Nuclear Information System (INIS)

    Mice heterozygous for Trp53 are radiation-sensitive and cancer-prone, spontaneously developing a variety of cancer types. Osteosarcomas in the spine lead to paralysis, while lymphomas lead rapidly to death, distinct events that provide objective measures of latency. The effects of a single low-dose (10 or 100 mGy), low-dose-rate (0.5 mGy/min) 60Co γ irradiation on lymphoma or spinal osteosarcoma frequency and latency, defined as time of death or of onset of paralysis, respectively, were examined. Compared to spontaneous lymphomas or to spinal osteosarcomas leading to paralysis in unexposed mice, an exposure of 7-8-week-old Trp53+/- mice to 10 or 100 mGy had no significant effect on tumor frequency, indicating no effect on tumor initiation. All tumors are therefore assumed to be of spontaneous origin. However, a 10-mGy exposure reduced the risk of both lymphomas and spinal osteosarcomas by significantly increasing tumor latency, indicating that the main in vivo effect of a low-dose exposure is a reduction in the rate at which spontaneously initiated cells progress to malignancy. The effect of this adaptive response persisted for the entire life span of all the animals that developed these tumors. Exposure to 100 mGy delayed lymphoma latency longer than the 10-mGy exposure. However, the 100-mGy dose increased spinal osteosarcoma risk by decreasing overall latency compared to unexposed control mice. That result suggested that this higher dose was in a transition zone between reduced and increased risk, but that the dose at which the transition occurs varies with the tumor type. (author)

  13. In vivo evaluation of cellular activity in αCaMKII heterozygous knockout mice using manganese-enhanced magnetic resonance imaging (MEMRI

    Directory of Open Access Journals (Sweden)

    Satoko eHattori

    2013-11-01

    Full Text Available The alpha-calcium/calmodulin-dependent protein kinase II (αCaMKII is a serine/threonine protein kinase predominantly expressed in the forebrain, especially in the postsynaptic density, and plays a key role in synaptic plasticity, learning and memory. αCaMKII heterozygous knockout (HKO mice exhibit abnormal emotional and aggressive behaviors and cognitive impairments and have been proposed as an animal model of psychiatric illness. Our previous studies have shown that the expression of immediate early genes (IEGs after exposure to electric foot shock or after performing a working memory task is decreased in the hippocampus, central amygdala, and medial prefrontal cortex of mutant mice. These changes could be caused by disturbances in neuronal signal transduction; however, it is still unclear whether neuronal activity is reduced in these regions. In this study, we performed in vivo manganese-enhanced magnetic resonance imaging (MEMRI to assess the regional cellular activity in the brains of αCaMKII HKO mice. The signal intensity of MEMRI 24 h after systemic MnCl2 administration reflects functional increases of Mn2+ influx into neurons and glia via transport mechanisms, such as voltage-gated and/or ligand-gated Ca2+ channels. αCaMKII HKO mice demonstrated a low signal intensity of MEMRI in the dentate gyrus (DG, in which almost all neurons were at immature status at the molecular, morphological, and electrophysiological levels. In contrast, analysis of the signal intensity in these mutant mice revealed increased activity in the CA1 area of the hippocampus, a region crucial for cognitive function. The signal intensity was also increased in the bed nucleus of the stria terminalis (BNST, which is involved in anxiety. These changes in the mutant mice may be responsible for the observed dysregulated behaviors, such as cognitive deficit and abnormal anxiety-like behavior, which are similar to symptoms seen in human psychiatric disorders.

  14. Increased extracellular dopamine concentrations and FosB/DeltaFosB expression in striatal brain areas of heterozygous GDNF knockout mice.

    Science.gov (United States)

    Airavaara, Mikko; Planken, Anu; Gäddnäs, Helena; Piepponen, Timo Petteri; Saarma, Mart; Ahtee, Liisa

    2004-11-01

    Glial cell line-derived neurotrophic factor (GDNF) has been shown to be involved in the maintenance of striatal dopaminergic neurons. To study whether reduced levels of endogenous GDNF affect the striatal dopaminergic transmission we estimated the basal extracellular levels of dopamine in vivo, the basal expression of FosB-related proteins in striatal brain areas as well as the effects of acute and repeated cocaine on locomotor activity and dopamine output in mice lacking one GDNF allele (heterozygous GDNF+/- mice). As expected the striatal GDNF protein content was found to be smaller in the GDNF+/- mice than in their wild-type littermates. Unexpectedly the extracellular dopamine concentration in the GDNF+/- mice in the dorsal striatum (CPu) was 2.0-fold, and in the nucleus accumbens (NAc) 1.6-fold the concentration found in the wild-type littermates. Also FosB/DeltaFosB-like immunoreactivity was found to be elevated in the CPu as well as in the core and in the shell of NAc of the GDNF+/- mice as compared with the wild-type mice. This suggests chronic postsynaptic activation of these brain areas and is in line with elevated extracellular dopamine concentrations. Cocaine's effects acutely and after repeated treatment on locomotor activity were similar in the GDNF+/- and the wild-type mice. Neither did cocaine's acute effects on dopamine output differ between the mice of the two strains. Our findings demonstrate that reduced levels of endogenous GDNF induce alterations in dorsal striatal and accumbal dopaminergic transmission, and stress the importance of endogenous GDNF in the regulation of the dopaminergic neurons. PMID:15525275

  15. 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.

  16. Decreased dopamine receptor 1 activity and impaired motor-skill transfer in Dyt1 ΔGAG heterozygous knock-in mice

    Science.gov (United States)

    Yokoi, Fumiaki; Dang, Mai T.; Liu, Jun; Gandre, Jason R.; Kwon, Kelly; Yuen, Robert; Li, Yuqing

    2014-01-01

    DYT1 dystonia is a movement disorder caused by a trinucleotide deletion (ΔGAG) in DYT1 (TOR1A), corresponding to a glutamic acid loss in the C-terminal region of torsinA. Functional alterations in the basal ganglia circuits have been reported in both DYT1 dystonia patients and rodent models. Dyt1 ΔGAG heterozygous knock-in (KI) mice exhibit motor deficits and decreased striatal dopamine receptor 2 (D2R) binding activity, suggesting a malfunction of the indirect pathway. However, the role of the direct pathway in pathogenesis of dystonia is not yet clear. Here, we report that Dyt1 KI mice exhibit significantly decreased striatal dopamine receptor 1 (D1R) binding activity and D1R protein levels, suggesting the alteration of the direct pathway. The decreased D1R may be caused by translational or post-translational processes since Dyt1 KI mice had normal levels of striatal D1R mRNA and a normal number of striatal neurons expressing D1R. Levels of striatal ionotropic glutamate receptor subunits, dopamine transporter, acetylcholine muscarinic M4 receptor and adenosine A2A receptor were not altered suggesting a specificity of affected polytopic membrane-associated proteins. Contribution of the direct pathway to motor-skill learning has been suggested in another pharmacological rat model injected with a D1R antagonist. In the present study, we developed a novel motor skill transfer test for mice and found deficits in Dyt1 KI mice. Further characterization of both the direct and the indirect pathways in Dyt1 KI mice will aid the development of novel therapeutic drugs. PMID:25451552

  17. Challenges of Parenting Multiples

    Science.gov (United States)

    ... the American Society for Reproductive Medicine Challenges of Parenting Multiples There are many psychological, social, and economic ... the unique challenges and rewards that come from parenting multiples. For more information on the medical aspects ...

  18. Overcoming Breastfeeding Challenges

    Medline Plus

    Full Text Available ... on Women's Health Skip Navigation Skip top navigation Home A-Z Health Topics ePublications News About Us ... Only Natural email updates. Enter email address Submit Home > It's Only Natural > Overcoming challenges Overcoming breastfeeding challenges ...

  19. Overcoming Breastfeeding Challenges

    Medline Plus

    Full Text Available ... size | Print | Skip left navigation It's Only Natural Planning ahead Overcoming challenges Overcoming breastfeeding challenges Dealing with lack of family support Is my baby getting enough milk? Breastfeeding ...

  20. Overcoming Breastfeeding Challenges

    Medline Plus

    Full Text Available A project of the U.S. Department of Health and Human Services Office on Women's Health Skip Navigation ... challenges Overcoming breastfeeding challenges Dealing with lack of family support Is my baby getting enough ...

  1. The Backpack Design Challenge

    Science.gov (United States)

    Roman, Harry T.

    2010-01-01

    Something as simple as carrying books to school can be an interesting design challenge for students. It's an old problem that gets reinvented from time to time. In this article, the author discusses a backpack design challenge in which teachers work with students to design another way to carry books to school. The challenge started by trying to…

  2. Energy transition - economic challenge, climate challenge, industrial challenge

    International Nuclear Information System (INIS)

    This document highlights and discusses the different economic, climate and industrial challenges, identifies and discusses the different objectives and main results for a successful energy transition respectively in its relationships with the energy mix (the result is to divide emissions by a factor 4), with governance (the result should be a balanced distribution of energy governance), with energy consumption

  3. Specific combination of compound heterozygous mutations in 17β-hydroxysteroid dehydrogenase type 4 (HSD17B4 defines a new subtype of D-bifunctional protein deficiency

    Directory of Open Access Journals (Sweden)

    McMillan Hugh J

    2012-11-01

    Full Text Available Abstract Background D-bifunctional protein (DBP deficiency is typically apparent within the first month of life with most infants demonstrating hypotonia, psychomotor delay and seizures. Few children survive beyond two years of age. Among patients with prolonged survival all demonstrate severe gross motor delay, absent language development, and severe hearing and visual impairment. DBP contains three catalytically active domains; an N-terminal dehydrogenase, a central hydratase and a C-terminal sterol carrier protein-2-like domain. Three subtypes of the disease are identified based upon the domain affected; DBP type I results from a combined deficiency of dehydrogenase and hydratase activity; DBP type II from isolated hydratase deficiency and DBP type III from isolated dehydrogenase deficiency. Here we report two brothers (16½ and 14 years old with DBP deficiency characterized by normal early childhood followed by sensorineural hearing loss, progressive cerebellar and sensory ataxia and subclinical retinitis pigmentosa. Methods and results Biochemical analysis revealed normal levels of plasma VLCFA, phytanic acid and pristanic acid, and normal bile acids in urine; based on these results no diagnosis was made. Exome analysis was performed using the Agilent SureSelect 50Mb All Exon Kit and the Illumina HiSeq 2000 next-generation-sequencing (NGS platform. Compound heterozygous mutations were identified by exome sequencing and confirmed by Sanger sequencing within the dehydrogenase domain (c.101C>T; p.Ala34Val and hydratase domain (c.1547T>C; p.Ile516Thr of the 17β-hydroxysteroid dehydrogenase type 4 gene (HSD17B4. These mutations have been previously reported in patients with severe-forms of DBP deficiency, however each mutation was reported in combination with another mutation affecting the same domain. Subsequent studies in fibroblasts revealed normal VLCFA levels, normal C26:0 but reduced pristanic acid beta-oxidation activity. Both DBP

  4. The GREAT3 Challenge

    OpenAIRE

    Miyatake, Hironao; Mandelbaum, Rachel; collaboration, Barnaby Rowe on behalf of the GREAT3

    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-base...

  5. Challenges of Relativistic Astrophysics

    CERN Document Server

    Opher, Reuven

    2013-01-01

    I discuss some of the most outstanding challenges in relativistic astrophysics in the subjects of: compact objects (Black Holes and Neutron Stars); dark sector (Dark Matter and Dark Energy); plasma astrophysics (Origin of Jets, Cosmic Rays and Magnetic Fields) and the primordial universe (Physics at the beginning of the Universe). In these four subjects, I discuss twelve of the most important challenges. These challenges give us insight into new physics that can only be studied in the large scale Universe. The near future possibilities, in observations and theory, for addressing these challenges, are also discussed.

  6. Science Challenge Day

    Science.gov (United States)

    Siegel, Deborah

    2013-01-01

    Science fairs can be good motivators, but as extracurricular activities, they leave some students behind. However, by staging a Science Challenge Day at school, educators can involve all students in doing everything from choosing activities to judging projects. This article presents a model for running a successful Science Challenge Day. The…

  7. Overcoming Breastfeeding Challenges

    Medline Plus

    Full Text Available ... size | Print | Skip left navigation It's Only Natural Planning ahead Overcoming challenges Overcoming breastfeeding challenges Dealing with ... it into your life My breastfeeding story Partner resources Subscribe ... at the U.S. Department of Health and Human Services 200 Independence Avenue, S.W. • Washington, DC 20201 ...

  8. 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…

  9. The challenges of dismantling

    International Nuclear Information System (INIS)

    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)

  10. 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.

  11. 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.

  12. Challenging behaviour: a challenge to change.

    Science.gov (United States)

    van Berckelaer-Onnes, I A; van Loon, J; Peelen, A

    2002-09-01

    People with intellectual disability often exhibit severe behavioural problems. Treatment of these problems is frequently very difficult. In The Netherlands, parents, institutes, schools and others can request the services of an independent advisory team with a pool of professionals who have experience with individuals who exhibit challenging behaviour. In this article the methods of the team will be described using a 24-year-old man as an example. The process took almost 7 years. Finally, this man, who had been living full time in one room in total isolation from the rest of the world, fulfilled his heart's desire--visiting the UK by Hovercraft. PMID:12212917

  13. 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...

  14. Brazil World Cup Challenges

    OpenAIRE

    MANSUR, R.

    2012-01-01

    Overcoming the productivity challenge is the main benefit of the 2014 World Cup for Brazilian people. The sustainable development of our cultural tourism industry will catapult the new middle class growing up rate.

  15. Better Buildings Challenge Overview

    Energy Technology Data Exchange (ETDEWEB)

    None

    2011-06-01

    The Better Buildings Challenge is a national leadership initiative calling on corporate chief executive officers, university presidents, and state and local leaders to make a significant commitment to building energy efficiency.

  16. Challenging Fieldwork Situations

    DEFF Research Database (Denmark)

    Bille, Thomas; Østergaard Steenfeldt, Vibeke

    2013-01-01

    understanding on the phenomenon of awkwardness as a natural way for researchers to respond to challenging fieldwork situations. Finally, they propose and unfold mutual interviewing and cooperative analysis as methods of investigating researcher’s subjectivity in facing such situations....

  17. The Electric Car Challenge.

    Science.gov (United States)

    Diehl, Brian E.

    1997-01-01

    Describes the Electric Car Challenge during which students applied methods of construction to build lightweight, strong vehicles that were powered by electricity. The activity required problem solving, sheet metal work, electricity, design, and construction skills. (JOW)

  18. A challenging read

    Directory of Open Access Journals (Sweden)

    Cathy Foley

    2004-11-01

    Full Text Available Andrei Mourachkine uses his new book to argue that superconductivity could be achieved at room temperature and, while his thesis may rest on some unconfirmed evidence, it does challenge preconceptions, says Cathy Foley.

  19. Brazil World Cup Challenges

    Directory of Open Access Journals (Sweden)

    MANSUR, R.

    2012-12-01

    Full Text Available Overcoming the productivity challenge is the main benefit of the 2014 World Cup for Brazilian people. The sustainable development of our cultural tourism industry will catapult the new middle class growing up rate.

  20. Challenges in marine instrumentation

    Digital Repository Service at National Institute of Oceanography (India)

    Afzulpurkar, S.; Desa, E.; Joseph, A.; Chakraborty, B.; Nayak, M.R.; Ranade, G.

    challenge for technology. Biosensors which can detect bioluminescence and other biological activities would play a major role. Autonomous instrumentation outfitted with different types of in-situ sensors would collect data without disturbing the system...

  1. Big Data Challenges

    OpenAIRE

    Alexandru Adrian TOLE

    2013-01-01

    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 manipul...

  2. Anthropocene Age Wicked Challenges

    DEFF Research Database (Denmark)

    Edgeman, Rick; Wu, Zhaohui

    2015-01-01

    weather events, drought, and desertification; threatened food supplies; water pollution, air pollution, and soil contamination; and the connection of these to disease, violence, and terrorism. Wicked challenges are discussed in relation to enterprise excellence, sustainability, resilience and robustness......Grand global challenges, including wicked human caused or influenced ones key to sustainability, characterize the Anthropocene Age. Among these are climate change driven by increased methane and CO2 in the atmosphere; consequent global warming and increasing intensity and incidence of extreme...

  3. Challenges in obesity research

    OpenAIRE

    Andreu Palou; Luisa Bonet, M.

    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 Safeguards Challenges

    International Nuclear Information System (INIS)

    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

  5. Optimal challenges in tennis

    OpenAIRE

    Clarke, S. R.; Norman, J.M.

    2012-01-01

    The use of technology in sport to assist umpires has been gradually introduced into several sports. This has now been extended to allow players to call upon technology to arbitrate when they disagree with the umpire's decision. Both tennis and cricket now allow the players to challenge a doubtful decision, which is reversed if the evidence shows it to be incorrect. However, the number of challenges is limited, and players must balance any possible immediate gain with the loss of a future righ...

  6. 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. PMID:24010755

  7. Challenges in obesity research

    Directory of Open Access Journals (Sweden)

    Andreu Palou

    2013-09-01

    Full Text Available 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.

  8. The challenge of sustainability

    International Nuclear Information System (INIS)

    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

  9. Meeting the Challenge

    Directory of Open Access Journals (Sweden)

    T. Reg Bott

    2009-01-01

    Full Text Available The first Chempor Conference held in Lisbon in 1975 under the auspices of the Calouste Gulbenkian Foundation, heralded a regular wide-ranging review of research and development in Portugal and the UK Progressively in later years the Conferences have attracted contributions from other European countries and indeed further afield. There is an increasing awareness of the problems for the environment, notably global warming, brought about by human activities. Recent predictions about the future are dire, particularly regarding food and water for a rapidly growing world population. They represent a substantial challenge to the scientific and technical fraternity. In response to that challenge it is important to keep up to date with technical developments, to meet and keep in touch with coworkers in associated fields, and to cooperate wherever possible. The papers presented at the Chempor and other conferences have made and continue to make a significant contribution to that objective of meeting the challenge.

  10. British Muslims: A Challenge

    OpenAIRE

    Abdel-Hady, Zakaryya Mohamed [زكريا محمد عبد الهادي

    2007-01-01

    The Muslim community in Britain today face multiple challenges covering a wide range of spectrum from the basic right to exists, fighting the increasing trends of Islamophobia, having equal opportunities, to participate in public life, fully integrate within the society and be a positive member of the community. The recent events of September 11th in the US, July 7th in UK and the more recent row over the ban of the headscarf in UK and other European countries have placed tremendous challenge...

  11. Banff Challenge 2

    CERN Document Server

    Junk, Thomas R

    2011-01-01

    Experimental particle physics collaborations constantly seek newer and better ideas for improving the sensitivity of their searches for new particles and phenomena. Statistical techniques are the last step in interpreting the results of an experiment; they are used to make discoveries (hypothesis testing), and to measure parameters (point estimation). They are also used in the first step - experiment and analysis design. Banff Challenge 2 asks participants to test their methods of disco vering hidden signals in simulated datasets and of measuring the properties of these signals. The Challenge problems are described, and the performances of the submitted entries is summarized, for datasets with and without simulated signals present.

  12. 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.

  13. The challenge of conceiving

    DEFF Research Database (Denmark)

    Hansen, Claus Thorp; Jørgensen, Ulrik

    2011-01-01

    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...... problem from 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...

  14. Long-term effects of high-fat or high-carbohydrate diets on glucose tolerance in mice with heterozygous carnitine palmitoyltransferase-1a deficiency

    OpenAIRE

    Nyman, L R; Tian, L.; Hamm, D A; Schoeb, T R; Gower, B. A.; Nagy, T.R.; P A Wood

    2011-01-01

    Background: Abnormal fatty acid metabolism is an important feature in the mechanisms of insulin resistance and β-cell dysfunction. Carnitine palmitoyltransferase-1a (CPT-1a, liver isoform) has a pivotal role in the regulation of mitochondrial fatty acid oxidation. We investigated the role of CPT-1a in the development of impaired glucose tolerance using a mouse model for CPT-1a deficiency when challenged by either a high-carbohydrate (HCD) or a high-fat diet (HFD) for a total duration of up to...

  15. 76 FR 56819 - Centennial Challenges 2012 Sample Return Robot Challenge

    Science.gov (United States)

    2011-09-14

    ... SPACE ADMINISTRATION Centennial Challenges 2012 Sample Return Robot Challenge AGENCY: National... 42 U.S.C. 2451(314)(d). The 2012 Sample Return Robot Challenge is scheduled and teams that wish to... technologies of interest and value to NASA and the nation. The 2012 Sample Return Robot Challenge is a...

  16. 77 FR 70835 - Centennial Challenges 2013 Sample Return Robot Challenge

    Science.gov (United States)

    2012-11-27

    ... SPACE ADMINISTRATION Centennial Challenges 2013 Sample Return Robot Challenge AGENCY: National... in accordance with 51 U.S.C. 20144(c). The 2013 Sample Return Robot Challenge is scheduled and teams... Robot Challenge is a prize competition designed to encourage development of new technologies...

  17. 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...

  18. The challenge of implementation

    DEFF Research Database (Denmark)

    Andersen, Karen Heide Hauge

    2015-01-01

    concepts in daily teaching, as it is strongly encouraged by policy makers and educations. This paper aims to discuss how lecturers experience the challenge of teaching their own discipline while being imposed to embrace and promote innovation and entrepreneurship teaching. Through a single study case of...

  19. Tackling the Unemployment Challenge

    Institute of Scientific and Technical Information of China (English)

    2004-01-01

    As the world's largest economy in transition, Chinafaces a severe unemployment challenge. With aworking population of 751 million, China'sunemployment rate stands at more than l O% in urbanareas," including rural surplus laborers, it is astaggering 20%. Since assuming office in March

  20. The blind hens’ challenge

    DEFF Research Database (Denmark)

    Sandøe, Peter; Hocking, Paul M.; Forkman, Björn;

    2014-01-01

    repellent, yet 'welfare-only' positions appear to be committed to endorsing this possibility if it produces welfare gains. We call this the 'Blind Hens' Challenge'. In this paper, we argue that there are both empirical and theoretical reasons why even those adopting 'welfare-only' views should be concerned...

  1. MALL: The Pedagogical Challenges

    Science.gov (United States)

    Burston, Jack

    2014-01-01

    In this paper the development of mobile-assisted language learning (MALL) over the past 20 years is reviewed with a particular focus on the pedagogical challenges facing its exploitation. Following a consideration of the definition of mobile learning, the paper describes the dominant mobile technologies upon which MALL applications have been…

  2. Overcoming Breastfeeding Challenges

    Medline Plus

    Full Text Available ... and Human Services Office on Women's Health Skip Navigation Skip top navigation Home A-Z Health Topics ePublications News About Us Contact Us Text size | Print | Skip left navigation It's Only Natural Planning ahead Overcoming challenges Overcoming ...

  3. Electric Vehicle Battery Challenge

    Science.gov (United States)

    Roman, Harry T.

    2014-01-01

    A serious drawback to electric vehicles [batteries only] is the idle time needed to recharge their batteries. In this challenge, students can develop ideas and concepts for battery change-out at automotive service stations. Such a capability would extend the range of electric vehicles.

  4. A Challenge to Watson

    Science.gov (United States)

    Detterman, Douglas K.

    2011-01-01

    Watson's Jeopardy victory raises the question of the similarity of artificial intelligence and human intelligence. Those of us who study human intelligence issue a challenge to the artificial intelligence community. We will construct a unique battery of tests for any computer that would provide an actual IQ score for the computer. This is the same…

  5. The Moon Challenge

    Science.gov (United States)

    Fitzsimmons, Pat; Leddy, Diana; Johnson, Lindy; Biggam, Sue; Locke, Suzan

    2013-01-01

    This article describes a first-grade research project that incorporates trade books and challenges misconceptions. Educators see the power of their students' wonder at work in their classrooms on a daily basis. This wonder must be nourished by students' own experiences--observing the moon on a crystal clear night--as well as by having…

  6. Ecommerce: Ongoing Challenges

    Directory of Open Access Journals (Sweden)

    Derek Mohammed

    2010-08-01

    Full Text Available This paper examines some of the challenges of online marketing, including the importance of adding online marketing to corporation budgets. A review of the pros and cons of social networking on the Internet, when used as a marketing tool by companies is presented. In addition, new forms of Internet shoppers and new niches for companies are identified

  7. Challenging the Boundaries

    DEFF Research Database (Denmark)

    Nørgaard, Nina

    2004-01-01

    To many people, challenging the boundaries between the traditional disciplines in foreign language studies means doing cultural studies. The aim of this article is to pull in a different direction by suggesting how the interface between linguistics and literature may be another fertile field to e...

  8. Challenging and valuable

    OpenAIRE

    Van Hal, J.D.M.

    2008-01-01

    Challenging and valuable Inaugural speech given on May 7th 2008 at the occasion of the acceptance of the position of Professor Sustainable Housing Transformation at the faculty of Architeeture of the Delft University of Technology by Prof. J.D.M. van Hal MSc PhD.

  9. 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.

  10. Ecommerce: Ongoing Challenges

    OpenAIRE

    Derek Mohammed

    2010-01-01

    This paper examines some of the challenges of online marketing, including the importance of adding online marketing to corporation budgets. A review of the pros and cons of social networking on the Internet, when used as a marketing tool by companies is presented. In addition, new forms of Internet shoppers and new niches for companies are identified

  11. The diesel challenge

    International Nuclear Information System (INIS)

    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)

  12. Fortification Challenges and Needs

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Experience in many parts of the developing world has shown thatfood fortification offers a cost-effective and sustainable solution to the problem of micronutrient malnutrition. Building on the advances in science and technology and backed by studies on the economic benefits of fortification programs, governments and industry are beginning to respond positively to the call of nutrition advocates to adopt fortification as a long-term strategy. On the other hand, formidable challenges still remain in many countries in Asia, constraining the widespread adoption of this strategy. The science and technology community needs to provide adequate scientific and technological information as basis for planning and decision making. The government faces the challenge of providing the enabling environment for all stakeholders to cooperate in the fortification effort. Industry faces the challenge of adapting its production system to the requirements of fortification in order that they can contribute to social objectives while pursuing their economic objectives. The international and bilateral aid agencies need to seek tried and innovative ways to support the multiple players of food fortification, as these players in turn face the challenges that confront them.

  13. Fortification Challenges and Needs

    Institute of Scientific and Technical Information of China (English)

    RODOLFOF.FLORENTINO

    2001-01-01

    Experience in many parts of the developing world has shown that food fortification offers a costeffective and sustainable solution to the problem of micronutrient malnutrition.Building on the advances in science and technology and backed by studies on the economic benefits of fortification programs,govenments and industry are beginning to respond positively to the call of nutrition advocates to adopt fortification as a long-term strategy.On the other hand,formidable challenges still remain in many countries in Asia,constraining the widespread adoption of this strategy,The science and technology community needs to provide adequate scientific and technological information as basis for planning and decision making,The governent faces the challenge of providing the enabling environment for all stakeholders to cooperate in the fortification effort.Industry faces the challenge of adapting its production system to the requirements of fortification in oreder that they can contribute to social bojectives while pursuing their economic objectives,The international and bilateral aid agencies need to seek tried and innovative ways to support the multiple players of food fortification,as these players in turn face the challenges that confront them.

  14. The Clay Challenge Continues...

    Science.gov (United States)

    Coy, Mary

    2007-01-01

    It was time for yet another challenge. Bright colored glazes were on hiatus; earth tones and mixed media took center stage. Inspiration was provided this time by the myriad Native American potters from the desert Southwest. The project: create a coil pot that demonstrates interesting form and good artistry and reflects, through symbolism or mixed…

  15. 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. PMID:24139651

  16. Pulmonary Embolism in a Sarcoidosis Patient Double Heterozygous for Methylenetetrahydrofolate Reductase Gene Polymorphisms and Factor V Leiden and Homozygous for the D-Allele of Angiotensin Converting Enzyme Gene

    Directory of Open Access Journals (Sweden)

    Nadim El-Majzoub

    2015-01-01

    Full Text Available Sarcoidosis is a multisystem granulomatous disease of unknown etiology and pathogenesis. It presents in patients younger than 40 years of age. The lungs are the most commonly affected organ. Till the present day, there is no single specific test that will accurately diagnose sarcoidosis; as a result, the diagnosis of sarcoidosis relies on a combination of clinical, radiologic, and histologic findings. Patients with sarcoidosis have been found to have an increased risk of pulmonary embolism compared to the normal population. MTHFR and factor V Leiden mutations have been reported to increase the risk of thrombosis in patients. We hereby present a case of a middle aged man with sarcoidosis who developed a right main pulmonary embolism and was found to be double heterozygous for methylenetetrahydrofolate reductase gene polymorphisms and factor V Leiden and homozygous for the D-allele of the angiotensin converting enzyme gene.

  17. Challenges in Request Management

    DEFF Research Database (Denmark)

    Sommer, Anita Friis

    2014-01-01

    profitability. This research study seeks to investigate the challenges of RQM in practice. Existing demand chain management literature is used as a basis for developing a RQM framework. RQM is investigated through an explorative research design in a dyadic B2B case study including a global industrial company......Request management (RQM) is a new term used for managing customer requests for new products. It is the counterpart to typical product development processes, which has no direct customer involvement. It is essential to manage customer requests in a structured and efficient way to obtain...... and its customers. The study provides an insight into a new area of supply chain management, including the process activity flow and challenges involved across the process. Furthermore, the method is dyadic including the customer in the case study, which is rare in related research....

  18. Supernova Photometric Classification Challenge

    CERN Document Server

    Kessler, Richard; Jha, Saurabh; Kuhlmann, Stephen

    2010-01-01

    We have publicly released a blinded mix of simulated SNe, with types (Ia, Ib, Ic, II) selected in proportion to their expected rate. The simulation is realized in the griz filters of the Dark Energy Survey (DES) with realistic observing conditions (sky noise, point spread function and atmospheric transparency) based on years of recorded conditions at the DES site. Simulations of non-Ia type SNe are based on spectroscopically confirmed light curves that include unpublished non-Ia samples donated from the Carnegie Supernova Project (CSP), the Supernova Legacy Survey (SNLS), and the Sloan Digital Sky Survey-II (SDSS-II). We challenge scientists to run their classification algorithms and report a type for each SN. A spectroscopically confirmed subset is provided for training. The goals of this challenge are to (1) learn the relative strengths and weaknesses of the different classification algorithms, (2) use the results to improve classification algorithms, and (3) understand what spectroscopically confirmed sub-...

  19. 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...

  20. Challenges in radioecology

    International Nuclear Information System (INIS)

    Today, radioecology covers a broad scientific field; from the source to long term environmental impact from ionizing radiation. To summarize key challenges within radioecology, the present paper focuses upon knowledge gaps related to processes, mechanisms and variables contributing most to the overall uncertainties in environmental impact assessments. A series of sources related to the nuclear weapon cycle and the civil nuclear cycle has contributed, is still contributing or can potentially contribute to release of radionuclides to the environment in the future. The speciation of most radionuclides depends on the source and release conditions, and will influence ecosystem transport, biological uptake, doses and effects in flora and fauna. Radionuclides may also co-occur in contaminant mixtures (e.g., metals, organics), which potentially could lead to synergisms or antagonisms. Thus, challenges associated with the links between the source or release term - radionuclide speciation - ecosystem transfer - exposure - response relationships are highlighted.

  1. Challenges in sexual medicine

    DEFF Research Database (Denmark)

    Cellek, Selim; Giraldi, Annamaria

    2012-01-01

    The sexual medicine field has been in mode of revolution until recently. Like all other fields of biomedical research, the economic situation around the world has had a negative impact on the field's momentum-research funding bodies, regulatory bodies and pharmaceutical companies seem to have...... placed sexual medicine in their low-priority list. But this is not the only challenge the field is facing. The successful development of phosphodiesterase type 5 (PDE5) inhibitors for treatment of erectile dysfunction (ED) means that research in this area seems to have slowed. However, there remain...... several unmet medical needs within sexual medicine such as premature ejaculation, severe ED and hypoactive sexual desire disorder, which await novel therapeutic approaches. Despite these challenges, research into finding and developing such therapies is likely to continue in the sexual medicine field...

  2. Challenges to Resistance Welding

    DEFF Research Database (Denmark)

    Song, Quanfeng

    This report originates from the compulsory defense during my Ph.D. study at the Technical University of Denmark. Resistance welding is an old and well-proven technology. Yet the emergence of more and more new materials, new designs, invention off new joining techniques, and more stringent...... requirement in quality have imposed challenges to the resistance welding. More some research and development have to be done to adapt the old technology to the manufacturing industry of the 21st century. In the 1st part of the report, the challenging factors to the resistance welding are reviewed. Numerical...... simulation of resistance welding has been under development for many years. Yet it is no easy to make simulation results reliable and accurate because of the complexity of resistance welding process. In the 2nd part of the report numerical modeling of resistance welding is reviewed, some critical factors to...

  3. Terabit Wireless Communication Challenges

    Science.gov (United States)

    Hwu, Shian U.

    2012-01-01

    This presentation briefly discusses a research effort on Terabit Wireless communication systems for possible space applications. Recently, terahertz (THz) technology (300-3000 GHz frequency) has attracted a great deal of interest from academia and industry. This is due to a number of interesting features of THz waves, including the nearly unlimited bandwidths available, and the non-ionizing radiation nature which does not damage human tissues and DNA with minimum health threat. Also, as millimeter-wave communication systems mature, the focus of research is, naturally, moving to the THz range. Many scientists regard THz as the last great frontier of the electromagnetic spectrum, but finding new applications outside the traditional niches of radio astronomy, Earth and planetary remote sensing, and molecular spectroscopy particularly in biomedical imaging and wireless communications has been relatively slow. Radiologists find this area of study so attractive because t-rays are non-ionizing, which suggests no harm is done to tissue or DNA. They also offer the possibility of performing spectroscopic measurements over a very wide frequency range, and can even capture signatures from liquids and solids. According to Shannon theory, the broad bandwidth of the THz frequency bands can be used for terabit-per-second (Tb/s) wireless communication systems. This enables several new applications, such as cell phones with 360 degrees autostereoscopic displays, optic-fiber replacement, and wireless Tb/s file transferring. Although THz technology could satisfy the demand for an extremely high data rate, a number of technical challenges need to be overcome before its development. This presentation provides an overview the state-of-the- art in THz wireless communication and the technical challenges for an emerging application in Terabit wireless systems. The main issue for THz wave propagation is the high atmospheric attenuation, which is dominated by water vapor absorption in the THz

  4. Energy challenges in Asia

    International Nuclear Information System (INIS)

    Energy challenges represent one of the most important security paradigms in the Asia Pacific region where you have a mixture of growing energy dependency, fuelled by high economic growth, the emergence of new major players like China and India, and a quasi-complete absence of regional regulatory mechanisms to tackle the challenges in a multilateral way. These challenges mostly concern Japan and China, where crucial energy issues are aggravated by power rivalry, historical and ideological issues, and a lack of both economic and political harmony between them. Neither countries are self sufficient in terms of energy needs. This can lead to a shared analysis and common approaches regarding Japan and China concerning this issue. Their cases are. however very different and the solutions applied are related to different world views that are not easily reconcilable. Both countries share common objectives: both want security and stable supply. But there are also big divergences and these divergences could be new sources of conflict and misunderstanding between Tokyo and Beijing. One of the main differences is history related. Both China and Japan are uneasy regarding outside energy dependency. In Japan, memories of the pre-war oil embargo have not disappeared. The oil shocks of the 70's renewed this uneasiness. However, Japan's outside dependency is not new. Tokyo has learned to live with it, finding a system to alleviate this vulnerability in cooperation with its partners, multilateral institutions like the International Energy Agency (IEA). China's outside dependency is new. The country's dependency on oil, which began in 1993, is particularly challenging since the principles of independence, non interference and military autonomy, principles at the core of Maoist foreign strategy, did not completely disappear in spite of China's new policy of reform and opening up. China's leadership, even the fourth generation, did not forget its isolation during the 60's and 70's

  5. Librarianship: A Challenging Profession

    OpenAIRE

    Lalithabai, K K.

    1996-01-01

    Defines librarianship as the art and science of managing recorded knowledge. Observes that in earlier days when the recorded sources of information were limited in number, scholars could be the users as well as managers of libraries. But today’s libraries with torrents of information sources and users on either side makes management a truly challenging task requiring highly specialized knowledge and training in the sophisticated techniques of information handling. Views that in information co...

  6. Challenges in Danish VET

    DEFF Research Database (Denmark)

    Aarkrog, Vibe

    2011-01-01

    In Denmark the 95 percent target, meaning that in 2015 95 percent of a youth cohort should complete a youth education programme, is particularly challenging for the vocational educational and training (VET) system. In the article is given a short outline of the significant characteristics of the...... Danish dual VET system as well as of the current central initiatives aimed at reaching the 95 percent target....

  7. PHARMACOVIGILANCE: BARRIERS AND CHALLENGES

    OpenAIRE

    Varma, S. K.; RAPELLIWAR A; S. Sutradhar; THAWARE P; Misra, A. K.

    2013-01-01

    Pharmacovigilance is a new discipline which deals with adverse drug or any drug related problems. Pharmacovigilance programme was not bed of roses but its path is laid with challenges and barriers. It is facing obstacles from deficiency from professional health personal to web-based sale of drugs, counterfeit drug to self-medication, etc. It is an integral part of the health sector and identification and reporting of adverse drug effects will have a positive impact on the public health. Impro...

  8. CHALLENGES FOR FOREIGN TEACHERS

    Institute of Scientific and Technical Information of China (English)

    DengJing

    2004-01-01

    The learner differences and contrasts between the two cultures involved are important aspects that influence foreign language teaching and learning. The foreign teacher as an outsider of the learner's native culture, inevitably faces quite a few challenges. With the focus on the self-esteem, character types, and motivation of the learner, the paper analyses how these factors influence the foreign teacher's teaching. Relevant solutions are also proposed.

  9. Challenges in Crowd Simulation

    OpenAIRE

    Thalmann, Daniel; Grillon, Helena; Maim, Jonathan; Yersin, Barbara

    2009-01-01

    The purpose of this paper is to identify the problems to solve in order to simulate real-time crowds in a Virtual Environment. We try to classify these problems and study how they have been addressed until now by the research community and our Lab in particular. We then discuss for each problem what are the,future challenges and how to address them.

  10. The First Provenance Challenge

    OpenAIRE

    Moreau, Luc; Ludaescher, Bertram; Altintas, Ilkay; Barga, Roger S.; Bowers, Shawn; Callahan, Steven; Chin Jr., George; Clifford, Ben; Cohen, Shirley; Cohen-Boulakia, Sarah; Davidson, Susan; Deelman, Ewa; Digiampietri, Luciano; Foster, Ian; Freire, Juliana

    2008-01-01

    The first Provenance Challenge was set up in order to provide a forum for the community to help understand the capabilities of different provenance systems and the expressiveness of their provenance representations. To this end, a Functional Magnetic Resonance Imaging workflow was defined, which participants had to either simulate or run in order to produce some provenance representation, from which a set of identified queries had to be implemented and executed. Sixteen teams responded to the...

  11. South China Sea Challenge

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    China's attempts to solve disputes with ASEAN over the South China Sea help regional peace China's marine economy and security are currently faced with new challenges, requiring careful handling, especially in disputes with ASEAN countries and in promoting common development of the South China Sea. The outcome of how this is dealt with could undoubtedly pave the way for solutions to other oceanic disputes. The South China Sea is located south of

  12. Public budgets: New challenges

    OpenAIRE

    Attila, György

    2010-01-01

    Budgeting is passing through changes all over the world in order to find more efficient ways to guide public money usage. The last half of century gave us multiple examples of how to improve budgetary performance, but there are a lot to do in next decades to accomplish this goal. The challenges regarding public budgeting are: using accrual based budgeting, use performance information to determine the allocations for each agency, and strengthening the budgetary transparency.

  13. Sustainability challenges and trends

    OpenAIRE

    De Ridder, M.

    2011-01-01

    In the coming decades, increases in population, income and health will put additional pressures on our planet’s biosphere. To meet the needs of future generations, we need to adapt our ways of living and definitions of economic development. A transition to a more sustainable world is imperative if we want to stop depleting the Earth’s resources more quickly than it can regenerate them. This paper synthesizes current trends and challenges that are relevant for the policy debate on sustainabili...

  14. ATLAS Data Challenge 1

    CERN Document Server

    DC1 TaskForce

    2003-01-01

    The ATLAS Collaboration at CERN is preparing for the data taking and analysis at LHC that will start in 2007. Therefore, in 2002 a series of Data Challenges (DC's) was started whose goals are the validation of the Computing Model, of the complete software suite, of the data model, and to ensure the correctness of the technical choices to be made. A major feature of the first Data Challenge (DC1) was the preparation and the deployment of the software required for the production of large event samples for the High Level Trigger and Physics communities, and the production of those large data samples as a worldwide distributed activity. It should be noted that it was not an option to "run everything at CERN" even if we had wanted to; the resources were not available at CERN to carry out the production on a reasonable time-scale. We were therefore faced with the great challenge of organising and then carrying out this large-scale production at a significant number of sites around the world. However, the benefits o...

  15. IDEOLOGICALLY CHALLENGING ENTERTAINMENT (ICE

    Directory of Open Access Journals (Sweden)

    Dana Lori Chalmers

    2015-09-01

    Full Text Available Ideologically Challenging Entertainment (ICE is entertainment that challenges ‘us vs. them’ ideologies associated with radicalization, violent conflict and terrorism. ICE presents multiple perspectives on a conflict through mainstream entertainment. This article introduces the theoretical underpinnings of ICE, the first ICE production and the audience responses to it. The first ICE production was Two Merchants: The Merchant of Venice adapted to challenge ideologies of the Arab-Israeli Conflict. A mixed-methods study of audience responses explored whether this production inspired audiences to shift their ideological views. Each performance included two versions of the adaptation: a Jewish dominated society with an Arab Muslim minority, contrasted with an Arab Muslim dominated society and a Jewish minority. A mixed-methods study of audience responses explored whether this production inspired audiences to shift their ideological views to become more tolerant of differences away from ideological radicalization. Of audience members who did not initially agree with the premise of the production, 40% reconsidered their ideological views, indicating increased tolerance, greater awareness of and desire to change their own prejudices. In addition, 86% of the audience expressed their intention to discuss the production with others, thereby encouraging critical engagement with, and broader dissemination of the message. These outcomes suggest that high quality entertainment – as defined by audience responses to it - can become a powerful tool in the struggle against radicalised ideologies.

  16. The challenges of introducing routine G6PD testing into radical cure: a workshop report.

    Science.gov (United States)

    Ley, Benedikt; Luter, Nick; Espino, Fe Esperanza; Devine, Angela; Kalnoky, Michael; Lubell, Yoel; Thriemer, Kamala; Baird, J Kevin; Poirot, Eugenie; Conan, Nolwenn; Kheong, Chong Chee; Dysoley, Lek; Khan, Wasif Ali; Dion-Berboso, April G; Bancone, Germana; Hwang, Jimee; Kumar, Ritu; Price, Ric N; von Seidlein, Lorenz; Domingo, Gonzalo J

    2015-01-01

    The only currently available drug that effectively removes malaria hypnozoites from the human host is primaquine. The use of 8-aminoquinolines is hampered by haemolytic side effects in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. Recently a number of qualitative and a quantitative rapid diagnostic test (RDT) format have been developed that provide an alternative to the current standard G6PD activity assays. The WHO has recently recommended routine testing of G6PD status prior to primaquine radical cure whenever possible. A workshop was held in the Philippines in early 2015 to discuss key challenges and knowledge gaps that hinder the introduction of routine G6PD testing. Two point-of-care (PoC) test formats for the measurement of G6PD activity are currently available: qualitative tests comparable to malaria RDT as well as biosensors that provide a quantitative reading. Qualitative G6PD PoC tests provide a binomial test result, are easy to use and some products are comparable in price to the widely used fluorescent spot test. Qualitative test results can accurately classify hemizygous males, heterozygous females, but may misclassify females with intermediate G6PD activity. Biosensors provide a more complex quantitative readout and are better suited to identify heterozygous females. While associated with higher costs per sample tested biosensors have the potential for broader use in other scenarios where knowledge of G6PD activity is relevant as well. The introduction of routine G6PD testing is associated with additional costs on top of routine treatment that will vary by setting and will need to be assessed prior to test introduction. Reliable G6PD PoC tests have the potential to play an essential role in future malaria elimination programmes, however require an improved understanding on how to best integrate routine G6PD testing into different health settings. PMID:26416229

  17. Perishable Inventory Challenges

    DEFF Research Database (Denmark)

    Damgaard, Cecilie Maria; Nguyen, Vivi Thuy; Hvolby, Hans-Henrik;

    2012-01-01

    The paper investigates how inventory control of perishable items is managed and line up some possible options of improvement. This includes a review of relevant literature dealing with the challenges of determining ordering policies for perishable products and a study of how the current procedures...... in the retail supply chains. The goal is to find and evaluate the parameters which affect the decision making process, when finding the optimal order quantity and order time. The paper takes a starting point in the retail industry but links to other industries....

  18. Caspian sea: petroleum challenges

    International Nuclear Information System (INIS)

    The Caspian sea is one of the world areas the most promising in terms of investments and petroleum development. This study presents the petroleum challenges generated by this hydrocarbons reserve. The first part discusses the juridical status (sea or lake), the petroleum and the gas reserves, the ecosystem and the today environment (fishing and caviar), the geostrategic situation and the transport of gas and oil. It provides also a chronology from 1729 to 2005, a selection of Internet sites, books and reports on the subject and identity sheets of the countries around the Caspian sea. (A.L.B.)

  19. Challenging the Innovation Paradigm

    CERN Document Server

    Sveiby, Karl Erik; Segercrantz, Beata

    2012-01-01

    Innovation is almost always seen as a "good thing". Challenging the Innovation Paradigm is a critical analysis of the innovation frenzy and contemporary innovation research. The one-sided focus on desirable effects of innovation misses many opportunities to reduce the undesirable consequences. Authors in this book show how systemic effects outside the innovating firms reduce the net benefits of innovation for individual employees, customers, as well as for society as a whole - also the innovators' own organizations. This book analyzes the dominant discourses that construct and recons

  20. Energy challenges in Asia

    Energy Technology Data Exchange (ETDEWEB)

    Niquet, V.

    2007-07-01

    Energy challenges represent one of the most important security paradigms in the Asia Pacific region where you have a mixture of growing energy dependency, fuelled by high economic growth, the emergence of new major players like China and India, and a quasi-complete absence of regional regulatory mechanisms to tackle the challenges in a multilateral way. These challenges mostly concern Japan and China, where crucial energy issues are aggravated by power rivalry, historical and ideological issues, and a lack of both economic and political harmony between them. Neither countries are self sufficient in terms of energy needs. This can lead to a shared analysis and common approaches regarding Japan and China concerning this issue. Their cases are. however very different and the solutions applied are related to different world views that are not easily reconcilable. Both countries share common objectives: both want security and stable supply. But there are also big divergences and these divergences could be new sources of conflict and misunderstanding between Tokyo and Beijing. One of the main differences is history related. Both China and Japan are uneasy regarding outside energy dependency. In Japan, memories of the pre-war oil embargo have not disappeared. The oil shocks of the 70's renewed this uneasiness. However, Japan's outside dependency is not new. Tokyo has learned to live with it, finding a system to alleviate this vulnerability in cooperation with its partners, multilateral institutions like the International Energy Agency (IEA). China's outside dependency is new. The country's dependency on oil, which began in 1993, is particularly challenging since the principles of independence, non interference and military autonomy, principles at the core of Maoist foreign strategy, did not completely disappear in spite of China's new policy of reform and opening up. China's leadership, even the fourth generation, did not forget its isolation

  1. Semantic Web Evaluation Challenge

    CERN Document Server

    2014-01-01

    This book constitutes the thoroughly refereed post conference proceedings of the first edition of the Semantic Web Evaluation Challenge, SemWebEval 2014, co-located with the 11th Extended Semantic Web conference, held in Anissaras, Crete, Greece, in May 2014. This book includes the descriptions of all methods and tools that competed at SemWebEval 2014, together with a detailed description of the tasks, evaluation procedures and datasets. The contributions are grouped in three areas: semantic publishing (sempub), concept-level sentiment analysis (ssa), and linked-data enabled recommender systems (recsys).

  2. New challenges? Well, certainly!

    DEFF Research Database (Denmark)

    Lauridsen, Karen M.

    New challenges? Well, certainly! With the internationalization of European higher education, teaching and learning through the medium of a foreign language has become more and more widespread in recent years. This requires, of course, that lecturers as well as students have the necessary language...... proficiency, but research as well as experience on the ground tells us that this is not enough. Everyone must learn to navigate in the multilingual and multicultural learning space because lecturers as well as students may come from different countries and cultures and therefore have different first languages...

  3. The New Asian Challenge

    OpenAIRE

    C. Fred Bergsten

    2000-01-01

    The initial postwar challenge from East Asia was economic. Japan crashed back into global markets in the 1960s, became the largest surplus and creditor country in the 1980s, and was viewed by many as the world’s dominant economy by 1990. The newly industrialized countries (Korea, Taiwan, Hong Kong, Singapore) followed suit on a smaller but still substantial scale shortly thereafter. China only re-entered world commerce in the 1980s but has now become the second largest economy (in purchasing ...

  4. The ALICE Data Challenges

    CERN Document Server

    Baud, J P; Carminati, F; Collignon, M; Collin, F; Divià, R; Durand, J D; Jarp, S; Jouanigot, J M; Panzer, B; Rademakers, F; Saiz, P; Schossmaier, K; Van de Vyvre, P; Vascotto, Alessandro

    2001-01-01

    Since 1998, the ALICE experiment and the CERN/IT division have jointly executed several large-scale high throughput distributed computing exercises: the ALICE data challenges. The goals of these regular exercises are to test hardware and software components of the data acquisition and computing systems in realistic conditions and to execute an early integration of the overall ALICE computing infrastructure. This paper reports on the third ALICE Data Challenge (ADC III) that has been performed at CERN from January to March 2001. The data used during the ADC III are simulated physics raw data of the ALICE TPC, produced with the ALICE simulation program AliRoot. The data acquisition was based on the ALICE online framework called the ALICE Data Acquisition Test Environment (DATE) system. The data after event building were then formatted with the ROOT I/O package and a data catalogue based on MySQL was established. The Mass Storage System used during ADC III is CASTOR. Different software tools have been used to mo...

  5. Challenge Based Innovation gala

    CERN Document Server

    CERN. Geneva; Utriainen, Tuuli Maria; Toivonen, Harri; Nordberg, Markus

    2014-01-01

    Challenge Based Innovation gala   There’s a new experiment starting in CERN called IdeaLab where we work together with detector R&D researchers to help them to bridge their knowledge into a more human, societally oriented context. Currently we are located in B153, but will move our activities to a new facility next to the Globe in May 2014. One of our first pilot projects is a 5 month course CBI (Challenge Based Innovation) where two multidisciplinary student teams join forces with Edusafe & TALENT projects at CERN. Their goal is to discover what kind of tools for learning could be created in collaboration with the two groups. After months of user interviews and low resolution prototyping they are ready to share the results with us in the form of an afternoon gala. We warmly welcome you to join us to see the students' results and experience the prototypes they have conceived. The event is in three parts, you are welcome to visit all of them,...

  6. Proteomics Technologies and Challenges

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Proteomics is the study of proteins and their interactions in a cell. With the completion of the Human Genome Project, the emphasis is shifting to the protein compliment of the human organism. Because proteome reflects more accurately on the dynamic state of a cell, tissue, or organism, much is expected from proteomics to yield better disease markers for diagnosis and therapy monitoring. The advent of proteomics technologies for global detection and quantitation of proteins creates new opportunities and challenges for those seeking to gain greater understanding of diseases. High-throughput proteomics technologies combining with advanced bioinformatics are extensively used to identify molecular signatures of diseases based on protein pathways and signaling cascades. Mass spectrometry plays a vital role in proteomics and has become an indispensable tool for molecular and cellular biology. While the potential is great, many challenges and issues remain to be solved, such as mining low abundant proteins and integration of proteomics with genomics and metabolomics data. Nevertheless, proteomics is the foundation for constructing and extracting useful knowledge to biomedical research. In this review, a snapshot of contemporary issues in proteomics technologies is discussed.

  7. The ALICE Data Challenges

    Institute of Scientific and Technical Information of China (English)

    J.P.Baud; W.Carena; 等

    2001-01-01

    Since 1998,the ALICE experiment and the CERN/IT division have jointly executed several large-scale high throughput distributed computing exercises:the ALICE data challenges.The goals of these regular exercises are to test hardware and software components of the data acqusition and computing systems in realistic conditions and to execute an early integration of the overall ALICE computing infrastructure.This paper reports on the third ALICE Data Challenge (ADC III) that has been performed at CERN from January to March 2001.The data used during the ADC Ⅲ are simulated physics raw data of the ALICE TPC,produced with the ALICE simulation program AliRoot.The data acquisition was based on the ALICE online framework called the ALICE Data Acquisition Test Environment (DATE) system.The data after event building,were then formatted with the ROOT I/O package and a data catalogue based on MySQl was established.The Mass Storage System used during ADC III is CASTOR.Different software tools have been used to monitor the performances,DATE has demonstrated performances of more than 500 MByte/s.An aggregate data throughput of 85 MByte/s was sutained in CASTOR over several days.The total collected data amounts to 100 TBytes in 100.00 files.

  8. Résultats challenge

    CERN Multimedia

    Club de pétanque

    2015-01-01

    C'est avec un temps magnifique que se disputait pour la deuxième année le Challenge de notre cher ami Patrick DURAND le jeudi 30 juillet 2015. Vingt-six personnes formées en doublettes s'affrontaient pour trois parties .Après des parties très serrées le juge arbitre Claude JOUVE épaulé par Alain PHILIPONA déclarait  vainqueur l'imbattable Claude MACARI suivi de très près par Eric DARMEDRU et à la troisième place Christian JOUVE. La première féminine était Mireille ROCHE. La soirée se clôturait par une succulente paëlla préparée par Jennifer et sa maman Sylvie JOUVE. Rendez-vous à tous pour le jeudi 27 août 2015 pour le challenge Jean-Claude FROT Nos concours sont ouverts à tous les amateurs de pétanque.

  9. Review - China's Environmental Challenges

    Directory of Open Access Journals (Sweden)

    Bill Bleisch

    2013-12-01

    Full Text Available Review of: Judith Shapiro. 2012. China's Environmental Challenges. Cambridge: UK and Malden, MA: Polity Press. Judith Shapiro's latest ambitious work picks up the story of modern China's checkered relationship with the environment at approximately the point where her previous study, Mao's War Against Nature (2001, left off. This latest book sets out to address questions of grave importance to China and to the world. The litany of challenges – poisonous water and toxic air, scarcity of water and other resources, deforestation, soil erosion, loss of biodiversity – seem nearly insurmountable, despite evidence of considerable attention from the Chinese government and from China's public, and despite the rocket-like rise of China's economic power and political influence in the world. Shapiro adds to this list the growing problems with lapses in environmental justice, both within China and passed on to its neighbours and to the countries with which it trades. Not only do growing environmental problems affect China's ability to achieve the government's stated goals of a 'harmonious society' with 'moderate prosperity for all,' but these problems, and the ways that ...

  10. Offshore northern Europe, the challenges

    International Nuclear Information System (INIS)

    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

  11. WCET Tool Challenge 2011: Report

    OpenAIRE

    Bonenfant, Armelle; Cassé, Hugues; Bünte, Sven; Fellger, Wolfgang; Gepperth, Sebastian; Gustafsson, Jan; Huber, Benedikt; Islam, Nazrul Mohammad; Kästner, Daniel; Kirner, Raimund; Kovács, Laura; Krause, Felix; De Michiel, Marianne; Olesen, Mads Christian; Prantl, Adrian

    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 kinds of problems to be solved by the Challenge participants with their tools, WCET problems, which ask for bounds on the execution time, and flow-analysis problems, which ask for bounds on the number ...

  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. 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...

  14. The Biofilm Challenge

    DEFF Research Database (Denmark)

    Alhede, Maria; Alhede, Morten

    2014-01-01

    The concept of biofilms has emerged in the clinical setting during the last decade. Infections involving biofilms have been documented in all parts of the human body, and it is currently believed that the presence of biofilm-forming bacteria is equivalent to chronic infection. A quick Pubmed search...... reveals the significance of biofilms, as evidenced by a dramatic increase in scientific publications on the topic, as well as in publications concerning wounds with biofilms, which reached 600 publications in 2013. Judged from the number of publications, it appears that biofilms play a significant role in...... wounds. However, the impact of biofilms is often debated, because infected wounds were also treated before the concept of biofilms was coined. In this short review, we will address the significance of biofilms and their role in wounds, and discuss the future tasks of the biofilm challenge....

  15. PHARMACOVIGILANCE: BARRIERS AND CHALLENGES

    Directory of Open Access Journals (Sweden)

    VARMA S. K

    2013-01-01

    Full Text Available Pharmacovigilance is a new discipline which deals with adverse drug or any drug related problems. Pharmacovigilance programme was not bed of roses but its path is laid with challenges and barriers. It is facing obstacles from deficiency from professional health personal to web-based sale of drugs, counterfeit drug to self-medication, etc. It is an integral part of the health sector and identification and reporting of adverse drug effects will have a positive impact on the public health. Improvement in knowledge in pharmacovigilance and communication from the top level to the grass-root level in the health sector will help in proper implementation of the programme. Patient should be educated to report any adverse effects after taking drug and stop relaying on acquiring information related to drugs in web. Proper detection, reporting and analysis would help to implement the programme for the betterment of society.

  16. Multicore Programming Challenges

    Science.gov (United States)

    Perrone, Michael

    The computer industry is facing fundamental challenges that are driving a major change in the design of computer processors. Due to restrictions imposed by quantum physics, one historical path to higher computer processor performance - by increased clock frequency - has come to an end. Increasing clock frequency now leads to power consumption costs that are too high to justify. As a result, we have seen in recent years that the processor frequencies have peaked and are receding from their high point. At the same time, competitive market conditions are giving business advantage to those companies that can field new streaming applications, handle larger data sets, and update their models to market conditions faster. The desire for newer, faster and larger is driving continued demand for higher computer performance.

  17. The Global Energy Challenge

    DEFF Research Database (Denmark)

    Connolly, David

    2011-01-01

    years. Afterwards, the security of the world’s energy supply is investigated and it becomes clear that there is both an inevitable shortage of fossil fuels and a dangerous separation of supply and demand. The final topic discussed is renewable energy, since it is one sustainable solution to the global......This report gives a brief overview of the global energy challenge and subsequently outlines how and where renewable energy could be developed to solve these issues. The report does not go into a lot of detail on these issues and hence, it is meant as an overview only. The report begins by outlining...... the causes of global climate change, concluding that energy-related emissions are the primary contributors to the problem. As a result, global energy production is analysed in more detail, discussing how it has evolved over the last 30 years and also, how it is expected to evolve in the coming 30...

  18. Sustainable Consumption: Research Challenges

    DEFF Research Database (Denmark)

    Reisch, Lucia A.; Cohen, Maurie J.; Thøgersen, John;

    policy) processes that are underway in Sweden and the rest of the European Union (EU) to tackle these challenges; ► to provide an overview of where the international research frontline is located and the status of Swedish research gaps in the area from an international perspective; ► to propose in detail......The Board of the Swedish Foundation for Strategic Environmental Research (Mistra) decided in October 2015 that a proposal for a funding application call in the research area of “sustainable consumption” should be drawn up. According to the statutes of Mistra, research funded by the foundation...... “shall promote the development of strong research environments of the highest international class with importance for Sweden’s future competitiveness. The research shall be of importance for finding solutions to important environmental problems and for a sustainable development of society. Opportunities...

  19. Media challenging capitalism

    DEFF Research Database (Denmark)

    Sandvik, Kjetil

    Digital media and especially so-called ‘social media’ have on the one hand been ascribed the power to change societies and empower democratic movements following the thoughts of e.g. Rheingold (2004), recently fueled by the democratic uprising in Arabic countries such as Egypt, Tunisia, Iran...... and communication research is currently engaging in a longer and deeper process of examining and assessing the cultural consequences of networked communication. One present challenge is to understand digital media and networked communication at the intersection of established and countercultural, utopian...... and dystopian trends in contemporary culture (Turner 2006). On that note, this paper examines the Occupy Wall Street-movement as an example on how social media with its democratic potential and its modes of communication through network structures – along with a variety of both historical and socio...

  20. Challenges in plastics recycling

    DEFF Research Database (Denmark)

    Pivnenko, Kostyantyn; Jakobsen, L. G.; Eriksen, Marie Kampmann;

    2015-01-01

    undertaken to investigate the factors affecting quality in plastics recycling. The preliminary results showed factors primarily influencing quality of plastics recycling to be polymer cross contamination, presence of additives, non-polymer impurities, and polymer degradation. Deprivation of plastics quality......Recycling of waste plastics still remains a challenging area in the waste management sector. The current and potential goals proposed on EU or regional levels are difficult to achieve, and even to partially fullfil them the improvements in collection and sorting should be considerable. A study was......, with respect to recycling, has been shown to happen throughout the plastics value chain, but steps where improvements may happen have been preliminary identified. Example of Cr in plastic samples analysed showed potential spreading and accumulation of chemicals ending up in the waste plastics. In order...

  1. Challenge Measurements For Authentication

    International Nuclear Information System (INIS)

    Authentication of systems with an information barrier that protects sensitive information is difficult; in particular, the information barrier can allow a hidden switch to be implemented by the system fabricator and operator. The hidden switch is the operator's ability to subvert the measurement system and force it to produce a desired and false result. It is usually discussed in the context of an attribute measurement in which a faked item is presented in place of a real item regulated by an agreement, with the driving motivation being the ability to preserve a stock of valuable items. In simple terms, the hidden switch enables a shell game with assets, and the information barrier protects the switch. This presentation outlines challenge measurements that could be used to detect the implementation of a hidden switch and assist the authentication process.

  2. Challenges of ecological restoration

    DEFF Research Database (Denmark)

    Halme, Panu; Allen, Katherine A.; Aunins, Ainars;

    2013-01-01

    The alarming rate of ecosystem degradation has raised the need for ecological restoration throughout different biomes and continents. North European forests may appear as one of the least vulnerable ecosystems from a global perspective, since forest cover is not rapidly decreasing and many...... Biological Diversity. Several northern countries are now taking up this challenge by restoring forest biodiversity with increasing intensity. The ecology and biodiversity of boreal forests are relatively well understood making them a good model for restoration activities in many other forest ecosystems. Here...... we introduce northern forests as an ecosystem, discuss the historical and recent human impact and provide a brief status report on the ecological restoration projects and research already conducted there. Based on this discussion, we argue that before any restoration actions commence, the ecology of...

  3. New challenges in gas

    Energy Technology Data Exchange (ETDEWEB)

    Mandil, C. [Institut Francais du Petrole (IFP), 92 - Rueil-Malmaison (France); Chabrelie, M.F. [Cedigaz, 92 - Rueil Malmaison (France); Streicher, C. [Prosernat, 92 - Paris la Defense (France)] [and others

    2003-07-01

    New developments in the area of gas treatment will be to a large extent driven by the need to find appropriate solutions to the fundamental need of sustainable development. New gas treatment processes are developed with the aim to minimise contaminant emissions and meet most stringent environmental specifications. A new major challenge for the industry will be to implement new cost effective technologies for reducing CO{sub 2} emissions. Industry has also to minimise its costs, and therefore, in order to ensure at the same time a better protection of the environment and a better safety, it is necessary to innovate. The purpose of this seminar is precisely to identify better the innovations which are required in the area of gas treatment. These proceedings comprise 8 papers and a summary of the contributions to a round-table discussion dealing with the options for CO{sub 2} capture and sequestration. The presentations treat of: the future prospects for the gas industry (M.F. Chabrelie, Cedigaz); the solutions for offshore gas treatment (C. Streicher, Prosernat); gas treatment with membranes (H. Meyer, GTI); the Axens Multibed{sub TM} technology for natural gas treatment (G. Jochem, Axens); the potentials and applications for the Propure co-current contactors (F.P. Nilsen, ProPure); the production of very-sour and super-sour large gas reserves: the new challenges (F. Lallemand, TotalFinaElf); Hybrisol, a new gas treatment process for sour natural gases (F. Lecomte, IFP); and the conception and building of large acid-gas removal units (J. Castel, Technip-Coflexip). (J.S.)

  4. Compound heterozygous DUOX2 gene mutations (c.2335-1G>C/c.3264_3267delCAGC) associated with congenital hypothyroidism. Characterization of complex cryptic splice sites by minigene analysis.

    Science.gov (United States)

    Belforte, Fiorella S; Citterio, Cintia E; Testa, Graciela; Olcese, María Cecilia; Sobrero, Gabriela; Miras, Mirta B; Targovnik, Héctor M; Rivolta, Carina M

    2016-01-01

    Iodide Organification defects (IOD) represent 10% of cases of congenital hypothyroidism (CH) being the main genes affected that of TPO (thyroid peroxidase) and DUOX2 (dual oxidasa 2). From a patient with clinical and biochemical criteria suggestive with CH associated with IOD, TPO and DUOX2 genes were analyzed by means of PCR-Single Strand Conformation Polymorphism analysis and sequencing. A novel heterozygous compound to the mutations c.2335-1G>C (paternal mutation, intron 17) and c.3264_3267delCAGC (maternal mutation, exon 24) was identified in the DUOX2 gene. Ex-vivo splicing assays and subsequent RT-PCR and sequencing analyses were performed on mRNA isolated from the HeLa cells transfected with wild-type and mutant pSPL3 expression vectors. The wild-type and c.2335-1G>C mutant alleles result in the complete inclusion or exclusion of exon 18, or in the activation of an exonic cryptic 5' ss with the consequent deletion of 169 bp at the end of this exon. However, we observed only a band of the expected size in normal thyroid tissue by RT-PCR. Additionally, the c.2335-1G>C mutation activates an unusual cryptic donor splice site in intron 17, located at position -14 of the authentic intron 17/exon 18 junction site, with an insertion of the last 14 nucleotides of the intron 17 in mutant transcripts with complete and partial inclusion of exon 18. The theoretical consequences of splice site mutation, predicted with the bioinformatics NNSplice, Fsplice, SPL, SPLM and MaxEntScan programs were investigated and evaluated in relation with the experimental evidence. These analyses confirm that c.2335-1G>C mutant allele would result in the abolition of the authentic splice acceptor site. The results suggest the coexistence in our patient of four putative truncated proteins of 786, 805, 806 and 1105 amino acids, with conservation of peroxidase-like domain and loss of gp91(phox)/NOX2-like domain. In conclusion a novel heterozygous compound was identified being responsible of

  5. Safeguards information challenges

    International Nuclear Information System (INIS)

    Full text: Overall, the aim of this paper is to provide the background and the broader vision in which the various information related presentations and posters proposed by the Department find their place, exploring solutions to the challenges faced. At a time when the Agency is expected to be a reference for the assessment of nuclear proliferation threats, providing the international community with independent, impartial, timely and credible conclusions that no declared nuclear material is diverted to non-peaceful purposes and that no undeclared nuclear material or activities exist in States, it has to address major challenges with regard to information. Drawing credible conclusions assumes that all relevant information is accessible and put into relevant context. Because of the legal constraints under which it operates, the limitation of resources for collecting existing but difficult to reach details and simply because of the overwhelming quantity of the information needed to properly evaluate proliferation issues, the Agency has to continually improve the way it collects, processes and internally disseminates safeguards relevant information. Developing a coherent picture of a State's nuclear capability is a complex process based on many experts' assessments and fusion of information. The search for better, broader and deeper information through dedicated collection processes is an ongoing effort aimed at filling the gaps of such pictures. Implementing well selected information collection tools is a sine qua non to render effective the Agency's detection capabilities. Beyond collection, another prerequisite to ensuring that the available information is accessible to those who need to know is the establishment of a proper information system architecture and an efficient set of standard business processes. At the same time, that information must be sufficiently protected by appropriate security measures, particularly at a time when private hacking has become a

  6. Safeguards information challenges

    International Nuclear Information System (INIS)

    The purpose of this paper is to provide the background and broader vision in which the various presentations and posters on information related matters, prepared by staff of the Department of Safeguards, find their place, exploring solutions to the challenges faced. At a time when the IAEA is expected to be a reference for the assessment of nuclear proliferation issues, it faces major challenges with regard to the information needed to provide the international community with independent, impartial, timely and soundly based conclusions regarding the non-diversion of declared nuclear material and the absence of undeclared nuclear material or activities in States. The drawing of such conclusions assumes that all relevant information is accessible and has been put in the relevant context. Unfortunately, because of legal constraints under which it operates, or because of limitations on resources available for collecting existing but difficult to reach facts, or simply because of the overwhelming aspect of the information needed to properly evaluate proliferation issues, the IAEA needs to enhance the way it collects, processes, analyses, evaluates and disseminates safeguards relevant information. The search for better, broader and deeper information through dedicated collection means is an ongoing effort aimed at filling the gaps that constrain the development of the coherent picture that analysts need to be comfortable with the results of complex analyses. Implementation of well-selected information collection tools is sine qua non for effective IAEA verification capabilities. Beyond collection, the establishment of a proper information architecture and documented business processes is a prerequisite for ensuring that the available information is accessible to those with a need to know. At the same time, information must be sufficiently protected by appropriate security measures, particularly when hacking has become an intellectual sport and institutional security

  7. Parental somatic and germ-line mosaicism for a multiexon deletion with unusual endpoints in a type III collagen (COL3Al) allele produces ehlers-danlos syndrome type IV in the heterozygous offspring

    Energy Technology Data Exchange (ETDEWEB)

    McGookey Milewicz, D.; Witz, A.M.; Byers, P.H. (Univ of Washington, Seattle (United States)); Smith, A.C.M.; Manchester, D.K.; Waldstein, G. (Children' s Hospital, Denver, CO (United States))

    1993-07-01

    Ehlers-Danlos syndrome (EDS) type IV is a dominantly inherited disorder that results from mutation in the type III collagen gene (COL3A1). The authors studied the structure of the COL3A1 gene of an individual with EDS type IV and that of her phenotypically normal parents. The proband was heterozygous for a 2-kb deletion in COL3A1, while her father was mosaic for the same deletion in somatic and germ cells. In fibroblasts from the father, approximately two-fifths of the COL3A1 alleles carried the deletion, but only 10% of the COL3A1 alleles in white blood cells were of the mutant species. The deletion in the mutant allele extended from intron 7 into intron 11. There was a 12-bp direct repeat in intron 7 and intron 11, the latter about 60 bp 5' to the junction. At the breakpoint there was a duplication of 10 bp from intron 11 separated by an insertion of 4 bp contained within the duplicated sequence. The father was mosaic for the deletion so that the gene rearrangement occurred during his early embryonic development prior to lineage allocation. These findings suggest that at least some of the deletions seen in human genes may occur during replication, rather than as a consequence of meiotic crossing-over, and that they thus have a risk for recurrence when observed de novo. 71 refs., 4 figs., 2 tabs.

  8. Osteomyelitis: a current challenge

    Directory of Open Access Journals (Sweden)

    Luciana Souza Jorge

    2010-06-01

    Full Text Available Over the last 30 years, the pathogenesis of osteomyelitis has almost been totally elucidated, and many factors responsible for the persistence of this infection have been identified. Numerous antimicrobial agents with distinct spectrums of action, pharmacokinetics, and pharmacodynamics have been used in its treatment. Surgical techniques, including muscle grafts, the Ilizarov technique, and antibiotic bone cements, have been applied. However, bone infections are still a challenge. Despite the importance of isolation and identification of microorganisms to determine the antimicrobial treatment of bone infections, there are few systematic national studies about the etiological profile of these diseases. This article describes the current knowledge of osteomyelitis and summarizes published national data based on the experience of different Orthopedic and Traumatology Services. In general, S. aureus was described as an important etiological agent; however, the difference in design of national studies makes a comparison between the prevalence of bone infection, the associated risk factors, and the different therapeutic approaches difficult. In conclusion, effort is necessary in order to stimulate systematic national studies in different Orthopedics and Traumatology Services to obtain a better consensus on preventive measures and therapies of bone infections.

  9. VISIR: Experiences and Challenges

    Directory of Open Access Journals (Sweden)

    Mohamed Tawfik

    2012-02-01

    Full Text Available It is of crucial importance the integration of practical sessions in engineering curricula owing to their significant role in understanding engineering concepts and scientific phenomena. However, the lack of practical sessions due to the high costs of the equipment and the unavailability of instructors has caused a significant declination in experimentation in engineering education. Remote laboratories have tackled this issues providing online reusable and shared workbenches unconstrained by neither geographical nor time considerations. Thereby, they have extremely proliferated among universities and integrated into engineering curricula over the last decade. This contribution compiles diverse experiences based on the deployment of the remote laboratory, Virtual Instrument Systems in Reality (VISIR, on the practices of undergraduate engineering grades at various universities within the VISIR community. It aims to show the impact of its usage on engineering education concerning the assessments of students and teachers as well. In addition, the paper address the next challenges and future works carried out at several universities within the VISIR community.

  10. Challenges in organ transplantation.

    Science.gov (United States)

    Beyar, Rafael

    2011-04-01

    Organ transplantation has progressed tremendously with improvements in surgical methods, organ preservation, and pharmaco-immunologic therapies and has become a critical pathway in the management of severe organ failure worldwide. The major sources of organs are deceased donors after brain death; however, a substantial number of organs come from live donations, and a significant number can also be obtained from non-heart-beating donors. Yet, despite progress in medical, pharmacologic, and surgical techniques, the shortage of organs is a worldwide problem that needs to be addressed internationally at the highest possible levels. This particular field involves medical ethics, religion, and society behavior and beliefs. Some of the critical ethical issues that require aggressive interference are organ trafficking, payments for organs, and the delicate balance in live donations between the benefit to the recipient and the possible harm to the donor and others. A major issue in organ transplantation is the definition of death and particularly brain death. Another major critical factor is the internal tendency of a specific society to donate organs. In the review below, we will discuss the various challenges that face organ donation worldwide, and particularly in Israel, and some proposed mechanisms to overcome this difficulty. PMID:23908807

  11. Challenges in Organ Transplantation

    Directory of Open Access Journals (Sweden)

    Rafael Beyar

    2011-04-01

    Full Text Available Organ transplantation has progressed tremendously with improvements in surgical methods, organ preservation, and pharmaco-immunologic therapies and has become a critical pathway in the management of severe organ failure worldwide. The major sources of organs are deceased donors after brain death; however, a substantial number of organs come from live donations, and a significant number can also be obtained from non-heart-beating donors. Yet, despite progress in medical, pharmacologic, and surgical techniques, the shortage of organs is a worldwide problem that needs to be addressed internationally at the highest possible levels. This particular field involves medical ethics, religion, and society behavior and beliefs. Some of the critical ethical issues that require aggressive interference are organ trafficking, payments for organs, and the delicate balance in live donations between the benefit to the recipient and the possible harm to the donor and others. A major issue in organ transplantation is the definition of death and particularly brain death. Another major critical factor is the internal tendency of a specific society to donate organs. In the review below, we will discuss the various challenges that face organ donation worldwide, and particularly in Israel, and some proposed mechanisms to overcome this difficulty.

  12. [Geriatrics - an interdisciplinary challenge].

    Science.gov (United States)

    Nau, Roland; Djukic, Marija; Wappler, Manfred

    2016-06-01

    The care of elderly patients will continue to challenge the healthcare system over the next decades. As a rule geriatric patients suffer from multimorbidities with complex disease patterns, and the ability to cope with everyday life is severely reduced. Treatment is provided by a multiprofessional geriatric team, and the primary goal is improvement of functional status, quality of life in the social environment and autonomy by employing a holistic approach. In Germany geriatric care is provided by physicians from various medical specialties (e.g. general practitioners, internists, neurologists and psychiatrists). In the training for the subspecialty clinical geriatrics, these specialties enjoy equal rights. Recent efforts to establish a qualification as physician for internal medicine and geriatrics have initiated a discussion to make the suitability for qualification as a geriatrician dependent on the medical specialty. Geriatric patients benefit from multidisciplinary cooperation. Neurologists possess great expertise in the treatment of patients with dementia, depression, delirium, consequences of degenerative spinal cord diseases and vertebral bone fractures, stroke, Parkinson's syndrome, epileptic seizures, vertigo and dizziness, neuropathies, lesions of peripheral nerves and in the multimodal therapy of pain. To function in a position of responsibility in a geriatric department, neurologists need skills in general internal medicine. These are acquired either on a geriatric ward or during specialization as a neurologist by full time secondment to large neurological or interdisciplinary intensive care units. PMID:27167886

  13. Opportunities and challenges ahead

    International Nuclear Information System (INIS)

    Achievements of the natural gas industry during the past 11 years, since the beginning of deregulation, have been reviewed. The period has been characterized as a decade of rapid growth, almost entirely due to exports, which more than tripled from 740 BCF in 1986 to 2,810 BCF in 1996. Two major pipeline projects, the Iroquois project to the U.S. Northeast in 1991, followed by the massive PGT expansion to markets in southern California and the Pacific Northwest, were the prime facilitators of this unprecedented growth. At present, and for the immediate future, expansion of the market is stalled due the lack of major pipeline expansions. Only modest expansions are planned for the 1995-1998 period, when the Northern Border expansion is scheduled to begin. Thus, excess deliverability (resulting from record drilling levels in the mid-1990s), and a pressing need for additional pipeline capacity constitute the principal challenges for the immediate future. In the longer term, prospects are encouraging, with a number of major pipeline projects ahead, including a 1.2BCF/day line from northern Alberta to the U.S. Midwest, the Palliser project to ship 1BCF/day from southern Alberta to the Alberta border, the Nexus project, an expansion of the TransCanada Pipelines to the U.S. Midwest, and the Sable Island project on the East Coast to bring eastern Canadian natural gas to Canada's heartland. Overall, the long-term prospects are very good, indeed

  14. Challenges in Piaget's legacy.

    Science.gov (United States)

    Bibace, Roger

    2013-03-01

    The publication of After Piaget (Martí and Rodríguez 2012) hopefully triggers a new effort to understand the richness of the efforts of that major psychologist of the 20th century. Piaget was consistently concerned with part/whole relationships throughout his life. He addressed this issue philosophically, epistemologically, and psychologically. Conceptually Piaget struggled with the issue of continuity/discontinuity in development and changed his mind about how to reconcile the discontinuities of stages with his concept of development. I also attribute his variability to the implications of his important work on perception, and to his willingness to get involved in widespread concrete applications of his approach to education including the education of children with special needs; his center for genetic epistemology, and his interest in psychoanalysis. Benefiting from all the authors of After Piaget, I want to point out that Piaget has identified many major issues that will continue to constitute challenges to psychology in this century. These include specifying terms such as 'development;' methodological issues such as sampling both quantitatively in one culture and across cultures; comprehensive inclusion of the psychological processes covered by introductory textbooks in psychology; and conceptual issues such as the relationships among all these parts within a whole. I make a distinction between an 'issue' and a 'problem'--problems have solutions; while issues refer to controversies in science generally as well as in psychology that have persisted for centuries. PMID:22733313

  15. 'Scrap yard challenge'

    International Nuclear Information System (INIS)

    'Plutonium'. The word evokes deep reactions outside of the nuclear industry. Although the majority of Plutonium currently in existence is man-made and therefore perceived as being unnatural, plutonium has been found as a product of the Oklo natural reactor in Gabon. This paper seeks to challenge two concepts, that of the Nuclear Control Institute that Plutonium is unnatural, 'fiendishly toxic' and one of the 'substances most hazardous to man' and the second image that a high security Plutonium store is merely a 'scrapyard' containing a material which has little use. The nuclear industry has often been accused of treating Plutonium and its accumulation casually in proportion to the risks perceived by those outside the industry. As a result this paper seeks to demonstrate that the industry is aware of the concerns of the public and is actively seeking viable solutions. The paper looks at Plutonium itself and explores the issues surrounding military and civil Plutonium in adding to the current stockpiles. It also suggests three possible alternatives for dealing with these Plutonium stockpiles and arrives at a conclusion as to which solutions currently appear most viable. (authors)

  16. Physician Challenges in 2015.

    Science.gov (United States)

    Cascardo, Debra

    2015-01-01

    While the influx of new patients resulting from the ACA will increase the number of people receiving healthcare, the regulations associated with it will add to physicians' administrative duties, as will government regulations associated with HIPAA and Meaningful Use. Further stress will come from the demands of both payers and patients, requiring doctors to walk a fine line to protect themselves from litigation. Technology also will play an increasing role. The continuing move toward EHRs and the new ICD-10 coding standard will require investments in software, testing, and training staff, and may also require an investment in new computer hardware. Physicians and staff will have to teach patients how to use EHR portals and how to follow the record-keeping requirements of their insurance providers. The regulatory changes and increased costs of time and money associated with them may drive many physicians out of private practice and into hospital system-based team practices, which will face a greater challenge in recruiting and retaining top talent. Other physicians, in contrast, may continue to seek the independence of private practice; some of them may decide to stop accepting insurance because of their need for autonomy in their practices. Regardless of what decisions doctors choose to make within the changing nature of healthcare, it is important to keep abreast of the changes and develop a plan for dealing with them, in 2015 and beyond. PMID:26182706

  17. Challenges in Astronomy Education

    Science.gov (United States)

    De Greve, Jean-Pierre

    2010-11-01

    Astronomy is an attractive subject for education. It deals with fascination of the unknown and the unreachable, yet is uses tools, concepts and insights from various fundamental sciences such as mathematics, physics, chemistry, biology. Because of this it can be well used for introducing sciences to young people and to raise their interest in further studies in that direction. It is also an interesting subject for teaching as its different aspects (observation techniques, theory, data sampling and analysis, modelling,?) offer various didactical approaches towards different levels of pupils, students and different backgrounds. And it gives great opportunities to teach and demonstrate the essence of scientific research, through tutorials and projects. In this paper we discuss some of the challenges education in general, and astronomy in particular, faces in the coming decades, given the major geophysical and technological changes that can be deducted from our present knowledge. This defines a general, but very important background in terms of educational needs at various levels, and in geographical distribution of future efforts of the astronomical community. Special emphasis will be given to creative approaches to teaching, to strategies that are successful (such as the use of tutorials with element from computer games), and to initiatives complementary to the regular educational system. The programs developed by the IAU will be briefly highlighted.

  18. Challenges in publication ethics.

    Science.gov (United States)

    Barbour, V; Astaneh, B; Irfan, M

    2016-04-01

    skill. Finally, the editor needs to deal with the journal's ethical policy when examples of plagiarism, author disputes or other forms of misconduct are evident. Breaches of publication ethics are forms of scientific misconduct that can undermine science and challenge editors, many of whom have little formal training in this field. In this respect, the Committee on Publication Ethics (COPE), founded in 1997 as a voluntary body, has become a central player. COPE provides a discussion forum and advice as well as guidelines for scientific editors with the aim of finding practical ways to deal with forms of misconduct. The Annals is a member of COPE and follows its code of conduct for journal editors. (2) It is a privilege that the current chair of COPE, Dr Barbour, and her colleagues have written this final article in the medical publishing series about challenges in publication ethics. I hope you have found this series useful and enjoyed reading the range of articles we have published from many experts in their fields. JYOTI SHAH Commissioning Editor References 1. Sanders SA , Reinisch JM . Would you say you 'had sex' if…? JAMA 1999 ; 281 : 275 - 277 . 2. Committee on Publication Ethics . Code of Conduct and Best Practice Guidelines for Journal Editors . Harleston, UK : COPE ; 2011 . PMID:26985812

  19. HEPEX - achievements and challenges!

    Science.gov (United States)

    Pappenberger, Florian; Ramos, Maria-Helena; Thielen, Jutta; Wood, Andy; Wang, Qj; Duan, Qingyun; Collischonn, Walter; Verkade, Jan; Voisin, Nathalie; Wetterhall, Fredrik; Vuillaume, Jean-Francois Emmanuel; Lucatero Villasenor, Diana; Cloke, Hannah L.; Schaake, John; van Andel, Schalk-Jan

    2014-05-01

    HEPEX is an international initiative bringing together hydrologists, meteorologists, researchers and end-users to develop advanced probabilistic hydrological forecast techniques for improved flood, drought and water management. HEPEX was launched in 2004 as an independent, cooperative international scientific activity. During the first meeting, the overarching goal was defined as: "to develop and test procedures to produce reliable hydrological ensemble forecasts, and to demonstrate their utility in decision making related to the water, environmental and emergency management sectors." The applications of hydrological ensemble predictions span across large spatio-temporal scales, ranging from short-term and localized predictions to global climate change and regional modeling. Within the HEPEX community, information is shared through its blog (www.hepex.org), meetings, testbeds and intercompaison experiments, as well as project reportings. Key questions of HEPEX are: * What adaptations are required for meteorological ensemble systems to be coupled with hydrological ensemble systems? * How should the existing hydrological ensemble prediction systems be modified to account for all sources of uncertainty within a forecast? * What is the best way for the user community to take advantage of ensemble forecasts and to make better decisions based on them? This year HEPEX celebrates its 10th year anniversary and this poster will present a review of the main operational and research achievements and challenges prepared by Hepex contributors on data assimilation, post-processing of hydrologic predictions, forecast verification, communication and use of probabilistic forecasts in decision-making. Additionally, we will present the most recent activities implemented by Hepex and illustrate how everyone can join the community and participate to the development of new approaches in hydrologic ensemble prediction.

  20. The stem factor challenge

    International Nuclear Information System (INIS)

    One of the most important challenges that still needs to be met in the effort to understand the operation of motor-operated, rising-stem valves is the ability to determine stem factor throughout the valve's load range. The stem factor represents the conversion of operator torque to stem thrust. Determining the stem factor is important because some motor-operated valves (MOVs) cannot be tested in the plant at design basis conditions. The ability of these valves to perform their design basis function (typically, to operate against specified flow and pressure loads) must be ensured by analytical methods or by extrapolating from the results of tests conducted at lower loads. Because the stem factor tends to vary in response to friction and lubrication phenomena that occur during loading and wedging, analytical methods and extrapolation methods have been difficult to develop and implement. Early investigations into variability in the stem factor tended to look only at the tip of the iceberg; they focused on what was happening at torque switch trip, which usually occurs at full wedging. In most stems, the stem factor is better (lower) in the wedging transient than before wedging, so working with torque switch trip data alone led many early researchers to false conclusions about the relationship between stem factor and load. However, research at the Idaho National Engineering Laboratory (INEL) has taken a closer look at what happens during the running portion of the closing stroke along with the wedging portion. This shift in focus is important, because functional failure of a valve typically consists of a failure to isolate flow, not a failure to achieve full wedging. Thus, the stem factor that must be determined for a valve's design basis closing requirements is the one that corresponds with the running load before wedging

  1. DIGITAL PAKISTAN: OPPORTUNITIES & CHALLENGES

    Directory of Open Access Journals (Sweden)

    Ghulam Muhammad Kundi

    2008-12-01

    Full Text Available ABSTRACT IT has revolutionized the social and organizational life around the globe. Given the newness of IT as a technology, there is a lot of potential that needs to be explored. It is however, argued that as IT can revolutionize the economic development, by the same coin, although its mismanagement in adoption process can end up in problems or even straight failure of the technology at the business-end. This study was conducted with reference to opportunities and challenges in the IT adoption process in Pakistan. The aim of the study was to point out the barriers that are impeding the country’s computerization process in order to provide facts to the policy makers for smooth computerization. The primary data collected through structured questionnaires was analyzed and tested through correlation, regressions analysis and t-test. Out of 10 hypotheses, 3 were accepted while in the rest null hypotheses were not substantiated. Based on primary and secondary data analysis this study has found that all independent bureaucratic, political, education and social and cultural variables are mutually correlated and have significant impact on shaping and reshaping of IT in Pakistan, while the Pakistan IT policy is inconsistent, administrative machinery attitude is negative and non cooperative, procedures are cumbersome and implementation is weak and ineffective, not to mention the lack of IT knowledge on the bureaucratic side. The political environment is instable and law and order is worse which is discouraging the investment. Moreover, physical and legal infrastructure is insufficient and the country is lacking good quality IT professionals. IT organization alignment is another serious issue in Pakistan. However, government incentives and growing interest from the private sector indicate positive attitude towards computerization of the country.

  2. WANO. Development, programs, challenges

    International Nuclear Information System (INIS)

    In the wake of the accident at the Soviet RBMK reactor unit 4 in Chernobyl the nuclear industry founded the World Association of Nuclear Operators (WANO). To this day, the purpose of the organization has been to enhance worldwide cooperation of nuclear industry and, in this way, strengthen the safety and availability of nuclear power plants. Following some first steps after 1986, the charter of the organization was signed at the WANO constituent assembly in Moscow on May 15 and 16, 1989. The member companies thus committed themselves to support WANO's mission. WANO was established for these purposes: ''The mission of WANO is to maximize the safety and reliability of nuclear power plants worldwide by working together to assess, benchmark and improve performance through mutual support, exchange of information, and emulation of best practices.'' The WANO programs developed speedily thereafter. The focus was on peer reviews. In 2000, the first interim objective had been reached: Fifty percent of all member nuclear power plants had undergone peer reviews. In addition, plant-related peer reviews were extended throughout all operator organizations, and corporate peer reviews were developed. The other WANO programs as well, i.e. exchanges of experience, technical support, and performance indicators, exerted more and more influence on industry. Peer reviews covered entire operator organizations, and corporate peer reviews were developed. The worldwide paradigm shift in evaluating the use of nuclear power, and the associated construction programs for new nuclear power plants already in their implementation phase, assigned a new quality to the work of WANO. The organization is preparing a long-term strategy in the face of the challenges to be expected. The ultimate objective of these efforts is to support member organizations from the first preparations of a nuclear power plant project to the end of commercial operation. (orig.)

  3. DIGITAL PAKISTAN: OPPORTUNITIES & CHALLENGES

    Directory of Open Access Journals (Sweden)

    Ghulam Muhammad Kundi

    2008-10-01

    Full Text Available IT has revolutionized the social and organizational life around the globe. Given the newness of IT as a technology, there is a lot of potential that needs to be explored. It is however, argued that as IT can revolutionize the economic development, by the same coin, although its mismanagement in adoption process can end up in problems or even straight failure of the technology at the business-end. This study was conducted with reference to opportunities and challenges in the IT adoption process in Pakistan. The aim of the study was to point out the barriers that are impeding the country’s computerization process in order to provide facts to the policy makers for smooth computerization. The primary data collected through structured questionnaires was analyzed and tested through correlation, regressions analysis and t-test. Out of 10 hypotheses, 3 were accepted while in the rest null hypotheses were not substantiated. Based on primary and secondary data analysis this study has found that all independent bureaucratic, political, education and social and cultural variables are mutually correlated and have significant impact on shaping and reshaping of IT in Pakistan, while the Pakistan IT policy is inconsistent, administrative machinery attitude is negative and non cooperative, procedures are cumbersome and implementation is weak and ineffective, not to mention the lack of IT knowledge on the bureaucratic side. The political environment is instable and law and order is worse which is discouraging the investment. Moreover, physical and legal infrastructure is insufficient and the country is lacking good quality IT professionals. IT organization alignment is another serious issue in Pakistan. However, government incentives and growing interest from the private sector indicate positive attitude towards computerization of the country.

  4. The WCET Tool Challenge 2011

    OpenAIRE

    Hanxleden, Reinhard von; Holsti, Niklas; Lisper, Björn; Gustafsson, Jan; Islam, Nazrul Mohammad; Ploedereder, Erhard; Fellger, Wolfgang; Gepperth, Sebastian; Krause, Felix; Wilhelm, Reinhard; Bonenfant, Armelle; Casse, Hugues; De Michiel, Marianne; Rochange, Christine; Bünte, Sven

    2012-01-01

    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) dened two kinds of problems to be solved by the Challenge participants with their tools, WCET problems, which ask for bounds on the execution time, and ow-analysis problems, which ask for bounds on the number of t...

  5. The challenges of green nanotechnology

    OpenAIRE

    Miguel de la Guardia

    2014-01-01

    Nanomaterials have great impacts on life sciences; however, these advanced materials may induce inadvertant consequences. Thus, this editorial will highlight the futuristic challenges ingreen nanotechnology.

  6. The challenges of fusion

    International Nuclear Information System (INIS)

    The new boss of the world's biggest fusion experiment cannot afford to fail. Kaname Ikeda will soon be a name on many physicists' lips. Though the outgoing Japanese ambassador to Croatia and former science administrator is not currently widely known, that will all change when he starts work later this month as director general of the International Thermonuclear Experimental Reactor (ITER). Set to be built at Cadarache near Marseille in southern France - assuming the ITER treaty is ratified - this Euro10bn facility is designed to show that fusion could be turned into a practical energy source.To do so would be huge achievement. Fusion reactors could play a massive role in meeting the world's rapidly growing demand for energy. They promise to be environmentally friendly and relatively safe to operate, while the raw materials they need are plentiful. However, early progress in fusion research led plasma physicists to be over optimistic about this energy source, and a commercial fusion plant remains as far off in the future as it was back in the 1970s. Ikeda therefore has a tough job on his hands, as he readily admits in our interview with him (see p12; print version only). It will be no mean feat to build ITER on time and to budget, and Ikeda will have to draw heavily on his undoubted diplomatic skills to ensure that everyone involved in this complex international project gets on. ITER is hugely ambitious in engineering terms, with vast superconducting magnets needed to confine a deuterium-tritium plasma within a doughnut-shaped 'tokamak' vessel. Numerous technical challenges will have to be addressed to ensure ITER fulfils its goal of releasing more energy than it consumes. These include choosing which material to line the inner wall of the tokamak with, overcoming the accumulation of radioactive tritium on this surface, and controlling the properties of the plasma. Fortunately, such issues are being addressed at the recently upgraded Joint European Torus near Oxford

  7. Challenges in Computational Commutative Algebra

    OpenAIRE

    Abbott, John

    2006-01-01

    In this paper we consider a number of challenges from the point of view of the CoCoA project one of whose tasks is to develop software specialized for computations in commutative algebra. Some of the challenges extend considerably beyond the boundary of commutative algebra, and are addressed to the computer algebra community as a whole.

  8. 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.

  9. Organizational leadership: meeting the challenge.

    Science.gov (United States)

    Hart, A L

    1994-06-01

    Leadership can be learned. Knowledge of leadership theories can serve as basis for developing skills and techniques. Style, trait, and transformational leadership can be applied in both health care institutions and professional associations. Organizational leadership is challenging, but those challenges can help individual nurses grow in the leadership skills that will continue to be demanded in the ever changing healthcare arena. PMID:8075165

  10. 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…

  11. A Window-Washing Challenge

    Science.gov (United States)

    Roman, Harry T.

    2010-01-01

    Skyscrapers sure do have a lot of windows, and these windows are cleaned and checked regularly. All this takes time, money, and puts workers at potential risk. Might there be a better way to do it? In this article, the author discusses a window-washing challenge and describes how students can tackle this task, pick up the challenge, and creatively…

  12. Higher Education Marketing: A Challenge.

    Science.gov (United States)

    Canterbury, Richard

    1999-01-01

    States that similarities between education and other services may not be sufficient to conclude that services marketing methods can be easily transferred to all markets in higher education. Article identifies and discusses why higher education marketing is a particular challenge. Suggests that understanding these challenges can help in making…

  13. Challenges When Introducing Electronic Exam

    Science.gov (United States)

    Kuikka, Matti; Kitola, Markus; Laakso, Mikko-Jussi

    2014-01-01

    Time pressures often necessitate the use of more efficient exam tools, such as electronic exams (e-exams), instead of traditional paper exams. However, teachers may face challenges when introducing e-exams in a higher education context. This paper describes what kinds of challenges teachers may face when introducing e-exams, based on experiences…

  14. Five Biggest Challenges for 2002.

    Science.gov (United States)

    Ishizuka, Kathy; Minkel, Walter; St. Lifer, Evan

    2002-01-01

    Addresses five themes that represent school librarians' overriding challenges for the year 2002: gaining the respect of school administrators; making information literacy a higher priority; recruiting new librarians to meet the growing demand; dealing with fiscal uncertainty in a recession; and the challenge of accessing information in a filtered…

  15. Adaptive challenges in medical practices.

    Science.gov (United States)

    Daiker, Barbara L

    2013-01-01

    The purpose of this qualitative grounded theory study was to describe the theoretical structures of the strategies used by medical practices to navigate adaptive challenges. The process of responding to adaptive challenges in five medical practices was studied using a grounded theory approach, collecting data from interviews with the organizations' leaders and managers. The leadership of these medical practices had successfully navigated adaptive challenges within two years of the study. The analysis revealed a model that describes the key elements in finding solutions to adaptive challenges. The model was named the Adaptation Solution Dynamic, which explains the elements of Rational Tools, Relationship Commitment, and Achievement Drive. The findings from the results of this study provide a theoretical basis for studying how leaders support identifying solutions to adaptive challenges. PMID:23866647

  16. Skin manifestations in familial heterozygous hypercholesterolemia:

    OpenAIRE

    Pietroleonardo, Lucia; Ruzicka, Thomas

    2009-01-01

    Familial hypercholesterolemia, a form of primary hyperlipoproteinemia, is an autosomal dominant disorder characterized by an increase in serum LDL cholesterol concentrations. Multiple types of xanthomas occur, such as tendinous, tuberous, subperiosteal, and xanthelasma. Intertriginous xanthomas are rare, but if present are pathognomonic in this disorder. We report a patient with multiple xanthomas including the very rare intertriginous variety.

  17. Climate change challenges for SEA

    DEFF Research Database (Denmark)

    Larsen, Sanne Vammen

    This paper takes a theoretical perspective on the challenges that climate changes pose for SEA. The theoretical framework used is the sociologist Ulrich Beck’s theory of risk society and the aspects that characterise this society. Climate change is viewed as a risk, and the theory is used to derive...... two challenges for the practice of SEA: delivering assessments and predictions; and handling differences in opinion and debate. Based on empirical evidence from document studies and interviews, the paper discusses the reflection of these theoretical challenges in practice....

  18. The Leadership Challenge Activities Book

    CERN Document Server

    Kouzes, James M; Biech, Elaine

    2010-01-01

    ACTIVE Learning for Exemplary Leaders. The best leaders are the best learners. This evidence-based truth has been a foundational principle of The Leadership Challenge since it was first published nearly twenty-five years ago. In this new work, bestselling Leadership Challenge authors Jim Kouzes and Barry Posner team up with experiential learning expert Elaine Biech to bring today's leaders over 100 engaging activities designed to expand and accelerate their leadership development efforts. Grounded in The Five Practices of Exemplary Leadership® model, The Leadership Challenge Activities Book in

  19. 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.

  20. Grand Challenges facing Storage Systems

    CERN Document Server

    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.

  1. Nuclear energy: meeting the challenges

    International Nuclear Information System (INIS)

    'Nuclear Energy - Meeting the Challenges' was the theme of the 25th Annual Conference of the Canadian Nuclear Society, held in Toronto, Ontario on June 6-9, 2004. The theme has the implication of optimism - that we WILL meet the many challenges needed to overcome if nuclear power is to play a significant role in our energy future. The organizers succeeded in presenting a thorough discussion of the challenges facing the nuclear power industry in Canada with close to 300 delegates attending the three-day event

  2. Refugee status determination: three challenges

    Directory of Open Access Journals (Sweden)

    Martin Jones

    2009-04-01

    Full Text Available Refugee status determination (RSD, which is vital to the protection of so many asylum seekers worldwide, is at best an imperfect, haphazard and challenging process. It merits greater attention and appropriate reform.

  3. The Humpty-Dumpty Challenge.

    Science.gov (United States)

    Chock, Jan S.

    1995-01-01

    Describes a twist on the egg-drop challenge activity for an 8th grade physical science unit. Students engage in active inquiry and explore the laws of physics, develop critical thinking skills, and practice problem-solving tasks. (NB)

  4. Challenge of COPD: Getting Tested

    Science.gov (United States)

    ... please turn JavaScript on. Feature: The Challenge of COPD Getting Tested Past Issues / Fall 2014 Table of Contents Getting Tested Everyone at risk for COPD who has cough, sputum production, or shortness of ...

  5. 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...

  6. The challenges of green nanotechnology

    Directory of Open Access Journals (Sweden)

    Miguel de la Guardia

    2014-03-01

    Full Text Available Nanomaterials have great impacts on life sciences; however,these advanced materials may induce inadvertant consequences.Thus, this editorial will highlight the futuristic challenges in green nanotechnology.

  7. Challenges in Soft Tissue Engineering

    OpenAIRE

    Yuksel, Eser; Choo, Joshua; Wettergreen, Matthew; Liebschner, Michael

    2005-01-01

    Soft tissue engineering strategies targeting restoration of volume loss have inherent critical challenges as they relate to the problem of restoration of defects with a high volume to surface ratio. We outline the problems associated with the limitations of translational applications regarding soft tissue engineering strategies as follows: cell survival, mechanical challenges: macroenvironment (scaffold collapse and on-the-shelf availability), compositional considerations: microenvironment, i...

  8. Challenges in Kurdish Text Processing

    OpenAIRE

    Esmaili, Kyumars Sheykh

    2012-01-01

    Despite having a large number of speakers, the Kurdish language is among the less-resourced languages. In this work we highlight the challenges and problems in providing the required tools and techniques for processing texts written in Kurdish. From a high-level perspective, the main challenges are: the inherent diversity of the language, standardization and segmentation issues, and the lack of language resources.

  9. Challenges to Nordic Police Research

    DEFF Research Database (Denmark)

    Holmberg, Lars

    2015-01-01

    The paper will cover three main points: A short description of published police research in the Nordic countries; a somewhat longer discussion of the nature of, and challenges to, Nordic police research and, finally, a critique of the homeliness of research.......The paper will cover three main points: A short description of published police research in the Nordic countries; a somewhat longer discussion of the nature of, and challenges to, Nordic police research and, finally, a critique of the homeliness of research....

  10. Challenges when introducing electronic exam

    OpenAIRE

    Kuikka, Matti; Kitola, Markus; Mikko-Jussi LAAKSO

    2014-01-01

    Time pressures often necessitate the use of more efficient exam tools, such as electronic exams (e-exams), instead of traditional paper exams. However, teachers may face challenges when introducing e-exams in a higher education context. This paper describes what kinds of challenges teachers may face when introducing e-exams, based on experiences in Turku University of Applied Sciences (TUAS) where e-exams have been used since 2012. For this research, the authors used their personal experience...

  11. Conclusion: challenges for the future

    OpenAIRE

    North, D. Warner

    1993-01-01

    The title “Challenges for the Future” implies the challenge to summarize a very complex meeting. Of necessity, I will present a personal impression. My interest is in risk assessment, which I define as a process for summarizing science in support of decision making. Risk assessment is sometimes regarded as arcane numerology, a rigid process of computing risk numbers in which much available science is unused. I am a strong advocate for the broader definition of risk assessment. It is encouragi...

  12. Internationalization challenges of Ethiopian SMEs

    OpenAIRE

    Yigzaw, Tamirat

    2014-01-01

    This study was made to find out what the internationalization challenges of Ethiopian small to medium size enterprises (SMEs) are. SMEs play a vital role in the economic development of a country. As the internationalization activities of these SMEs is affected by various factors, a research to identify the challenges that hinder their internationalization activities was made in order to minimize the internationalization problems faced in the future. A detailed literature review related to the...

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

    International Nuclear Information System (INIS)

    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

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

    CERN Document Server

    Babak, Stanislav; Benacquista, Matthew J; Cornish, Neil J; Crowder, Jeff; Larson, Shane L; Plagnol, Eric; Porter, Edward K; Vallisneri, Michele; Vecchio, Alberto; Arnaud, Keith; Barack, Leor; Błaut, Arkadiusz; Cutler, Curt; Fairhurst, Stephen; Gair, Jonathan; Gong, Xuefei; Harry, Ian; Khurana, Deepak; Królak, Andrzej; Mandel, Ilya; Prix, Reinhard; Sathyaprakash, B S; Savov, Pavlin; Shang, Yu; Trias, Miquel; Veitch, John; Wang, Yan; Wen, Linqing; Whelan, John T

    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 article we provide a critical analysis of 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 article 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.

  15. 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

  16. Endosperm genotyping as a strategy to differentiate the allele source in maize heterozygous progeny Genotipagem do endosperma como estratégia para diferenciar a origem de alelos em progênies heterozigóticas de milho

    Directory of Open Access Journals (Sweden)

    Francielle Alline Martins

    2009-10-01

    Full Text Available The objective of this work was to distinguish the parental source of alleles in heterozygous progeny using semiquantitative polymerase chain reaction (PCR in maize endosperm. Endosperms derived from direct and reciprocal single-cross hybrids between maize inbred lines L3 and L1113-01 were genotyped by semiquantitative PCR methodology (SQ-PCR using fluorescent microsatellite primers. The amplification products were evaluated by the ratios of fluorescence intensity (RFI, calculated between the peaks corresponding to the alleles derived from each parental line. Based on the statistically significant contrast between RFI mean values of direct and reciprocal single-cross hybrids, it was possible to distinguish the number of alleles received from each parental line and, ultimately, to determine the origin of the alleles of each cross. Thus, endosperm genotyping using SQ-PCR is a promising strategy to map QTL in maize outbred populations.O objetivo deste trabalho foi distinguir a origem de alelos em progênies heterozigóticas usando reação em cadeia da polimerase (PCR semiquantitativa em endosperma de milho. Endospermas derivados de híbridos simples diretos e recíprocos entre as linhagens de milho L3 e L1113-01 foram genotipados pela metodologia de PCR semiquantitativa (PCR-SQ com uso de primers microssatélites fluorescentes. Os produtos de amplificação foram avaliados por meio da razão de intensidade de fluorescência (RIF, calculada entre os valores de intensidade dos picos correspondentes aos alelos derivados de cada genitor. Com base no contraste estatisticamente significativo dos valores médios das RIF entre os híbridos simples direto e recíproco, foi possível distinguir o número de alelos recebidos de cada genitor e, finalmente, determinar a origem dos alelos de cada híbrido. Assim, a genotipagem de endosperma utilizando PCR-SQ é uma estratégia promissora no mapeamento de QTLs em populações exogâmicas de milho.

  17. Challenges and counter challenges in HIV/AIDS

    Institute of Scientific and Technical Information of China (English)

    Qingsheng Li; Charles Wood

    2010-01-01

    @@ Since the beginning of the HIV/AIDS pandemic, there has been significant progress in combating the virus.In addition to identifying HIV,1 scientists have developed an array of antiretroviral drugs and successfully converted the once deadly disease into a treatable and chronic condition.2 Nevertheless, this battle is far from over and HIV still outsmarts humans in multiple ways and poses tremendous challenges. Within this context, the Chinese Medical Journal has timely published this special issue on HIV/AIDS, highlighting the ongoing challenges posed by HIV and potential solutions to these problems.

  18. ITER safety challenges and opportunities

    International Nuclear Information System (INIS)

    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. 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.

  20. The Challenges of Becoming Agile

    DEFF Research Database (Denmark)

    Ovesen, Nis

    use of a radically different and empirically based process control model originating from the domain of software development, namely the process framework called Scrum. Scrum as a process framework is often identified with the overall development paradigm coined as Agile Development and during the...... last decade it has gained a vast success in software development due to its lightweight character and efficient way of handling the challenges of increased market speed, change and product complexity. Now, traditional product development companies are beginning to discover the Scrum framework as a...... potential solution to their struggles with similar challenges. This Ph.D. project is based on case studies of the development environments of seven Danish companies working with the implementation of Scrum. The outcome of the project is an identification and overview of the challenges of implementing and...

  1. The Challenges of Becoming Agile

    DEFF Research Database (Denmark)

    Ovesen, Nis; Dowlen, Chris

    2012-01-01

    During the last decade agile methods have been a vast success in the domain of software development. This paper investigates whether these methods can be successfully transferred to the domain of physical product development in order to address the fundamental challenges of increased marked speed......, development uncertainty and product complexity. The paper compares two cases from industry and education where agile methods are used in physical product development. The comparison between the cases is conducted within five thematic areas, which creates an overview of the challenges that may occur when...... implementing agile methods. The present paper is concluded by a discussion and conclusion drawing up the main challenges experienced and well as the benefits of utilising agile methods in physical product development....

  2. Challenges in future linear colliders

    CERN Document Server

    Chattopadhyay, S

    2002-01-01

    For decades, electron-positron colliders have been complementing proton-proton colliders. But the circular LEP, the largest e/sup -/e /sup +/ collider, represented an energy limit beyond which energy losses to synchrotron radiation necessitate moving to e/sup -/e/sup + / linear colliders (LCs), thereby raising new challenges for accelerator builders. Japanese-American, German, and European collaborations have presented options for the "Future Linear Collider " (FLC). Key accelerator issues for any FLC option are the achievement of high enough energy and luminosity. Damping rings, taking advantage of the phenomenon of synchrotron radiation, have been developed as the means for decreasing beam size, which is crucial for ensuring a sufficiently high rate of particle-particle collisions. Related challenges are alignment and stability in an environment where even minute ground motion can disrupt performance, and the ability to monitor beam size. The technical challenges exist within a wider context of socioeconomi...

  3. Higgs Machine Learning Challenge 2014

    CERN Multimedia

    Olivier, A-P; Bourdarios, C ; LAL / Orsay; Goldfarb, S ; University of Michigan

    2014-01-01

    High Energy Physics (HEP) has been using Machine Learning (ML) techniques such as boosted decision trees (paper) and neural nets since the 90s. These techniques are now routinely used for difficult tasks such as the Higgs boson search. Nevertheless, formal connections between the two research fields are rather scarce, with some exceptions such as the AppStat group at LAL, founded in 2006. In collaboration with INRIA, AppStat promotes interdisciplinary research on machine learning, computational statistics, and high-energy particle and astroparticle physics. We are now exploring new ways to improve the cross-fertilization of the two fields by setting up a data challenge, following the footsteps of, among others, the astrophysics community (dark matter and galaxy zoo challenges) and neurobiology (connectomics and decoding the human brain). The organization committee consists of ATLAS physicists and machine learning researchers. The Challenge will run from Monday 12th to September 2014.

  4. 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…

  5. Success of Breast Cancer Startup Challenge Inspires Second Challenge | Poster

    Science.gov (United States)

    By Thomas Stackhouse, Joseph Conrad, and Michele Newton, Contributing Writers, and Rosemarie Truman, Guest Writer Sixty-one teams have been accepted into, and are now competing in, the Neuro Startup Challenge, a new collaboration established by the National Institutes of Health (NIH) with The Center for Advancing Innovation (CAI) and Heritage Provider Network, Inc.

  6. Challenged

    Science.gov (United States)

    Manzo, Kathleen Kennedy

    2006-01-01

    The work of librarians can be a lifeline to youths dealing with difficult personal issues, such as family strife, growing up, and sexuality. This paper presents an issue where school library books at Fayetteville High School are questioned because their books are too sexually explicit or mature for teenagers. In the midst of intense media coverage…

  7. ITER safety challenges and opportunities

    International Nuclear Information System (INIS)

    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

  8. Statistical Challenges in Modern Astronomy

    CERN Document Server

    Feigelson, E D

    2003-01-01

    Despite centuries of close association, statistics and astronomy are surprisingly distant today. Most observational astronomical research relies on an inadequate toolbox of methodological tools. Yet the needs are substantial: astronomy encounters sophisticated problems involving sampling theory, survival analysis, multivariate classification and analysis, time series analysis, wavelet analysis, spatial point processes, nonlinear regression, bootstrap resampling and model selection. We review the recent resurgence of astrostatistical research, and outline new challenges raised by the emerging Virtual Observatory. Our essay ends with a list of research challenges and infrastructure for astrostatistics in the coming decade.

  9. The challenges of big data.

    Science.gov (United States)

    Mardis, Elaine R

    2016-05-01

    The largely untapped potential of big data analytics is a feeding frenzy that has been fueled by the production of many next-generation-sequencing-based data sets that are seeking to answer long-held questions about the biology of human diseases. Although these approaches are likely to be a powerful means of revealing new biological insights, there are a number of substantial challenges that currently hamper efforts to harness the power of big data. This Editorial outlines several such challenges as a means of illustrating that the path to big data revelations is paved with perils that the scientific community must overcome to pursue this important quest. PMID:27147249

  10. Grand Challenges of Enterprise Integration

    Energy Technology Data Exchange (ETDEWEB)

    Brosey, W.D; Neal, R.E.; Marks, D.

    2001-04-01

    Enterprise Integration connects and combines people, processes, systems, and technologies to ensure that the right people and the right processes have the right information and the right resources at the right time. A consensus roadmap for Technologies for Enterprise Integration was created as part of an industry/government/academia partnership in the Integrated Manufacturing Technology Initiative (IMTI). Two of the grand challenges identified by the roadmapping effort will be addressed here--Customer Responsive Enterprises and Totally Connected Enterprises. Each of these challenges is briefly discussed as to the current state of industry and the future vision as developed in the roadmap.

  11. The challenges of big data

    Science.gov (United States)

    2016-01-01

    ABSTRACT The largely untapped potential of big data analytics is a feeding frenzy that has been fueled by the production of many next-generation-sequencing-based data sets that are seeking to answer long-held questions about the biology of human diseases. Although these approaches are likely to be a powerful means of revealing new biological insights, there are a number of substantial challenges that currently hamper efforts to harness the power of big data. This Editorial outlines several such challenges as a means of illustrating that the path to big data revelations is paved with perils that the scientific community must overcome to pursue this important quest. PMID:27147249

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

    CERN Document Server

    Babak, Stanislav; Benacquista, Matthew J; Cornish, Neil J; Larson, Shane L; Mandel, Ilya; Petiteau, Antoine; Porter, Edward K; Robinson, Emma L; Vallisneri, Michele; Vecchio, Alberto; Adams, Matt; Arnaud, Keith A; Błaut, Arkadiusz; Bridges, Michael; Cohen, Michael; Cutler, Curt; Feroz, Farhan; Gair, Jonathan R; Graff, Philip; Hobson, Mike; Key, Joey Shapiro; Królak, Andrzej; Lasenby, Anthony; Prix, Reinhard; Shang, Yu; Trias, Miquel; Veitch, John; Whelan, John T

    2009-01-01

    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 Apr 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 Omega_gw(f) ~ 10^-11, slightly below the LISA instrument noise.

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

    International Nuclear Information System (INIS)

    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 Ωgw(f) ∼ 10-11, slightly below the LISA instrument noise.

  15. 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.

  16. 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...

  17. The Concrete and Pavement Challenge

    Science.gov (United States)

    Roman, Harry T.

    2012-01-01

    The modern world is characterized by the extensive use of concrete and asphalt pavement. Periodically, these materials are replaced and the old materials disposed of. In this challenge, students will be asked to develop ways to reuse the old materials. It is important for students to understand how concrete and asphalt are made and applied, as…

  18. Challenges for cancer vaccine development.

    Science.gov (United States)

    Tabi, Z; Man, S

    2006-10-01

    The first generation of human cancer vaccines has been tested in phase III clinical trials, but only a few of these have demonstrated sufficient efficacy to be licensed for clinical use. This article reviews some of the mechanisms that could contribute to these limited clinical responses, and highlights the challenges faced for development of future vaccines. PMID:16979786

  19. Challenging Sexual Harassment on Campus

    Science.gov (United States)

    Baker, Nancy V.

    2010-01-01

    More than thirty years ago, an administrative assistant at Cornell University first challenged her university's indifference to her boss's sexually predatory behavior. While she did not prevail, her case sparked a movement. Litigation, news stories, and government guidelines defining sexual harassment followed. And universities responded: policies…

  20. Tuberculosis 2004: Challenges and Opportunities

    OpenAIRE

    Glassroth, Jeffrey

    2005-01-01

    Tuberculosis (TB) continues as a major public health challenge worldwide. HIV-TB coinfection is especially concerning as it accelerates progression of infection to active disease and amplifies spread of TB including drug resistant disease. Application of molecular biology and insights from classic microbiology to TB control have resulted in important innovations in diagnosis and treatment.

  1. CHALLENGES FACING THE ESP PRACTITIONER

    Directory of Open Access Journals (Sweden)

    SIMION MINODORA OTILIA

    2015-12-01

    Full Text Available The ESP teacher has to face certain challenges in his profession: One of the biggest challenges of the ESP teacher is the fact that he/she lacks the necessary knowledge of the subject to teach Business English, for instance, some researchers believing that such courses should be taught by subject teachers. The task of teaching ESP by ESL teachers is not an easy one. Dudley- Evans and St. John pointed out its complexity, identifying five key roles of the ESP practitioner: teacher, course designer and materials provider, collaborator, researcher and evaluator and this is probably the biggest challenge of the profession. The ESP practitioner has also to be aware of the fact that using a foreign language for workplace or study purposes requires not only linguistic proficiency and knowledge but also knowledge of work –related and disciplinary concepts.Last but not least, another challenge for the ESP practitioner is the use of technology in class, a valuable tool for helping with traditional forms of teaching and for creating new forms of communicating.Thus, the ESP practitioner has many things in common with the teacher of general English: he has to be familiar with linguistic development and teaching theories ,he has to be aware of contemporary ideas related to his position and role and he has to become familiar with the new technologies which can be used to improve his methodology.However,his role is more complex than that of a General English teacher.

  2. Plain language and organisational challenges

    DEFF Research Database (Denmark)

    Pedersen, Karsten

    2014-01-01

    Changing the language in an organization is a major organizational change. In this article, I discuss some of the organizational challenges for one specific language change implementation, taking the stance that language change must be treated as any other organizational change for it to have an ...

  3. The Real Challenge of ESD

    Science.gov (United States)

    Jackson, M. G.

    2011-01-01

    Between the Inter-governmental Conference on Environmental Education at Tbilisi in 1977 and the Fourth International Conference on Environmental Education at Ahmedabad in 2007, our conception of the challenge posed by the global crises of climate change, environmental destruction, social disintegration, poverty, natural resources exhaustion and…

  4. Challenges of blended-learning

    OpenAIRE

    Lugovtsova, Y. D.; Mylnikova, Tatyana Stepanovna

    2014-01-01

    Creation of the virtual environment as an educational resource to increase motivation and inquisition of the students is a great challenge for Russian educational system. The paper considers some issues of blended-learning. Some elements of blended-learning are analyzed through the ways they are implemented in Tomsk Polytechnic University.

  5. Climate Change: Meeting the Challenge

    Science.gov (United States)

    Chance, Paul; Heward, William L.

    2010-01-01

    In "Climate Change: Meeting the Challenge," we conclude the special section by assuming that you have been persuaded by Thompson's paper or other evidence that global warming is real and poses a threat that must be dealt with, and that for now the only way to deal with it is by changing behavior. Then we ask what you, as behavior analysts, can do…

  6. Efficient audio power amplification - challenges

    Energy Technology Data Exchange (ETDEWEB)

    Andersen, Michael A.E.

    2005-07-01

    For more than a decade efficient audio power amplification has evolved and today switch-mode audio power amplification in various forms are the state-of-the-art. The technical steps that lead to this evolution are described and in addition many of the challenges still to be faced and where extensive research and development are needed is covered. (au)

  7. The Speeding Car Design Challenge

    Science.gov (United States)

    Roman, Harry T.

    2009-01-01

    All too often, one reads about high-speed police chases in pursuit of stolen cars that result in death and injury to people and innocent bystanders. Isn't there another way to accomplish the apprehension of the thieves that does not put people at such great risk? This article presents a classroom challenge to use technology to remotely shutdown…

  8. The Health and Fitness Challenge.

    Science.gov (United States)

    Snelling, Anastasia M.

    1999-01-01

    "Health and Fitness Challenge" program was implemented using the "social marketing model" to raise awareness of health education and related services to students. Collaboration between faculty, student affairs professionals, and students occurred from design through evaluation. The primary goal of bringing students, faculty and staff together was…

  9. Accountability: new challenges, new forms

    NARCIS (Netherlands)

    C. van Woerkum; N. Aarts

    2012-01-01

    The general call for more accountability, affecting all western institutions, has reached the communication professionals as well. How can they cope with this new challenge? The danger is that they focus mainly on outcomes, so on performative accountability, whereas decisional accountability, meanin

  10. Challenges to 5G standardization

    DEFF Research Database (Denmark)

    Mihovska, Albena D.; Prasad, Ramjee

    2013-01-01

    Interoperable, ubiquitous and dynamic are key objectives for fifth-generation (5G) communication systems and applications. These characteristics are also at the core of the main challenges that researchers, manufacturers, regulators and standardization bodies face when designing targeted strategies...... for the successful deployment of 5G enabling technologies....

  11. A Water-Service Challenge

    Science.gov (United States)

    Roman, Harry T.

    2011-01-01

    It is important to let students see the value of mathematics in design--and how mathematics lends perspective to problem solving. In this article, the author describes a water-service challenge which enables students to design a water utility system that uses surface runoff into an open reservoir as the potable water source. This challenge…

  12. NASA Space Rocket Logistics Challenges

    Science.gov (United States)

    Neeley, James R.; Jones, James V.; Watson, Michael D.; Bramon, Christopher J.; Inman, Sharon K.; Tuttle, Loraine

    2014-01-01

    The Space Launch System (SLS) is the new NASA heavy lift launch vehicle and is scheduled for its first mission in 2017. The goal of the first mission, which will be uncrewed, is to demonstrate the integrated system performance of the SLS rocket and spacecraft before a crewed flight in 2021. SLS has many of the same logistics challenges as any other large scale program. Common logistics concerns for SLS include integration of discreet programs geographically separated, multiple prime contractors with distinct and different goals, schedule pressures and funding constraints. However, SLS also faces unique challenges. The new program is a confluence of new hardware and heritage, with heritage hardware constituting seventy-five percent of the program. This unique approach to design makes logistics concerns such as commonality especially problematic. Additionally, a very low manifest rate of one flight every four years makes logistics comparatively expensive. That, along with the SLS architecture being developed using a block upgrade evolutionary approach, exacerbates long-range planning for supportability considerations. These common and unique logistics challenges must be clearly identified and tackled to allow SLS to have a successful program. This paper will address the common and unique challenges facing the SLS programs, along with the analysis and decisions the NASA Logistics engineers are making to mitigate the threats posed by each.

  13. Efficient Audio Power Amplification - Challenges

    DEFF Research Database (Denmark)

    Andersen, Michael Andreas E.

    2005-01-01

    For more than a decade efficient audio power amplification has evolved and today switch-mode audio power amplification in various forms are the state-of-the-art. The technical steps that lead to this evolution are described and in addition many of the challenges still to be faced and where...

  14. The Kiki-Bouba Challenge

    DEFF Research Database (Denmark)

    Sturm, Bob L.; Collins, Nick

    2014-01-01

    We propose the “Kiki-Bouba Challenge” (KBC) for the re- search and development of content-based music informa- tion retrieval (MIR) systems. This challenge is unencum- bered by several problems typically encountered in MIR research: insufficient data, restrictive copyrights, imper- fect ground...

  15. Training Information Consumers: Today's Challenge.

    Science.gov (United States)

    Gordon, Dena W.

    The revolution in the information environment caused by new technology is making the training of information consumers a major challenge for publishers of business-targeted databases and vendors of online systems. Research conducted by Data Courier in 1981 and 1982 suggests that online searching by information consumers will continue to increase.…

  16. Challenges in a Physics Course

    DEFF Research Database (Denmark)

    Hernández, Carola Hernández; Ravn, Ole; Forero Shelton, Antonio Manu

    2014-01-01

    This article identifies and analyses some of the challenges that arose in a development process of changing from a content-based teaching environment to a student-centred environment in an undergraduate physics course for medicine and biology students at Universidad de los Andes. Through the use...

  17. Identification of a new lesch-nyhan syndrome mutation (HPRT BRASIL and analysis of potentially heterozygous females Identificação de uma nova mutação (HPRT BRASIL em uma família brasileira com a síndrome de Lesch-Nyhan e análise de mulheres potencialmente heterozigotas

    Directory of Open Access Journals (Sweden)

    PATRICK O'NEILL

    1999-12-01

    Full Text Available The mutation in the hypoxanthine-guanine phosphoribosyltransferase (HPRT gene has been determined in two brothers affected with Lesch-Nyhan syndrome. Female members of the family who are at risk for being heterozygous carriers of the HPRT mutation were also studied to determine whether they carry the mutation. DNA sequencing revealed that the boys' mother is heterozygous for the mutation in her somatic cells, but that three maternal aunts are not heterozygous. Such carrier information is important for the future pregnancy plans of at-risk females. The mutation, an A-->T transversion at cDNA base 590 (590A-->T, results in an amino acid change of glutamic acid to valine at codon 197, and has not been reported previously in a Lesch-Nyhan syndrome male. This mutation is designated HPRT Brasil.Uma mutação no gene hipoxantina-guanina fosforibosiltransferase (HPRT foi determinada em dois irmãos afetados pela síndrome de Lesch-Nyhan. O sequenciamento do cDNA do gene HPRT das mulheres desta família, potencialmente portadoras heterozigotas da mutação HPRT, que é uma transissão de A-->T na base 590 do cDNA (590A-->T, revelou que a mãe dos meninos é heterozigota para esta mutação, mas que três tias maternas não são heterozigotas. Este tipo de informação é importante no planejamento de gestações futuras, nas mulheres em risco. Como esta mutação ainda não havia sido relatada em indivíduos do sexo masculino na síndrome de Lesch-Nyhan, foi, portanto, denominada HPRT Brazil.

  18. Success of Breast Cancer Startup Challenge Inspires Second Challenge | Poster

    Science.gov (United States)

    By Thomas Stackhouse, Joseph Conrad, and Michele Newton, Contributing Writers, and Rosemarie Truman, Guest Writer Sixty-one teams have been accepted into, and are now competing in, the Neuro Startup Challenge, a new collaboration established by the National Institutes of Health (NIH) with The Center for Advancing Innovation (CAI) and Heritage Provider Network, Inc.

  19. The use of rabbits in atherosclerosis research. Diet and drug intervention in different rabbit models exposed to selected dietary fats and the calcium antagonist (-)-anipamil : evaluation and comparison of rabbit models

    OpenAIRE

    Mortensen, Alicja

    1995-01-01

    Laboratory animal models play an important role in atherosclerosis research. One of the most popular laboratory animal species in this field of research is the rabbit. The rabbit fulfils most of the criteria for an animal model for human atherosclerosis. Three rabbit models were established and used for dietary or drug intervention: 1) the cholesterol-fed normolipidemic rabbit, 2) the 1% cholesterol- fed heterozygous Watanabe heritable hyperlipidemic (WHHL) rabbit and ...

  20. Novel compound heterozygous mutations of TGM1 gene identified in a Chinese collodion baby%一例火棉胶婴儿TGM1基因新的复合杂合性突变鉴定

    Institute of Scientific and Technical Information of China (English)

    张永玲; 岳智慧; 袁萍; 周庆; 黄玮俊; 胡彬; 王一鸣

    2012-01-01

    Objective To identify potential mutations in a Chinese collodion baby.Methods The patient was investigated clinically.DNA was extracted from peripheral blood of the baby and his parents.All coding exons (exons 2-15) and splicing sites of transglutaminase 1 (TGM1) were amplified by polymerase chain reaction (PCR).Mutation detection was performed by directed sequencing of the PCR products.A total of 100 healthy unrelated subjects were used as controls.Haplotypes were constructed with microsatellites flanking the locus,and TGM1 genotypes of the family were used to determine parental origins of the mutations.CLUSTAL X (1.81) was employed to analyze cross-species conservation of the mutant protein sequence. Results The boy was found to be a compound heterozygote for two novel mutations:c.420A>G (I140M) from his father and c.832G>A (G278R) from his mother,with the former occurring in the transglutaminase N domain and the latter between transglutaminase N and transglutaminase-like domains.Both mutations were absent from the control subjects.Conclusion The boy's condition was caused by two novel compound heterozygous mutations of c.420A>G and c.832G>A of TGM1.Author's results may provide new clues for molecular diagnosis of this disease.%目的 鉴定1例火棉胶婴儿转谷氨酰胺酶1基因(transglutaminase 1,TGM1)的致病性突变.方法 提取患儿及其父母的外周血DNA,PCR扩增TGM1基因的编码及剪切位点序列,对PCR产物进行直接测序.同时检测100名无血缘关系的正常人作为对照.用TGM1邻近的微卫星标记在家系中构建单倍型以确定突变的来源.应用CLUSTAL X(1.81)软件分析突变氨基酸的跨种属保守性.结果 患儿携带了TGM1的两个复合杂合性突变:c.420A>G (I140M)及c.832G>A (G278R),均为国际上未报道过的新突变.两个错义突变均造成了TGM1蛋白内高度保守区的氨基酸置换.突变c.420A>G (I140M)遗传自父亲,位于蛋白的转谷氨

  1. Challenges in Complex Systems Science

    CERN Document Server

    Miguel, Maxi San; Kertesz, Janos; Kaski, Kimmo; Díaz-Guilera, Albert; MacKay, Robert S; Loreto, Vittorio; Erdi, Peter; Helbing, Dirk

    2012-01-01

    FuturICT foundations are social science, complex systems science, and ICT. The main concerns and challenges in the science of complex systems in the context of FuturICT are laid out in this paper with special emphasis on the Complex Systems route to Social Sciences. This include complex systems having: many heterogeneous interacting parts; multiple scales; complicated transition laws; unexpected or unpredicted emergence; sensitive dependence on initial conditions; path-dependent dynamics; networked hierarchical connectivities; interaction of autonomous agents; self-organisation; non-equilibrium dynamics; combinatorial explosion; adaptivity to changing environments; co-evolving subsystems; ill-defined boundaries; and multilevel dynamics. In this context, science is seen as the process of abstracting the dynamics of systems from data. This presents many challenges including: data gathering by large-scale experiment, participatory sensing and social computation, managing huge distributed dynamic and heterogeneou...

  2. The Higgs Machine Learning Challenge

    Science.gov (United States)

    Adam-Bourdarios, C.; Cowan, G.; Germain-Renaud, C.; Guyon, I.; Kégl, B.; Rousseau, D.

    2015-12-01

    The Higgs Machine Learning Challenge was an open data analysis competition that took place between May and September 2014. Samples of simulated data from the ATLAS Experiment at the LHC corresponding to signal events with Higgs bosons decaying to τ+τ- together with background events were made available to the public through the website of the data science organization Kaggle (kaggle.com). Participants attempted to identify the search region in a space of 30 kinematic variables that would maximize the expected discovery significance of the signal process. One of the primary goals of the Challenge was to promote communication of new ideas between the Machine Learning (ML) and HEP communities. In this regard it was a resounding success, with almost 2,000 participants from HEP, ML and other areas. The process of understanding and integrating the new ideas, particularly from ML into HEP, is currently underway.

  3. Terahertz applications: trends and challenges

    Science.gov (United States)

    Robin, Thierry; Bouye, Clementine; Cochard, Jacques

    2014-03-01

    The objective of our work [1] was to determine the opportunities and challenges for Terahertz application development for the next years with a focus on systems: for homeland security and for Non Destructive Testing (NDT). Terahertz radiation has unique abilities and has been the subject of extensive research for many years. Proven concepts have emerged for numerous applications including Industrial NDT, Security, Health, Telecommunications, etc. Nevertheless, there has been no widely deployed application and Businesses based on THz technologies are still in their infancy. Some technological, market and industrial barriers are still to be broken. We summarize the final analysis and data: study of the technology trends and major bottlenecks per application segment, main challenges to be addressed in the next years, key opportunities for THz technologies based on market needs and requirements.

  4. The Higgs Machine Learning Challenge

    CERN Document Server

    Cowan, Glen; Adam-Bourdarios, C; Kégl, B; Rousseau, D; Germain-Renaud, C; Guyon, I

    2015-01-01

    The Higgs Machine Learning Challenge was an open data analysis competition that took place between May and September 2014. Samples of simulated data from the ATLAS Experiment at the LHC corresponding to signal events with Higgs bosons decaying to $\\tau^+\\tau^-$ together with background events were made available to the public through the website of the data science organization Kaggle (\\verb=kaggle.com=). Participants attempted to identify the search region in a space of 30 kinematic variables that would maximize the expected discovery significance of the signal process. One of the primary goals of the Challenge was promote communication of new ideas between the Machine Learning (ML) and HEP communities. In this regard it was a resounding success, with almost 2,000 participants from HEP, ML and other areas. The process of understanding and integrating the new ideas, particularly from ML into HEP, is currently underway.

  5. Smart textiles: Challenges and opportunities

    Science.gov (United States)

    Cherenack, Kunigunde; van Pieterson, Liesbeth

    2012-11-01

    Smart textiles research represents a new model for generating creative and novel solutions for integrating electronics into unusual environments and will result in new discoveries that push the boundaries of science forward. A key driver for smart textiles research is the fact that both textile and electronics fabrication processes are capable of functionalizing large-area surfaces at very high speeds. In this article we review the history of smart textiles development, introducing the main trends and technological challenges faced in this field. Then, we identify key challenges that are the focus of ongoing research. We then proceed to discuss fundamentals of smart textiles: textile fabrication methods and textile interconnect lines, textile sensor, and output device components and integration of commercial components into textile architectures. Next we discuss representative smart textile systems and finally provide our outlook over the field and a prediction for the future.

  6. Challenges in pediatric endothelial keratoplasty

    Directory of Open Access Journals (Sweden)

    Vikas Mittal

    2014-01-01

    Full Text Available We performed endothelial keratoplasty (EK in three eyes of two siblings (2.5 years, male and 3.5 years, female with congenital hereditary endothelial dystrophy (CHED and report the intraoperative and postoperative difficulties. Repeated iris prolapse, apprehension of crystalline lens touch due to positive vitreous pressure, and need for frequent air injections to attach the graft were intraoperative challenges in all three eyes. These were addressed by use of Sheet′s glide instead of Busin′s glide during graft insertion and suturing of main and side ports before air injection. One eye had graft dislocation on second postoperative day due to eye rubbing by the child. Graft was repositioned with air and a venting incision was created. Postoperative examination required repeated general anesthesia. Corneal edema resolved completely in all three eyes. Present case series highlights the possible intraoperative and postoperative challenges and their solutions in pediatric EK for CHED.

  7. Challenges for Research on Intelligence

    Directory of Open Access Journals (Sweden)

    Earl Hunt

    2013-10-01

    Full Text Available After 100 years of research, the definition of the field is still inadequate. The biggest challenge we see is moving away from a de-factor definition of intelligence in terms of test scores, but at the same time making clear what the boundaries of the field are. We then present four challenges for the field, two within a biological and two within a social context. These revolve around the issues of the malleability of intelligence and its display in everyday life, outside of a formal testing context. We conclude that developments in cognitive neuroscience and increases in the feasibility of monitoring behavior outside of the context of a testing session offer considerable hope for expansion of our both the biological and social aspects of individual differences in cognition.

  8. Challenges of Human Space Flight

    Science.gov (United States)

    Davis, Jeffrey R.; Charles, John B.

    2006-01-01

    The presentations will be given during the X-Prize symposium, exploring the multi-faceted dimensions of spaceflight ranging from the technical developments necessary to achieve safe routine flight to and from and through space to the new personal business opportunities and economic benefits that will open in space and here on Earth. The symposium will delve into the technical, regulatory, market and financial needs and challenges that must be met in charting and executing the incremental developments leading to Personal Spaceflight and the opening of a Place Called Space. The presentation covers facets of human space flight including descriptions of life in space, the challenges of delivering medical care in space, and the preparations needed for safe and productive human travel to the moon and Mars.

  9. Embracing the challenge of competition

    Energy Technology Data Exchange (ETDEWEB)

    MacDonald, C. [Edmonton Power Inc., Edmonton, AB (Canada)

    1998-07-01

    The new and creative solutions that Edmonton Power is using to meet the challenges of deregulation, competition and demand for customer choice in the electric power industry are discussed. Among these creative initiatives, in 1997 Edmonton Power extended account management services to 850 accounts to deliver commercial and operational analysis of energy consumption and management. Another major focus of effort has been the introduction of time of use (TOU) pricing options to commercial and industrial customers above 150 kWh. This required the installation of the latest hourly metering technology and the establishment of new price plans and contracts. Two major challenges were highlighted: (1) the mismatch between the prices utilities pay at the power pool and what the customer pays at the meter, and (2) the increased volatility of hour to hour price changes are just some of the risks that will have to be resolved under the new market structure.

  10. Challenges in Regulating Pesticide Mixtures

    OpenAIRE

    Debra Denton; Bruce Hammock; Craig Wheelock; Jason Belden; Michael Lydy

    2004-01-01

    This paper introduces the field of mixture toxicity and the challenges in regulating pesticide mixtures. Even though pesticides are unique chemical stressors designed to have biological activity that can affect a number of nontarget species, they are intentionally placed into the environment in large quantities. Currently, methods and terminology for evaluating mixture toxicity are poorly established. The most common approach used is the assumption of additive concentration, with the concentr...

  11. ETHICAL CHALLENGES IN AESTHETIC DENTISTRY

    OpenAIRE

    Marius NEAGU; Bianca HANGANU; Magdalena IORGA; Beatrice IOAN

    2015-01-01

    Aesthetic dentistry is a branch of dentistry which aims primarily at improving patient’s physical appearance and, to a lesser extent, the functionality of teeth. This field raises particular ethical dilemmas and requires a careful evaluation of patient’s needs and wishes versus his/her clinical best interests. In this article, the authors discuss the main ethical challenges in the field of aesthetic dentistry in the light of the four “classical” principles of bioethics: autonomy, beneficence,...

  12. The challenges of managing migration

    Energy Technology Data Exchange (ETDEWEB)

    Tacoli, Cecilia

    2005-10-15

    Migration and urbanisation are driven by economic growth and social change, but also by deepening inequalities. Managing migration should not be equated with curbing it, as this inevitably reduces migrants' rights. But managing population movement whilst respecting the rights of migrants and nonmigrants, supporting the contribution of migration to poverty reduction and economic growth in sending and receiving areas and reducing the human and material costs of movement means that fundamental challenges need to be addressed.

  13. Computational photography: advances and challenges

    OpenAIRE

    Lam, EYM

    2011-01-01

    In the mid-1990s when digital photography began to enter the consumer market, Professor Joseph Goodman and I set out to explore how computation would impact the imaging system design. The field of study has since grown to be known as computational photography. In this paper I'll describe some of its recent advances and challenges, and discuss what the future holds. © 2011 Copyright Society of Photo-Optical Instrumentation Engineers (SPIE).

  14. Diagnostic challenges in celiac disease

    Directory of Open Access Journals (Sweden)

    M Haghighat

    2014-04-01

    Full Text Available   1-The most important challenge in diagnosis of celiac disease is not- performing the diagnostic tests in suspected persons. Because of multi-organ damage and multiple manifestations of disease, diagnosis of celiac disease may be delayed. It seems general physicians should be awared about uncommon presentations of disease and indications of celiac tests 2-The second most important challenge is in patients with suspected disease but negative serologic tests. In these cases evaluating of HLA can be useful. 3- The third challenge is in cases with positive serologic tests but negative histopathological findings. There may be false positive serologic response or consumption of gluten before testing. We recommend introduction of gluten for at least 3 mo and re- endoscopy and if diagnosis is equivocal HLA-typing  for DQ8 and  DQ2 should be done. 4-The forth challenge is about performing endoscopy. Based on guideline from ESPGHAN if there are typical clinical manifestations of celiac disease, Anti-TTG more than ten times UPN , positive Anti-EMA and HLA DQ2, performing endoscopy may not be necessary, but many physicians don’t agree with this idea. 5-In people who are genetically predisposed to celiac disease antibody levels may be fluctuating thus endoscopy with biopsy should be done in these patients. 6-In children lower than 2years, Anti- TTG and Anti –EMA have low sensitivity. we recommend Anti-TTG and Anti-DGP in these patients. 7-Resolution of symptoms after gluten free diet is not necessarily a feature of celiac disease. This condition may be seen in patients with IBS or non-celiac gluten sensitivity.  

  15. Economic challenges in the Anthropocene

    OpenAIRE

    Musu, Ignazio

    2013-01-01

    The evolution during the Anthropocene is analyzed through the interaction between economic and technological development, characterized by the role of fossil fuels and by the progressive dominance of those with a higher energy and density power. The challenge is how to make the rising demand for economic growth, mainly coming from developing and emerging countries, compatible with the sustainability of the processes concerning the Earth system. Mainly by focusing on the energy-environment cha...

  16. Challenges of operational river forecasting

    OpenAIRE

    T. C. Pagano; Wood, A.W.; Ramos, M.H.; H. L. Cloke; Pappenbreger, F.; Verkade, J. S.; et al, ...

    2014-01-01

    Skillful and timely streamflow forecasts are critically important to water managers and emergency protection services. To provide these forecasts, hydrologists must predict the behavior of complex coupled human–natural systems using incomplete and uncertain information and imperfect models. Moreover, operational predictions often integrate anecdotal information and unmodeled factors. Forecasting agencies face four key challenges: 1)making themost of available data, 2)making accurate predictio...

  17. Challenges in PFBR civil construction

    International Nuclear Information System (INIS)

    Civil works of PFBR has posed numerous design and construction challenges. Eight safety related nuclear buildings of PFBR are founded on a single raft, first of its kind in Indian nuclear Reactors. Construction of eight interconnected buildings on the common raft has been challenge for construction material transportation. Thus Herculean task, require storage of massive quantities of raw materials and ice. The civil construction scope in PFBR expanded to critical steel fabricated structures integrated with civil works. This includes huge embedment erected to very close tolerances. Large size panels for upper lateral, lower lateral and bottom shields were to be fabricated to intricate contours with tight tolerances and were required to be transported to locations from far off distances; this was well accomplished without loss of tolerances of fabricated structures. Novel construction practices and stringent quality control procedures were implemented to accomplish this critical requirement. Integration of cooling coils inside the safety vessel flanges after completing the reactor vault and safety vessel erection, required special contour bending for numerous reinforcement and development of special construction methodology. The neutron detector box integration with bottom shield was also a construction challenge posed and well addressed by site. Many mock ups were to be carried out for demonstrating the construction procedures and methodology for critical construction activities. Maintaining the stringent requirements such as clean room conditions was a major challenge and was met effectively. Equipment erection in parallel to civil works too required innovative solutions for clean condition maintenance while civil works are in progress. it can be said that the civil construction of PFBR has emerged as a marvel of technology handled professionally by competent engineers deploying scientific construction techniques and stringent quality control procedures. (author)

  18. Challenges of operational river forecasting

    OpenAIRE

    T. C. Pagano; Wood, A.W.; Ramos, M.H.; H. L. Cloke; Pappenberger, F.; Clark, M. P.; Cranston, M.; Kavetski, D.; T. Mathevet; Sorooshian, S; Verkade, J. S.

    2014-01-01

    Skillful and timely streamflow forecasts are critically important to water managers and emergency protection services. To provide these forecasts, hydrologists must predict the behavior of complex coupled human–natural systems using incomplete and uncertain information and imperfect models. Moreover, operational predictions often integrate anecdotal information and unmodeled factors. Forecasting agencies face four key challenges: 1) making the most of available data, 2) making accurate ...

  19. EMU Challenges European Labor Markets

    OpenAIRE

    Soltwedel, Rüdiger; Dohse, Dirk; Krieger-Boden, Christiane

    1999-01-01

    This paper discusses the challenges that European Monetary Union (EMU) poses for European labor markets, emphasizing in particular the regional dimension of the European unemployment problem. The authors argue that the inability of labor markets to adjust to shocks is largely a regional problem within EMU member countries, requiring structural reforms to enhance labor market flexibility bur also a decentralization of competencies and greater diversity of labor market outcomes. Any attempt to ...

  20. PETS 2014: dataset and challenge

    OpenAIRE

    Patino, Luis; Ferryman, James

    2015-01-01

    This paper describes the dataset and vision challenges that form part of the PETS 2014 workshop. The datasets are multisensor sequences containing different activities around a parked vehicle in a parking lot. The dataset scenarios were filmed from multiple cameras mounted on the vehicle itself and involve multiple actors. In PETS2014 workshop, 22 acted scenarios are provided of abnormal behaviour around the parked vehicle. The aim in PETS 2014 is to provide a standard benchmark that indicate...

  1. Challenges in global genomics education

    Directory of Open Access Journals (Sweden)

    Ashwini de Abrew

    2014-12-01

    Full Text Available In spite of high expectations for the integration of genomics into medicine, it is not clear that health providers are competent to appropriately use new genomic approaches. The issue is further complicated by differences across the globe in terms of educational systems, access to genomic technologies, and priorities in health care. In this commentary we will review some of the major challenges in educating the health provider workforce about genomic medicine.

  2. Challenges Facing Entrepreneurship in Nigeria

    OpenAIRE

    Onyeka Uche Ofili

    2014-01-01

    Entrepreneurship is critical to the development of societies. Entrepreneurs however, cannot work in isolation; they need the right environment to thrive. The judicial system, the educational system, the financial system and generalgovernment policies should be such that encourage and promote entrepreneurship. Basic infrastructures such aspower, water, and transport systems are necessary to boost entrepreneurship. This paper looks at the challenges facing entrepreneurship in Nigeria and recomm...

  3. Statistical Challenges in Functional Genomics

    OpenAIRE

    Sebastiani, Paola; Gussoni, Emanuela; Kohane, Isaac S.; Ramoni, Marco F

    2003-01-01

    On February 12, 2001 the Human Genome Project announced the completion of a draft physical map of the human genome---the genetic blueprint for a human being. Now the challenge is to annotate this map by understanding the functions of genes and their interplay with proteins and the environment to create complex, dynamic living systems. This is the goal of functional genomics. Recent technological advances enable biomedical investigators to observe the genome of entire orga...

  4. The 5-second marketing challenge

    OpenAIRE

    Wilson, Jonathan

    2015-01-01

    Talk by: Dr Jonathan A.J. Wilson, looking at the challenges of marketing and advertising on social media - in the face of shorter attention spans and greater clutter. (Introduction by Iwan Setiwan in Bahasa Indonesia) At: the MarkPlus Inc. and KIN ASEAN Kellogg Innovation Network Annual Conference. To: an audience of 5,000 marketing delegates. In: The Ritz Carlton Pacific Place Hotel Ballroom, Jakarta, Indonesia. On: 10th December 2015. Having already delivered his confer...

  5. Challenges for Contextualizing Language Learning

    DEFF Research Database (Denmark)

    Eskildsen, Søren; Rehm, Matthias

    2013-01-01

    To help facilitate language learning for immigrants or foreigners arriving to another culture and language, we propose a context-aware mobile application. To expand on the known elements like location, activity, time and identity, we investigate the challenges on including cultural awareness to...... ensure a better experience-based learning. We present methods used to collect information about everyday activities collected by immigrants or foreigners. This information will help structuring language learning assignments presented through the context-aware mobile application....

  6. Plain language and organisational challenges

    OpenAIRE

    Pedersen, Karsten

    2014-01-01

    Changing the language in an organization is a major organizational change. In this article, I discuss some of the organizational challenges for one specific language change implementation, taking the stance that language change must be treated as any other organizational change for it to have an effect. I work with the case of the Danish tax authorities’ language project aimed at producing more readable letters. The empirical data that I work with are two qualitative informant interviews. One...

  7. Proceedings: International conference Reforestation Challenges

    OpenAIRE

    Vladan Ivetić; Dragica Stanković

    2015-01-01

    This book of Proceedings compiles 35 papers presented by researchers and scientists at The International Conference on Reforestation Challenges. Topics included various aspects of reforestation: 1) Planning and management of reforestation programs; 2) Stocktypes and seedlings quality; 3) Monitoring reforestation successes; 4) Planting and seedling-site interaction; 5) Species, intra-species and seed source selection and 6) Plant health in nurseries and plantations. In addition to country repo...

  8. Challenges of aircraft design integration

    OpenAIRE

    Kafyeke, F.; Abdo, M.; Pepin, F; Piperni, P.; Laurendeau, E.

    2007-01-01

    The design of a modern airplane brings together many disciplines: structures, aerodynamics, controls, systems, propulsion with complex interdependencies and many variables. Recent aircraft programs, such as Bombardier's Continental Jet program use participants located around the world and selected for their cost, quality and delivery capability. These participants share the risk on the program and must therefore be fully implicated in the design. A big challenge is to provide information on c...

  9. Challenges and Advances in Nanotoxicology

    Directory of Open Access Journals (Sweden)

    Robert L. Tanguay

    2014-08-01

    Full Text Available This Special Issue of Nanomaterials examines the potential for engineered nanomaterials to negatively impact biological systems and highlights some advances in evaluating key areas of their hazard potential. Nanomaterial science is evolving rapidly with the generation of more complex nanostructures with exciting potential applications. Keeping modern toxicology abreast of this innovation to the point that it guides a safer nanotechnology presents an equally exciting and eminently worthwhile challenge. [...

  10. A Challenge to Entropic Gravity

    OpenAIRE

    Roveto, Jonathan J.; Munoz, Gerardo

    2012-01-01

    In a recent publication in this journal, Erik Verlinde attempts to show that gravity should be viewed not as a fundamental force, but rather as an emergent thermodynamic phenomenon arising from an unspecified microscopic theory via equipartition and holography. This paper presents a challenge to his reformulation of gravity. A detailed examination of Verlinde's derivation leads to a number of questions that severely weaken the claim that such a theory correctly reproduces Newton's laws or Ein...

  11. Challenges to sustainable risk management

    Energy Technology Data Exchange (ETDEWEB)

    Pinto, Ariel C., Aurora, Ashish, Hall, Dennis E.,

    2004-08-09

    This paper summarizes the intermediate lessons learned from the analyses of the risk management problems in three technological endeavors. These problems are: the absence of a structure for rewarding successful project risk management; the need for an ever-more accurate economic measure of risk; and the difficulty of transferring risks to contract-bound independent outsourcing entity. This paper also describes recent advancement towards providing answers to these challenges and future research endeavors in this field.

  12. Challenges for Contextualizing Language Learning

    DEFF Research Database (Denmark)

    Eskildsen, Søren; Rehm, Matthias

    To help facilitate language learning for immigrants or foreigners arriving to another culture and language, we propose a context-aware mobile application. To expand on the known elements like location, activity, time and identity, we investigate the challenges on including cultural awareness to...... ensure a better experience-based learning. We present methods used to collect information about everyday activities collected by immigrants or foreigners. This information will help structuring language learning assignments presented through the context-aware mobile application....

  13. Mathematical challenges in integrative physiology

    OpenAIRE

    Brook, B.S.; Waters, S. L.

    2008-01-01

    Traditional approaches to biomedical research are based on the subdivision of biological systems—by length (or time) scales (body, organ, tissue, cell, and molecule), discipline (biology, physiology, bioengineering, etc.), or sub-systems (cardiovascular, musculoskeletal, gastrointestinal, etc.). These subdivisions, however, make it difficult to unravel the systemic nature of the mechanisms that govern many of the (patho-) physiological processes in the human body. The challenge now is to comp...

  14. Challenges when introducing electronic exam

    Directory of Open Access Journals (Sweden)

    Matti Kuikka

    2014-10-01

    Full Text Available Time pressures often necessitate the use of more efficient exam tools, such as electronic exams (e-exams, instead of traditional paper exams. However, teachers may face challenges when introducing e-exams in a higher education context. This paper describes what kinds of challenges teachers may face when introducing e-exams, based on experiences in Turku University of Applied Sciences (TUAS where e-exams have been used since 2012. For this research, the authors used their personal experiences as administrators and teachers of current e-systems used for e-exams in universities in Turku, Finland. Quantitative data were collected by survey from teachers in TUAS (the case study. The learning management systems, Moodle, Optima and ViLLE, and dedicated e-examination systems, Soft Tutor and Tenttis, were also compared to clarify what kind of features are available in order to ease teachers’ work with examinations. The results identified various challenges during e-exam introduction in TUAS. The paper also provides a list of essential services or features for teachers to ease the introduction of e-exams. Among the analysed systems, ViLLE supported most of the required features, and can be used for both learning management and e-examination systems, providing teachers with one single system, which was found to be important to teachers. The key service found by this paper is ‘support for teachers’, which is in line with previous studies.

  15. Flue gas desulphurization retrofit challenge

    International Nuclear Information System (INIS)

    The challenges faced by the Suncor Oil Sands Group when retrofitting a flue gas desulphurization (FGD) plant were discussed. The objectives of the retrofit were to: (1) reduce SO2 emissions from three 750,000 lb/hr coke fired boilers to the lesser of 24 tonnes per day or 0.17 ppm per hour, (2) achieve a plant 98 per cent on-line factor, and (3) no increase in particulate emission. The process chosen was the Thoroughbred CT-121 wet limestone FGD process patented by Chiyoda of Japan in which boiler flue gas bubbles through a limestone slurry liquor in a jet bubbling reactor (JBR). The reaction to convert the SO2 in the flue gas to hydrated gypsum takes place in the JBR with the addition of oxidizing air. The project faced several challenges because of materials selection, design changes, weather, the need for uninterrupted boiler operation and plant location. The challenges were overcome and the project now operates to specifications, achieving greater than 95 per cent reduction of SO2 emissions. 9 figs

  16. Challenges in complex systems science

    Science.gov (United States)

    San Miguel, M.; Johnson, J. H.; Kertesz, J.; Kaski, K.; Díaz-Guilera, A.; MacKay, R. S.; Loreto, V.; Érdi, P.; Helbing, D.

    2012-11-01

    FuturICT foundations are social science, complex systems science, and ICT. The main concerns and challenges in the science of complex systems in the context of FuturICT are laid out in this paper with special emphasis on the Complex Systems route to Social Sciences. This include complex systems having: many heterogeneous interacting parts; multiple scales; complicated transition laws; unexpected or unpredicted emergence; sensitive dependence on initial conditions; path-dependent dynamics; networked hierarchical connectivities; interaction of autonomous agents; self-organisation; non-equilibrium dynamics; combinatorial explosion; adaptivity to changing environments; co-evolving subsystems; ill-defined boundaries; and multilevel dynamics. In this context, science is seen as the process of abstracting the dynamics of systems from data. This presents many challenges including: data gathering by large-scale experiment, participatory sensing and social computation, managing huge distributed dynamic and heterogeneous databases; moving from data to dynamical models, going beyond correlations to cause-effect relationships, understanding the relationship between simple and comprehensive models with appropriate choices of variables, ensemble modeling and data assimilation, modeling systems of systems of systems with many levels between micro and macro; and formulating new approaches to prediction, forecasting, and risk, especially in systems that can reflect on and change their behaviour in response to predictions, and systems whose apparently predictable behaviour is disrupted by apparently unpredictable rare or extreme events. These challenges are part of the FuturICT agenda.

  17. CHALLENGES IN CROSS CULTURAL ADVERTISING

    Directory of Open Access Journals (Sweden)

    Yuni Retnowati

    2015-10-01

    Full Text Available At first, marketing practitioners and academics consider standardized approaches to marketing and advertising strategies in globalization, and then some studies proved that the standardization of advertising across culture is not valid. Therefore, cross cultural advertising takes local culture into account when conveying messages in advertisements. Cross cultural understanding is very important in order to produce successful localized advertising that would reflect the cultural values and norms of intended audience. Challenge in cross cultural advertising is the problem of communicating to people of diverse cultural background. Cross cultural solutions are applied in areas such as language, communication style, images and cultural values. Cross cultural advertising is simply about using common sense and analyzing how the different elements of an advertising campaign are impacted by culture and modifying them to best speak to the target audience. Other challenges are determining between standardization and adaptation of cultural values content of advertising when facing different people from diverse cultures. In academic side, the challenge is preparing students to design advertisements that communicate effectively to diverse cultures.

  18. Challenges in tropical plant nematology.

    Science.gov (United States)

    De Waele, Dirk; Elsen, Annemie

    2007-01-01

    A major challenge facing agricultural scientists today is the need to secure food for an increasing world population. This growth occurs predominantly in developing, mostly tropical countries, where the majority of hungry people live. Reducing yield losses caused by pathogens of tropical agricultural crops is one measure that can contribute to increased food production. Although plant-parasitic nematodes are often not as important as some other biotic and nonbiotic constraints on crop production in the tropics, they can nevertheless cause extensive damage and substantial yield losses. The effects of agricultural, environmental, socioeconomic, and policy changes on the occurrence of plant-parasitic nematodes in the tropics and the losses these pathogens cause are largely undocumented. Recent developments pose new challenges to tropical nematology. The increased application of molecular diagnostics may widen the knowledge gap between nematologists working in developed countries and in the tropics. Uncertainties concerning the validity of nematode species will lead to practical problems related to quarantine measures and nematode management. The study of interactions between nematodes and other pathogens in disease complexes provide opportunities for multidisciplinary research with scientists from other disciplines but remain underexploited. Difficulties in recognizing emerging nematode threats prevent the timely implementation of management strategies, thus increasing yield losses. Research is needed to address these challenges. Examples are presented mainly but not exclusively from banana, peanut, and rice nematology. PMID:17489690

  19. International Collaboration: Promises and Challenges

    Directory of Open Access Journals (Sweden)

    R. Jay Widmer

    2015-04-01

    Full Text Available Rambam Maimonides Medical Journal 2015 April; 6(2: e0012. ISSN: 2076-9172 Published online 2015 April 29. Special Issue on the Rambam-Mayo Collaboration Guest Editor: John H. Davidson, M.D., M.A.H.L. doi: 10.5041/RMMJ.10196. International Collaboration: Promises and Challenges R. Jay Widmer, M.D., Ph.D.,1 Jocelyn M. Widmer, Ph.D., M.P.H.,2 and Amir Lerman, M.D.1* 1Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic and College of Medicine, Rochester, MN, USA; 2Department of Urban and Regional Planning, College of Design, Construction and Planning, University of Florida, Gainesville, FL, USA Conflict of interest: No potential conflict of interest relevant to this article was reported. * To whom correspondence should be addressed. E-mail: lerman.amir@mayo.edu Copyright: © 2015 Widmer et al. This is an open-access article. All its content, except where otherwise noted, is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract We currently face a myriad of grand global challenges in fields such as poverty, the environment, education, science, and medicine. However, our current means of dealing with such challenges has fallen short, and ingenious solutions are required to overcome the inherent resistance to progress toward ameliorating such difficulties. Here, we highlight the promises and challenges of international collaboration in achieving success toward these trials. We note prior successes in fields such as education, medicine, science, and environmental issues made to date, yet at the same time we do note deficiencies and shortcomings in these efforts. Hence, the notion of international collaboration should be strengthened and encouraged by governments, non-profit organizations, and others moving forward using creative

  20. 75 FR 21044 - Notice of Centennial Challenges 2011 CAFE Green Flight Challenge

    Science.gov (United States)

    2010-04-22

    ... SPACE ADMINISTRATION Notice of Centennial Challenges 2011 CAFE Green Flight Challenge AGENCY: National Aeronautics and Space Administration (NASA). ACTION: Notice of Centennial Challenges 2011 CAFE Green Flight... Flight Challenge is scheduled and teams that wish to compete may register. Centennial Challenges is...

  1. Addressing verification challenges [International safeguards symposium on addressing verification challenges

    International Nuclear Information System (INIS)

    In his welcome address the Director General of the International Atomic Energy Agency (IAEA), Mr. M. ElBaradei, stated that safeguards activities are probably the most difficult task entrusted to an international organization and to determine all the details of a country's nuclear programme is a daunting challenge that raises a number of questions. There is an increase in nuclear power around the globe as a result of shortages of energy and concerns about energy independence and climate change. On the one hand, this is good, because without energy there is no hope for development on the other hand, however, it means that nuclear know-how and nuclear technology will continue to spread to more and more countries. There is also an increase in the number of countries interested in developing nuclear fuel cycle capabilities: sensitive fuel cycle activities, reprocessing and above all uranium enrichment. It even seems that some countries might be hedging their bets in order to have the know-how should they need to develop their own deterrence. Verifying enrichment or reprocessing facilities is quite difficult, and the so-called conversion time is extremely short. Thus, the IAEA is dealing with what is called 'virtual nuclear weapon States'. The IAEA has been talking for a number of years about the need to develop a new international or multinational approach to the fuel cycle in order to avoid a situation with nine nuclear weapon States and another 20 or 30 States having the capacity to develop nuclear weapons in a very short period of time. There is a need to remember that there is a linkage between nuclear disarmament and non-proliferation. Furthermore safeguards activities, though fundamentally technical in nature, are carried out in a political charged environment. The security dimension - that is, nuclear terrorism - also presents a new challenge, because State systems of accounting for and control of nuclear material are no longer simply tools for safeguards, but

  2. Challenges in PFBR civil construction

    International Nuclear Information System (INIS)

    Civil works of PFBR has posed numerous design and construction challenges. Eight safety related nuclear buildings of PFBR are founded on a single raft, first of its kind in Indian nuclear Reactors. Construction of eight interconnected buildings on the common raft has been challenge for construction material transportation. The construction of Nuclear Island Connected Buildings (NICB) raft was completed in three and a half months. This massive 100mx100m raft for NICB, requiring 35000 cubic meter of concrete was undertaken in twelve pours. This Herculean task required storage of massive quantities of raw materials and ice. The construction of Turbo Generator (TG) building including TG mat and deck and interconnection with NICB posed enormous construction challenges that were well planned and executed. The intake and outfall structures too are exemplary construction handled effectively at PFBR. The excavation for the nuclear and power islands was large and deep. Rock out crops were found starting at various depths of excavation, requiring extensive planning controlled blasting and mechanization in excavation. This also required innovative dewatering procedures in sandy terrain often mixed with clay. Ground water table at PFBR site being high, water proofing for massive underground structure of PFBR was required to be carefully engineered and handled. This started with innovative grouting of excavated strata below the raft till required permeability was met and bone dry condition was achieved for laying of waterproofing membranes. Concurrent construction and regulatory reviews and stage wise clearance for civil construction required dynamic construction planning and sequencing. The scope of civil construction in PFBR expands to critical steel fabricated structures integrated with civil works. This includes huge embedment erected to very close tolerances. Large size panels for upper lateral, lower lateral and bottom shields were fabricated to intricate contours with

  3. International migration: a global challenge.

    Science.gov (United States)

    Martin, P; Widgren, J

    1996-04-01

    Trends in international migration are presented in this multiregional analysis. Seven of the world's wealthiest countries have about 33% of the world's migrant population, but under 16% of the total world population. Population growth in these countries is substantially affected by the migrant population. The migration challenge is external and internal. The external challenge is to balance the need for foreign labor and the commitment to human rights for those migrants seeking economic opportunity and political freedom. The internal challenge is to assure the social adjustment of immigrants and their children and to integrate them into society as citizens and future leaders. Why people cross national borders and how migration flows are likely to evolve over the next decades are explained. This report also presents some ways that countries can manage migration or reduce the pressures which force people to migrate. It is recommended that receiving nations control immigration by accelerating global economic growth and reducing wars and human rights violations. This report examines the impact of immigration on international trade, aid, and direct intervention policies. Although migration is one of the most important international economic issues, it is not coordinated by an international group. The European experience indicates that it is not easy to secure international cooperation on issues that affect national sovereignty. It is suggested that countries desiring control of their borders should remember that most people never cross national borders to live or work in another country, that 50% of the world's migrants move among developing countries, and that countries can shift from being emigration to immigration countries. The author suggests that sustained reductions in migration pressure are a better alternative than the "quick fixes" that may invite the very much feared mass and unpredictable movements. PMID:12320315

  4. Silicon photonics: some remaining challenges

    Science.gov (United States)

    Reed, G. T.; Topley, R.; Khokhar, A. Z.; Thompson, D. J.; Stanković, S.; Reynolds, S.; Chen, X.; Soper, N.; Mitchell, C. J.; Hu, Y.; Shen, L.; Martinez-Jimenez, G.; Healy, N.; Mailis, S.; Peacock, A. C.; Nedeljkovic, M.; Gardes, F. Y.; Soler Penades, J.; Alonso-Ramos, C.; Ortega-Monux, A.; Wanguemert-Perez, G.; Molina-Fernandez, I.; Cheben, P.; Mashanovich, G. Z.

    2016-03-01

    This paper discusses some of the remaining challenges for silicon photonics, and how we at Southampton University have approached some of them. Despite phenomenal advances in the field of Silicon Photonics, there are a number of areas that still require development. For short to medium reach applications, there is a need to improve the power consumption of photonic circuits such that inter-chip, and perhaps intra-chip applications are viable. This means that yet smaller devices are required as well as thermally stable devices, and multiple wavelength channels. In turn this demands smaller, more efficient modulators, athermal circuits, and improved wavelength division multiplexers. The debate continues as to whether on-chip lasers are necessary for all applications, but an efficient low cost laser would benefit many applications. Multi-layer photonics offers the possibility of increasing the complexity and effectiveness of a given area of chip real estate, but it is a demanding challenge. Low cost packaging (in particular, passive alignment of fibre to waveguide), and effective wafer scale testing strategies, are also essential for mass market applications. Whilst solutions to these challenges would enhance most applications, a derivative technology is emerging, that of Mid Infra-Red (MIR) silicon photonics. This field will build on existing developments, but will require key enhancements to facilitate functionality at longer wavelengths. In common with mainstream silicon photonics, significant developments have been made, but there is still much left to do. Here we summarise some of our recent work towards wafer scale testing, passive alignment, multiplexing, and MIR silicon photonics technology.

  5. Fossil Energy: Drivers and Challenges.

    Science.gov (United States)

    Friedmann, Julio

    2007-04-01

    Concerns about rapid economic growth, energy security, and global climate change have created a new landscape for fossil energy exploration, production, and utilization. Since 85% of primary energy supply comes from fossil fuels, and 85% of greenhouse gas emissions come from fossil fuel consumption, new and difficult technical and political challenges confront commercial, governmental, and public stakeholders. As such, concerns over climate change are explicitly weighed against security of international and domestic energy supplies, with economic premiums paid for either or both. Efficiency improvements, fuel conservation, and deployment of nuclear and renewable supplies will help both concerns, but are unlikely to offset growth in the coming decades. As such, new technologies and undertakings must both provide high quality fossil energy with minimal environmental impacts. The largest and most difficult of these undertakings is carbon management, wherein CO2 emissions are sequestered indefinitely at substantial incremental cost. Geological formations provide both high confidence and high capacity for CO2 storage, but present scientific and technical challenges. Oil and gas supply can be partially sustained and replaced through exploitation of unconventional fossil fuels such as tar-sands, methane hydrates, coal-to-liquids, and oil shales. These fuels provide enormous reserves that can be exploited at current costs, but generally require substantial energy to process. In most cases, the energy return on investment (EROI) is dropping, and unconventional fuels are generally more carbon intensive than conventional, presenting additional carbon management challenges. Ultimately, a large and sustained science and technology program akin to the Apollo project will be needed to address these concerns. Unfortunately, real funding in energy research has dropped dramatically (75%) in the past three decades, and novel designs in fission and fusion are not likely to provide any

  6. Nanometrology - challenges for health regulation

    Directory of Open Access Journals (Sweden)

    Jailton Carreteiro Damasceno

    2013-11-01

    Full Text Available The relationship between metrology, nanotechnology and nanoscience and sanitary regulation is discussed from the point of view of its importance and the interrelationship between the themes for the development of products and services involving nanotech-nology. The discussion involves the main techniques for measuring dimensional, chemical and biological properties of materials, and presents some of the challenges for the future. Issues such as processes of standardization and regulation in Europe, U.S. and Brazil are also addressed, providing an overview of how these processes are related to sanitary regulation.

  7. Meeting the Challenges for Agriculture

    OpenAIRE

    Les Copeland

    2011-01-01

    Ensuring food security is an ongoing global challenge. Many forecasts point to a need to increase food production by at least 70% if we are to feed the world’s projected population of nine billion in 2050. Recent volatility in commodity prices and the general upward trend in the cost of food are indicators that global food systems are now driven by demand rather than supply. There are various reasons for this: greater demand for animal protein with economic growth in developing countries; the...

  8. University education: Demands and challenges

    OpenAIRE

    Eduardo Pinos Vélez

    2013-01-01

    This paper presents a study on the current situation prevailing in the Universities from the point of view of a teacher whose academic since its inception has been Salesian, which allows for a “best approach” to young students and where the passion for teaching is clearly influenced by the teachings of one of the greatest teachers, Don Bosco. Also, these teachings are still of great relevance in our time, seek to adopt these methodologies in our workspaces teaching is challenging, where you c...

  9. IAEA safeguards: Challenges and opportunities

    International Nuclear Information System (INIS)

    The history of the IAEA safeguards regime is described. New challenges and opportunities are discussed in connection with the discovery in Iraq of a clandestine nuclear weapons development programme, the difficulties experienced in the implementation of the safeguards agreement with the Democratic People's Republic of Korea, the conclusion of a comprehensive safeguards agreement with Argentina, Brazil and the Brazilian-Argentine Agency for Accounting and Control of Nuclear Materials, recent developments in South Africa, the emergence of newly independent States that made up the former USSR. 2 figs

  10. Addressing the workforce pipeline challenge

    International Nuclear Information System (INIS)

    A secure and affordable energy supply is essential for achieving U.S. national security, in continuing U.S. prosperity and in laying the foundations to enable future economic growth. To meet this goal the next generation energy workforce in the U.S., in particular those needed to support instrumentation, controls and advanced operations and maintenance, is a critical element. The workforce is aging and a new workforce pipeline, to support both current generation and new build has yet to be established. The paper reviews the challenges and some actions being taken to address this need. (authors)

  11. Cleaning insertions and collimation challenges

    CERN Document Server

    Redaelli, S; Bertarelli, A; Bruce, R; Jowett, J M; Lechner, A; Losito, R

    2015-01-01

    High-performance collimation systems are essential for operating efficiently modern hadron machine with large beam intensities. In particular, at the LHC the collimation system ensures a clean disposal of beam halos in the superconducting environment. The challenges of the HL-LHC study pose various demanding requests for beam collimation. In this paper we review the present collimation system and its performance during the LHC Run 1 in 2010–2013. Various collimation solutions under study to address the HL-LHC requirements are then reviewed, identifying the main upgrade baseline and pointing out advanced collimation concept for further enhancement of the performance.

  12. Nonlinear dynamics: Challenges and perspectives

    Indian Academy of Sciences (India)

    M Lakshmanan

    2005-04-01

    The study of nonlinear dynamics has been an active area of research since 1960s, after certain path-breaking discoveries, leading to the concepts of solitons, integrability, bifurcations, chaos and spatio-temporal patterns, to name a few. Several new techniques and methods have been developed to understand nonlinear systems at different levels. Along with these, a multitude of potential applications of nonlinear dynamics have also been enunciated. In spite of these developments, several challenges, some of them fundamental and others on the efficacy of these methods in developing cutting edge technologies, remain to be tackled. In this article, a brief personal perspective of these issues is presented.

  13. University education: Demands and challenges

    Directory of Open Access Journals (Sweden)

    Eduardo Pinos Vélez

    2013-06-01

    Full Text Available This paper presents a study on the current situation prevailing in the Universities from the point of view of a teacher whose academic since its inception has been Salesian, which allows for a “best approach” to young students and where the passion for teaching is clearly influenced by the teachings of one of the greatest teachers, Don Bosco. Also, these teachings are still of great relevance in our time, seek to adopt these methodologies in our workspaces teaching is challenging, where you can suggest new strategies for communication and integration with students and in this way to service the needy, such as programs aid Persons with Disabilities.

  14. Asymmetry a challenge for orthodontists

    DEFF Research Database (Denmark)

    Melsen, Birte

    2007-01-01

      Asymmetry is considered a challenge and often the reason for which the optimal result cannot be obtained. The explanations are many. Only rarely, the cause of the asymmetry is localized and camouflage is frequently resulting in the development a different type of asymmetry occurring in all three...... planes of space. A systematic approach to the identification of the cause of the asymmetry head precede the decision whether to correct or to camouflage. The definition of a specific treatment goal should be done only following an analysis of the likelihood that the force system necessary to perform the...

  15. Addressing the workforce pipeline challenge

    Energy Technology Data Exchange (ETDEWEB)

    Leonard Bond; Kevin Kostelnik; Richard Holman

    2006-11-01

    A secure and affordable energy supply is essential for achieving U.S. national security, in continuing U.S. prosperity and in laying the foundations to enable future economic growth. To meet this goal the next generation energy workforce in the U.S., in particular those needed to support instrumentation, controls and advanced operations and maintenance, is a critical element. The workforce is aging and a new workforce pipeline, to support both current generation and new build has yet to be established. The paper reviews the challenges and some actions being taken to address this need.

  16. PETS 2015: datasets and challenge

    OpenAIRE

    Li, Longzhen; Nawaz, Tahir; Ferryman, James

    2015-01-01

    This paper presents the two datasets (ARENA and P5) and the challenge that form a part of the PETS 2015 workshop. The datasets consist of scenarios recorded by us- ing multiple visual and thermal sensors. The scenarios in ARENA dataset involve different staged activities around a parked vehicle in a parking lot in UK and those in P5 dataset involve different staged activities around the perimeter of a nuclear power plant in Sweden. The scenarios of each dataset are grouped into ‘Normal’, ‘War...

  17. Plain language and organisational challenges

    DEFF Research Database (Denmark)

    Pedersen, Karsten

    2014-01-01

    Changing the language in an organization is a major organizational change. In this article, I discuss some of the organizational challenges for one specific language change implementation, taking the stance that language change must be treated as any other organizational change for it to have...... an effect. I work with the case of the Danish tax authorities’ language project aimed at producing more readable letters. The empirical data that I work with are two qualitative informant interviews. One recorded at the language project’s headquarters where they lay out the general lines for the project...

  18. Developmental psychopathology: concepts and challenges.

    Science.gov (United States)

    Rutter, M; Sroufe, L A

    2000-01-01

    The defining features of developmental psychopathology concepts include attention to the understanding of causal processes, appreciation of the role of developmental mechanisms, and consideration of continuities and discontinuities between normality and psychopathology. Accomplishments with respect to these issues are reviewed in relation to attachment disorders, antisocial behavior, autism, depressive disorder, schizophrenia, and intellectual development. Major research challenges remain in relation to measurement issues, comorbidity, gender differences, cognitive processing, nature-nurture interplay, heterotypic continuity, continuities between normal variations and disorders, developmental programming, and therapeutic mechanisms in effective treatments. PMID:11014739

  19. The Challenges of Community Engagement.

    Science.gov (United States)

    Cormick, Craig

    2010-12-01

    Lyons and Whelan provide a useful list of recommendations as to how community engagement on nanotechnology could be improved, which very few people working in community engagement could disagree with. However, as the conclusions of any study are dependent on the data obtained, if more data had been obtained and analysed then different conclusions might have been reached. Addressing the key issues in the paper and providing more data, also allows an opportunity to expand on current issues relating to community engagement on nanotechnology and the challenges it provides for practitioners. PMID:21258427

  20. The coffee-time challenge

    CERN Multimedia

    CERN Bulletin

    2010-01-01

    The challenge to identify the LEP events displayed on coffee tables in Restaurant 1 (Bulletin 02-03/2010) sparked interest among readers who do not have the opportunity to see them . Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, Table 10, Table 11, Table 12 Table 13, Table 14, Table 15, Table 16       We have therefore decided to open the challenge to these readers by displaying the events on the web. We are also extending the deadline accordingly to 2 March. There are 16 events in total (in two areas), four from each of the four LEP experiments, and they include examples of different particle decays observed at LEP during its 11 years of operation. The list below indicates the decay channels represented. We are offering a prize of the ATLAS pop-up book, Voyage to the Heart of Matter, for the correct identification of all 16 events.  Entries should indicate the table number corresponding to each of the decays listed. There wi...

  1. Managing neurocysticercosis: challenges and solutions.

    Science.gov (United States)

    Fogang, Yannick Fogoum; Savadogo, Abdoul Aziz; Camara, Massaman; Toffa, Dènahin Hinnoutondji; Basse, Anna; Sow, Adjaratou Djeynabou; Ndiaye, Mouhamadou Mansour

    2015-01-01

    Taenia solium neurocysticercosis (NCC) is a major cause of neurological morbidity in the world. Variability in the neuropathology and clinical presentation of NCC often make it difficult to diagnose and manage. Diagnosis of NCC can be challenging especially in endemic and resource-limited countries where laboratory and imaging techniques are often lacking. NCC management can also be challenging as current treatment options are limited and involve symptomatic agents, antiparasitic agents, or surgery. Although antiparasitic treatment probably reduces the number of active lesions and long-term seizure frequency, its efficacy is limited and strategies to improve treatment regimens are warranted. Treatment decisions should be individualized in relation to the type of NCC. Initial measures should focus on symptomatic management, with antiparasitic therapy only to be considered later on, when appropriate. Symptomatic treatment remains the cornerstone in NCC management which should not only focuses on epilepsy, but also on other manifestations that cause considerable burden (recurrent headaches, cognitive decline). Accurate patients' categorization, better antiparasitic regimens, and definition of new clinical outcomes for trials on NCC could improve management quality and prognosis of NCC. Prevention strategies targeting tapeworm carriers and infected pigs are yielding good results in local models. If local elimination of transmission is confirmed and replicated, this will open the door to cysticercosis eradication efforts worldwide. PMID:26527895

  2. The challenge to balloon science

    Science.gov (United States)

    Jones, W. Vernon

    A thorough review of the NASA balloon program in 1995 confirmed both the inherent importance of balloon science investigations and their value for developing technology for future space missions. A follow-on study in 1996 looked into restructuring the entire suborbital program, in order to find more efficient and effective ways of doing business. These studies were mandated by the adverse impact of NASA's declining budgets and work force constraints on all aspects of space research. The challenge is to accomplish more with less. The balloon program began stepping up to this challenge several years ago with the advent of 10 - 20 day long-duration flights in Antarctica. We must now push ahead with enhanced flight capabilities and with new science instrument technologies, as we forge alliances with other modes of low-cost access to space. Specifically, the development of sealed superpressure balloons could extend flight duration by another order of magnitude, to about 100 days, making ballooning even more competitive with space missions.

  3. LHC an unprecedented technological challenge

    International Nuclear Information System (INIS)

    This article presents the future LHC (large hadron collider) in simple terms and gives some details concerning radiation detectors and supra-conducting magnets. LHC will take the place of the LEP inside the 27 km long underground tunnel near Geneva and is scheduled to operate in 2007. 8 years after its official launching the LHC project has piled up 2 year delay and has exceeded its initial budget (2 milliard euros) by 18%. Technological challenges and design difficulties are the main causes of these shifts. The first challenge has been carried out successfully, it was the complete clearing out of the LEP installation. In order to release 14 TeV in each proton-proton collision, powerful magnetic fields (8,33 Tesla) are necessary. 1248 supra-conducting 15 m-long bipolar magnets have to be built. 30% of the worldwide production of niobium-titanium wires will be used each year for 5 years in the design of these coils. The global cryogenic system will be gigantic and will use 94 tons of helium. 4 radiation detectors are being built: ATLAS (a toroidal LHC apparatus), CMS (compact muon solenoid), ALICE (a large ion collider experiment) and LHC-b (large hadron collider beauty). The 2 first will search after the Higgs boson, ALICE will be dedicated to the study of the quark-gluon plasma and LHC-b will gather data on the imbalance between matter and anti-matter. (A.C.)

  4. Meeting the Challenges for Agriculture

    Directory of Open Access Journals (Sweden)

    Les Copeland

    2011-06-01

    Full Text Available Ensuring food security is an ongoing global challenge. Many forecasts point to a need to increase food production by at least 70% if we are to feed the world’s projected population of nine billion in 2050. Recent volatility in commodity prices and the general upward trend in the cost of food are indicators that global food systems are now driven by demand rather than supply. There are various reasons for this: greater demand for animal protein with economic growth in developing countries; the continuing increase in world population; competition between food and bioenergy crops for land and water; low inventories of world grain stocks; reduced investment in agricultural R&D; and unfavorable weather resulting in a succession of poor harvests around the world. Increasing production of grains, which are the foundation of the human food supply, will have to be achieved through higher crop yields without boosting inputs of land, water and energy. Meeting community expectations for environmental stewardship and sustainability, and adapting food production to increasingly variable climate, add greatly to the challenge.

  5. Managerial challenges in nuclear training

    International Nuclear Information System (INIS)

    Nuclear personnel training programs have existed since the infancy of the commercial nuclear power industry. The scope and complexity of these programs have increased dramatically, especially since the Three Mile Island mishap in 1979. Whether voluntary or regulated, the changes of the past several years have greatly increased the responsibilities and roles of the nuclear training managers. Events and our own diligence have compounded two problems (or challenges) that have been with us all along. First, training managers have frequently been excluded from the change-making process, leaving them to react as best they can to new regulatory mandates and new utility innovations in a de facto fashion. Second, the additional resources needed to meet new requirements (personnel, equipment, facilities, and funds) have not been made available, or have been insufficient to accomplish new tasks. This paper discusses these challenges and considers several responses (including a national nuclear trainers association) that can go a long way to place nuclear training managers and their employees more in control of their own fate

  6. Multiphysics simulations: challenges and opportunities.

    Energy Technology Data Exchange (ETDEWEB)

    Keyes, D.; McInnes, L. C.; Woodward, C.; Gropp, W.; Myra, E.; Pernice, M. (Mathematics and Computer Science); (KAUST and Columbia Univ.); (Lawrence Livermore National Laboratory); (Univ. of Illinois at Urbana-Champaign); (Univ. of Mich.); (Idaho National Lab.)

    2012-11-29

    This report is an outcome of the workshop Multiphysics Simulations: Challenges and Opportunities, sponsored by the Institute of Computing in Science (ICiS). Additional information about the workshop, including relevant reading and presentations on multiphysics issues in applications, algorithms, and software, is available via https://sites.google.com/site/icismultiphysics2011/. We consider multiphysics applications from algorithmic and architectural perspectives, where 'algorithmic' includes both mathematical analysis and computational complexity and 'architectural' includes both software and hardware environments. Many diverse multiphysics applications can be reduced, en route to their computational simulation, to a common algebraic coupling paradigm. Mathematical analysis of multiphysics coupling in this form is not always practical for realistic applications, but model problems representative of applications discussed herein can provide insight. A variety of software frameworks for multiphysics applications have been constructed and refined within disciplinary communities and executed on leading-edge computer systems. We examine several of these, expose some commonalities among them, and attempt to extrapolate best practices to future systems. From our study, we summarize challenges and forecast opportunities. We also initiate a modest suite of test problems encompassing features present in many applications.

  7. Challenges in Double Beta Decay

    Directory of Open Access Journals (Sweden)

    Oliviero Cremonesi

    2014-01-01

    Full Text Available In the past ten years, neutrino oscillation experiments have provided the incontrovertible evidence that neutrinos mix and have finite masses. These results represent the strongest demonstration that the electroweak Standard Model is incomplete and that new Physics beyond it must exist. In this scenario, a unique role is played by the Neutrinoless Double Beta Decay searches which can probe lepton number conservation and investigate the Dirac/Majorana nature of the neutrinos and their absolute mass scale (hierarchy problem with unprecedented sensitivity. Today Neutrinoless Double Beta Decay faces a new era where large-scale experiments with a sensitivity approaching the so-called degenerate-hierarchy region are nearly ready to start and where the challenge for the next future is the construction of detectors characterized by a tonne-scale size and an incredibly low background. A number of new proposed projects took up this challenge. These are based either on large expansions of the present experiments or on new ideas to improve the technical performance and/or reduce the background contributions. In this paper, a review of the most relevant ongoing experiments is given. The most relevant parameters contributing to the experimental sensitivity are discussed and a critical comparison of the future projects is proposed.

  8. Engineering ethics challenges and opportunities

    CERN Document Server

    Bowen, W Richard

    2014-01-01

    Engineering Ethics: Challenges and Opportunities aims to set a new agenda for the engineering profession by developing a key challenge: can the great technical innovation of engineering be matched by a corresponding innovation in the acceptance and expression of ethical responsibility?  Central features of this stimulating text include:   ·         An analysis of engineering as a technical and ethical practice providing great opportunities for promoting the wellbeing and agency of individuals and communities. ·         Elucidation of the ethical opportunities of engineering in three key areas:             - Engineering for Peace, emphasising practical amelioration of the root causes of    conflict rather than military solutions.             - Engineering for Health, focusing on close collaboration with healthcare professionals      for both the promotion and restoration of health.             - Engineering for Development, providing effective solution...

  9. Space Shuttle Star Tracker Challenges

    Science.gov (United States)

    Herrera, Linda M.

    2010-01-01

    The space shuttle fleet of avionics was originally designed in the 1970's. Many of the subsystems have been upgraded and replaced, however some original hardware continues to fly. Not only fly, but has proven to be the best design available to perform its designated task. The shuttle star tracker system is currently flying as a mixture of old and new designs, each with a unique purpose to fill for the mission. Orbiter missions have tackled many varied missions in space over the years. As the orbiters began flying to the International Space Station (ISS), new challenges were discovered and overcome as new trusses and modules were added. For the star tracker subsystem, the growing ISS posed an unusual problem, bright light. With two star trackers on board, the 1970's vintage image dissector tube (IDT) star trackers track the ISS, while the new solid state design is used for dim star tracking. This presentation focuses on the challenges and solutions used to ensure star trackers can complete the shuttle missions successfully. Topics include KSC team and industry partner methods used to correct pressurized case failures and track system performance.

  10. Science solving the XXI century challenges

    OpenAIRE

    USAID. Office of Agriculture and Food Security; EGAT Agriculture and Agribusiness. R&D Management Unit

    2001-01-01

    Presentation describes the government and university partnerships that are taking on the challenges of food insecurity and poverty, challenges to agricultural development and and food security, and expectations in natural resource management.

  11. 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....

  12. Unpacking the grand challenges of nanotechnology

    OpenAIRE

    Lente, H. van; Bos, C

    2012-01-01

    Important societal themes, such as sustainability or the ageing society, are referred to as 'grand challenges'. During the last decade, many funding programs were set up to address these and other grand challenges. While grand challenges have a moral component – it is difficult to contest that it is 'good' to address them – they do not convey clear-cut goals for action. When they are related to the actual development of new technologies, grand challenges are articulated in different ways. Art...

  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. 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…

  15. The Climate Change Challenge for Land Professionals

    DEFF Research Database (Denmark)

    Enemark, Stig

    2014-01-01

    “Climate change is the defining challenge of our time”. This statement by UN Secretary General Ban Ki Moon (2009) is still valid. The challenges of food shortage, environmental degradation and natural disasters are to a large extent caused by the overarching challenge of climate change, while the...

  16. 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...

  17. Health Care Challenges in Iran

    Directory of Open Access Journals (Sweden)

    M Davari

    2005-10-01

    Full Text Available All health systems across the world have faced new challenges, which is primarily referable to increasing the cost of health care services as well as growing demands for new and expensive health technologies. The aim of this study is to analyse the main challenges facing the Iranian health system. A review of available governmental and relevant publications about Iranian health care system was undertaken to assess the direction of future healthcare policy. Electronic news agencies, newspapers, and parliament’s electronic news also reviewed to realise policy-makers points of view about the health system. Healthcare services in Iran have had a great success in primary healthcare services in last 25 years, which is mainly attributable to National Health Networks policy. Between 1979 and 2003, average life expectancy at birth increased from 57 to 70 and infant mortality rate fell from 104 to 26 per thousand live births. Active vaccination system, very good distribution and coverage, free end point services, family planning, maternal teaching, and primary referral system are of strong advantages of health networks in Iran. However, the healthcare system is now subject to a range of new pressures that must be addressed. Many of these pressures are common to all health services (rising consumer demands and expectations for expensive new technologies, changing disease patterns, and resources shortage, but some are largely specific to Iran. Financial fairness contribution of the population to health system, responsiveness of health system, overusing new technologies, inadequate integration of health services, and inequitable distribution of the resources are of the main challenges of health system in Iran. In addition, considering demographic changes of the Iranian population in recent decades, which made Iranian population young, potential pressures due to an aging population will reveal in coming years. Many of these pressures relate to policies and

  18. Crowdsourcing. A Citizen Participation Challenge

    Directory of Open Access Journals (Sweden)

    Junia Borges

    2014-05-01

    Full Text Available This paper is a work in progress on Crowdsourcing. First, its concepts and importance are discussed and then its value for citizenship and urban planning. The motivation for participation and the display of geo-tagged information, as well as its possible applications in dynamic spatial temporal issues are presented, as well as its different approaches and applications. Furthermore, Crowdsourcing is discussed when the “ONVCêVIU”, a VGI case study, is presented, revealing its origin, objective, free platform comparison - to select the proper tool to implement, the project’s main challenges, results so far and further steps to be taken. To conclude a short review of the author’s vision about what is to come in the future research.

  19. The new challenges of petroleum

    International Nuclear Information System (INIS)

    Petroleum in in the center of our civilization: abundant, easy to use and energy powerful, it is used almost everywhere: transports, lighting, space heating, plastics, fertilizers, cloth industry etc. The 'black-gold' is the object of all stakes, from richness to power. However, petroleum is also at the origin of many evils: pollution, corruption, violence. Today, petroleum is a source of worries: how long will it last? How long will we be able to stand its impacts on environment? This book shades light on all these questions and supplies some concrete elements about this energy source. Content: technological challenges of petroleum; producers: powers and risks; consumers' dependence; to learn more about petroleum. (J.S.)

  20. Materials for Space: It's Challenging!

    Science.gov (United States)

    Johnson, Sylvia M.

    2016-01-01

    Space environments place tremendous demands on materials that must perform with exceptional reliability to realize the goals of human or robotic space exploration missions. Materials are subjected to extremes of temperature, pressure, radiation and mechanical loads during all phases of use, including takeoff and ascent, exposure to space or entry into an atmosphere, and operation in a planetary atmosphere. Space materials must be robust and enable the formation of lightweight structures or components that perform the required functions; materials that perform multiple functions are of particular interest. This talk will review the unique challenges for materials in space and some of the specific material capabilities that will be needed for future exploration missions. A description of needs and trends in thermal protection materials and systems will complete the talk.