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Sample records for a5 apoa5 gene

  1. Association between glucokinase regulatory protein (GCKR) and apolipoprotein A5 (APOA5) gene polymorphisms and triacylglycerol concentrations in fasting, postprandial, and fenofibrate-treated states

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Hypertriglyceridemia is a risk factor for cardiovascular disease. Variation in the apolipoprotein A5 (APOA5) and glucokinase regulatory protein (GCKR) genes has been associated with fasting plasma triacylglycerol. Objective: We investigated the combined effects of the GCKR rs780094C-->T,...

  2. The apolipoprotein A5 -1131T>C promoter polymorphism in Koreans: association with plasma APOA5 and serum triglyceride concentrations, LDL particle size and coronary artery disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    BACKGROUND: The association between -1131T>C single nucleotide polymorphism (SNP) of the apolipoprotein A5 gene (APOA5) and hypertriglyceridemia raised the possibility that this SNP could be related to coronary artery disease (CAD) risk. Therefore, we investigated the association of this APOA5 -1131...

  3. The liver X receptor ligand T0901317 down-regulates APOA5 gene expression through activation of SREBP-1c.

    PubMed

    Jakel, Heidelinde; Nowak, Maxime; Moitrot, Emanuelle; Dehondt, Hélène; Hum, Dean W; Pennacchio, Len A; Fruchart-Najib, Jamila; Fruchart, Jean-Charles

    2004-10-29

    Alterations in the expression of the recently discovered apolipoprotein A5 gene strongly affect plasma triglyceride levels. In this study, we investigated the contribution of APOA5 to the liver X receptor (LXR) ligand-mediated effect on plasma triglyceride levels. Following treatment with the LXR ligand T0901317, we found that APOA5 mRNA levels were decreased in hepatoma cell lines. The observation that no down-regulation of APOA5 promoter activity was obtained by LXR-retinoid X receptor (RXR) co-transfection prompted us to explore the possible involvement of the known LXR target gene SREBP-1c (sterol regulatory element-binding protein 1c). In fact, we found that co-transfection with the active form of SREBP-1c down-regulated APOA5 promoter activity in a dose-dependent manner. We then scanned the human APOA5 promoter sequence and identified two putative E-box elements that were able to bind specifically SREBP-1c in gel-shift assays and were shown to be functional by mutation analysis. Subsequent suppression of SREBP-1 mRNA through small interfering RNA interference abolished the decrease of APOA5 mRNA in response to T0901317. Finally, administration of T0901317 to hAPOA5 transgenic mice revealed a significant decrease of APOA5 mRNA in liver tissue and circulating apolipoprotein AV protein in plasma, confirming that the described down-regulation also occurs in vivo. Taken together, our results demonstrate that APOA5 gene expression is regulated by the LXR ligand T0901317 in a negative manner through SREBP-1c. These findings may provide a new mechanism responsible for the elevation of plasma triglyceride levels by LXR ligands and support the development of selective LXR agonists, not affecting SREBP-1c, as beneficial modulators of lipid metabolism.

  4. The Liver X Receptor Ligand T0901317 Down-regulates APOA5 GeneExpression through Activation of SREBP-1c

    SciTech Connect

    Jakel, Heidelinde; Nowak, Maxime; Moitrot, Emanuelle; Dehondt, Helene; Hum, Dean W.; Pennacchio, Len A.; Fruchart-Najib, Jamila; Fruchart,Jean-Charles

    2004-07-23

    Alterations in the expression of the recently discovered apolipoprotein A5 gene strongly affect plasma triglyceride levels. In this study, we investigated the contribution of APOA5 to the liver X-receptor (LXR) ligand mediated effect on plasma triglyceride levels.Following treatment with the LXR ligand T0901317, we found that APOA5mRNA levels were decreased in hepatoma cell lines. The observation that no down-regulation of APOA5 promoter activity was obtained by LXR-retinoid X receptor (RXR) co-transfection prompted us to explore the possible involvement of the known LXR target gene SREBP-1c (sterol regulatory element-binding protein 1c). In fact, we found that co-transfection with the active form of SREBP-1c down-regulated APOA5promoter activity in a dose-dependent manner. We then scanned the human APOA5 promoter sequence and identified two putative E-box elements that were able to bind specifically SREBP-1c in gel-shift assays and were shown to be functional by mutation analysis. Subsequent suppression of SREBP-1 mRNA through small interfering RNA interference abolished the decrease of APOA5 mRNA in response to T0901317. Finally, administration of T0901317 to hAPOA5 transgenic mice revealed a significant decrease OF APOA5 mRNA in liver tissue and circulating apolipoprotein AV protein in plasma, confirming that the described down-regulation also occurs in vivo. Taken together, our results demonstrate that APOA5 gene expression is regulated by the LXR ligand T0901317 in a negative manner through SREBP-1c. These findings may provide a new mechanism responsible for the elevation of plasma triglyceride levels by LXR ligands and support the development of selective LXR agonists, not affecting SREBP-1c, as beneficial modulators of lipid metabolism.

  5. Hypertriglyceridaemia and low plasma HDL in a patient with apolipoprotein A-V deficiency due to a novel mutation in the APOA5 gene.

    PubMed

    Priore Oliva, C; Carubbi, F; Schaap, F G; Bertolini, S; Calandra, S

    2008-04-01

    APOA5 encodes a novel apolipoprotein (apo A-V) which appears to be a modulator of plasma triglyceride (TG). In apoA5 knock out mice plasma TG level increases almost fourfold, whereas in human APOA5 transgenic mice it decreases by 70%. Some SNPs in the APOA5 gene have been associated with variations in plasma TG in humans. In addition, hypertriglyceridaemic (HTG) patients have been identified who carried rare nonsense mutations in the APOA5 gene (Q139X and Q148X), predicted to result in apo A-V deficiency. In this study we report a 17-year-old male with high TG and low high density lipoprotein cholesterol (HDL-C), who at the age of two had been found to have severe HTG and eruptive xanthomas suggesting a chylomicronaemia syndrome. Plasma postheparin LPL activity, however, was normal and no mutations were found in LPL and APOC2 genes. The sequence of APOA5 gene revealed that the patient was homozygous for a point mutation (c.289 C>T) in exon 4, converting glutamine codon at position 97 into a termination codon (Q97X). Apo A-V was not detected in patient's plasma, indicating that he had complete apo A-V deficiency. The administration of a low-fat and low-oligosaccharide diet, either alone or supplemented with omega-3 fatty acids, started early in life, reduced plasma TG to a great extent but had a negligible effect on plasma HDL-C. Loss of function mutations of APOA5 gene may be the cause of severe HTG in patients without mutations in LPL and APOC2 genes. PMID:18324930

  6. ApoA5 knockdown improves whole-body insulin sensitivity in high-fat-fed mice by reducing ectopic lipid content

    PubMed Central

    Camporez, João Paulo G.; Kanda, Shoichi; Petersen, Max C.; Jornayvaz, François R.; Samuel, Varman T.; Bhanot, Sanjay; Petersen, Kitt Falk; Jurczak, Michael J.; Shulman, Gerald I.

    2015-01-01

    ApoA5 has a critical role in the regulation of plasma TG concentrations. In order to determine whether ApoA5 also impacts ectopic lipid deposition in liver and skeletal muscle, as well as tissue insulin sensitivity, we treated mice with an antisense oligonucleotide (ASO) to decrease hepatic expression of ApoA5. ASO treatment reduced ApoA5 protein expression in liver by 60–70%. ApoA5 ASO-treated mice displayed approximately 3-fold higher plasma TG concentrations, which were associated with decreased plasma TG clearance. Furthermore, ApoA5 ASO-treated mice fed a high-fat diet (HFD) exhibited reduced liver and skeletal muscle TG uptake and reduced liver and muscle TG and diacylglycerol (DAG) content. HFD-fed ApoA5 ASO-treated mice were protected from HFD-induced insulin resistance, as assessed by hyperinsulinemic-euglycemic clamps. This protection could be attributed to increases in both hepatic and peripheral insulin responsiveness associated with decreased DAG activation of protein kinase C (PKC)-ε and PKCθ in liver and muscle, respectively, and increased insulin-stimulated AKT2 pho­sphory­lation in these tissues. In summary, these studies demonstrate a novel role for ApoA5 as a modulator of susceptibility to diet-induced liver and muscle insulin resistance through regulation of ectopic lipid accumulation in liver and skeletal muscle. PMID:25548259

  7. Interactions of Environmental Factors and APOA1-APOC3-APOA4-APOA5 Gene Cluster Gene Polymorphisms with Metabolic Syndrome

    PubMed Central

    Wu, Yanhua; Yu, Yaqin; Zhao, Tiancheng; Wang, Shibin; Fu, Yingli; Qi, Yue; Yang, Guang; Yao, Wenwang; Su, Yingying; Ma, Yue; Shi, Jieping; Jiang, Jing; Kou, Changgui

    2016-01-01

    than 2 servings a week were positively associated with MetS (P<0.05). A family history of diabetes (OR = 1.630, 95%CI = 1.484–1.791), cardiovascular disease or cerebral diseases (OR = 1.297, 95%CI = 1.211–1.389) was associated with MetS. APOA1 rs670, APOA5 rs662799 and rs651821 revealed significant differences in genotype distributions between the MetS patients and control subjects. The minor alleles of APOA1 rs670, APOA5 rs662799 and rs651821, and APOA5 rs2075291 were associated with MetS (P<0.0016). APOA1 rs5072 and APOC3 rs5128, APOA5 rs651821 and rs662799 were in strong linkage disequilibrium to each other with r2 greater than 0.8. Five haplotypes were associated with an increased risk of MetS (OR = 1.23, 1.58, 1.80, 1.90, and 1.98). When we investigated the interactions of environmental factors and APOA1/C3/A4/A5 gene cluster gene polymorphisms, we found that APOA5 rs662799 had interactions with tobacco use and alcohol consumption (PGE<0.05). Conclusions There was a high prevalence of MetS in the northeast of China. Male gender, increasing age, mental labor, family history of diabetes, cardiovascular disease or cerebral diseases, current smoking, excess salt intake, fruit and dairy intake less than 2 servings a week, and drinking were associated with MetS. The APOA1/C3/A4/A5 gene cluster was associated with MetS in the Han Chinese. APOA5 rs662799 had interactions with the environmental factors associated with MetS. PMID:26824674

  8. Association of APOA5 Gene Promoter Region -1131T>C Polymorphism (rs662799) to Plasma Triglyceride Level in Patients with Type 2 Diabetic Nephropathy

    PubMed Central

    Mahrooz, Abdolkarim; Ansari, Vahid; Makhlough, Atieh; Hashemi-Sooteh, Mohammad-Bagher

    2016-01-01

    Introduction Diabetic Nephropathy (DN), a serious complication of Type 2 Diabetic Mellitus (T2DM), is progressive and susceptibility to DN varies among T2DM patients. ApoA5-1131T>C polymorphism revealed that is strongly associated with triglyceride levels and proposed as a predisposing factor for DN. Aim The purpose of this study was to investigate the association -1131T>C ApoA5 gene polymorphism with serum lipids levels in Type 2 diabetic (DM) patients with or without DN in north of Iran (Mazandaran province). Materials and Methods This study comprised patients with established T2DM (n=161) and controls (n=58). Genotyping of APOA5 -1131T>C polymorphisms was performed by PCR–RFLP. Diabetic patients were divided into two groups: with nephropathy (DN+, n = 90) and without nephropathy (DN-, n = 71). Lipids and lipoproteins were assessed by enzymatic methods. Results The genotype frequencies were 63.8 % TT, 31 % TC, 5.2 % CC in controls, 33.8% TT, 52.1 % TC, 14.1 % CC in DN- and 44.4 % TT, 36.7 % TC, 18.9 % CC in DN+ patients. The TC genotype and the CC genotype were overexpressed among DN+ and DN-population in comparison to the control group. The highest and the lowest TG levels in both diabetic patients and controls belonged to CC+TC and TT genotypes, respectively. Furthermore in both patients TG increased with this order: TT< TCAPOA5 -1131T>C polymorphisms influence lipid levels in type 2 diabetic patients. PMID:27437205

  9. Frameshift mutation in the APOA5 gene causing hypertriglyceridemia in a Pakistani family: Management and considerations for cardiovascular risk.

    PubMed

    Thériault, Sébastien; Don-Wauchope, Andrew; Chong, Michael; Lali, Ricky; Morrison, Katherine M; Paré, Guillaume

    2016-01-01

    We report a novel homozygous apolipoprotein A5 (APOA5) frameshift mutation (c.G425del-C, p.Arg143AlafsTer57) identified in a 12-year-old boy of Pakistani origin with severe hypertriglyceridemia (up to 35 mmol/L) and type V hyperlipoproteinemia. The patient did not respond to fibrate therapy, but his condition improved under a very low fat diet, although compliance was suboptimal. Heterozygous status was detected in both parents (consanguineous union) and one sibling, all showing moderate hypertriglyceridemia (between 5 and 10 mmol/L). There was a significant family history of premature cardiovascular disease. The index case was also diagnosed with a coronary artery anomaly. Considering the recently reported association of rare mutations in APOA5 with the risk of early myocardial infarction, we discuss the implications of these findings for the young man and his family. PMID:27678447

  10. In Vivo Characterization of Human APOA5 Haplotypes

    SciTech Connect

    Ahituv, Nadav; Akiyama, Jennifer; Chapman-Helleboid, Audrey; Fruchart, Jamila; Pennacchio, Len A.

    2006-10-01

    Increased plasma triglycerides concentrations are an independent risk factor for cardiovascular disease. Numerous studies support a reproducible genetic association between two minor haplotypes in the human apolipoprotein A5 gene (APOA5) and increased plasma triglyceride concentrations. We thus sought to investigate the effect of these minor haplotypes (APOA5*2 and APOA5*3) on ApoAV plasma levels through the precise insertion of single-copy intact APOA5 haplotypes at a targeted location in the mouse genome. While we found no difference in the amount of human plasma ApoAV in mice containing the common APOA5*1 and minor APOA5*2 haplotype, the introduction of the single APOA5*3 defining allele (19W) resulted in 3-fold lower ApoAV plasma levels consistent with existing genetic association studies. These results indicate that S19W polymorphism is likely to be functional and explain the strong association of this variant with plasma triglycerides supporting the value of sensitive in vivo assays to define the functional nature of human haplotypes.

  11. Transcriptional Regulation of Apolipoprotein A5 Gene Expression by the Nuclear Receptor ROR alpha

    SciTech Connect

    Genoux, Annelise; Dehondt, Helene; Helleboid-Chapman, Audrey; Duhem, Christian; Hum, Dean W.; Martin, Genevieve; Pennacchio, Len; Staels, Bart; Fruchart-Najib, Jamila; Fruchart, Jean-Charles

    2004-10-01

    Apolipoprotein A5 has recently been identified as a crucial determinant of plasma triglyceride levels. Our results showed that RORa up-regulates human APOA5 but has no effect on mouse apoa5 promoter. These data suggest an additional important physiological role for RORa in the regulation of genes involved in plasma triglyceride homeostasis in human and probably in the development of atherosclerosis

  12. Insulin-Mediated Down-Regulation of Apolipoprotein A5 Gene Expression through the Phosphatidylinositol 3-Kinase Pathway: Role of Upstream Stimulatory Factor

    PubMed Central

    Nowak, Maxime; Helleboid-Chapman, Audrey; Jakel, Heidelinde; Martin, Geneviève; Duran-Sandoval, Daniel; Staels, Bart; Rubin, Edward M.; Pennacchio, Len A.; Taskinen, Marja-Riitta; Fruchart-Najib, Jamila; Fruchart, Jean-Charles

    2005-01-01

    The apolipoprotein A5 gene (APOA5) has been repeatedly implicated in lowering plasma triglyceride levels. Since several studies have demonstrated that hyperinsulinemia is associated with hypertriglyceridemia, we sought to determine whether APOA5 is regulated by insulin. Here, we show that cell lines and mice treated with insulin down-regulate APOA5 expression in a dose-dependent manner. Furthermore, we found that insulin decreases human APOA5 promoter activity, and subsequent deletion and mutation analyses uncovered a functional E box in the promoter. Electrophoretic mobility shift and chromatin immunoprecipitation assays demonstrated that this APOA5 E box binds upstream stimulatory factors (USFs). Moreover, in transfection studies, USF1 stimulates APOA5 promoter activity, and the treatment with insulin reduced the binding of USF1/USF2 to the APOA5 promoter. The inhibition of the phosphatidylinositol 3-kinase (PI3K) pathway abolished insulin's effect on APOA5 gene expression, while the inhibition of the P70 S6 kinase pathway with rapamycin reversed its effect and increased APOA5 gene expression. Using an oligonucleotide precipitation assay for USF from nuclear extracts, we demonstrate that phosphorylated USF1 fails to bind to the APOA5 promoter. Taken together, these data indicate that insulin-mediated APOA5 gene transrepression could involve a phosphorylation of USFs through the PI3K and P70 S6 kinase pathways that modulate their binding to the APOA5 E box and results in APOA5 down-regulation. The effect of exogenous hyperinsulinemia in men showed a decrease in the plasma ApoAV level. These results suggest a potential contribution of the APOA5 gene in hypertriglyceridemia associated with hyperinsulinemia. PMID:15684402

  13. Glucose Regulates the Expression of the Apolipoprotein A5 Gene

    SciTech Connect

    Fruchart, Jamila; Nowak, Maxime; Helleboid-Chapman, Audrey; Jakel, Heidelinde; Moitrot, Emmanuelle; Rommens, Corinne; Pennacchio, Len A.; Fruchart-Najib, Jamila; Fruchart, Jean-Charles

    2008-04-07

    The apolipoprotein A5 gene (APOA5) is a key player in determining triglyceride concentrations in humans and mice. Since diabetes is often associated with hypertriglyceridemia, this study explores whether APOA5 gene expression is regulated by alteration in glucose homeostasis and the related pathways. D-glucose activates APOA5 gene expression in a time- and dose-dependent manner in hepatocytes, and the glycolytic pathway involved was determined using D-glucose analogs and metabolites. Together, transient transfections, electrophoretic mobility shift assays and chromatin immunoprecipitation assays show that this regulation occurs at the transcriptional level through an increase of USF1/2 binding to an E-box in the APOA5 promoter. We show that this phenomenon is not due to an increase of mRNA or protein expression levels of USF. Using protein phosphatases 1 and 2A inhibitor, we demonstrate that D-glucose regulates APOA5 gene via a dephosphorylation mechanism, thereby resulting in an enhanced USF1/2-promoter binding. Last, subsequent suppressions of USF1/2 and phosphatases mRNA through siRNA gene silencing abolished the regulation. We demonstrate that APOA5 gene is up regulated by D-glucose and USF through phosphatase activation. These findings may provide a new cross talk between glucose and lipid metabolism.

  14. Orphan nuclear receptor Nur77 participates in human apolipoprotein A5 gene expression

    SciTech Connect

    Song, Kwang-Hoon

    2010-01-29

    The orphan nuclear receptor Nur77 (NR4A1) has been reported to play a crucial role in the modulation of diverse metabolic processes in liver. Here, we reported the identification of human apolipoprotein A5 (ApoA5), which implicated in lowering plasma triglyceride levels, as a novel target gene of Nur77. Nur77 induced the human ApoA5 promoter activity. Using 5'-deletion and mutagenesis of human ApoA5 promoter analysis and chromatin immunoprecipitation assays, it was shown that Nur77 directly regulated human ApoA5 gene expression by binding to a Nur77 response element (AAAGGTCA) located in the proximal human ApoA5 promoter region. In addition, we demonstrated that blocking of Nur77 transcriptional activity via overexpression of dominant negative Nur77 suppressed human ApoA5 promoter activity and mRNA expression in human hepatoma cells, HepG2. Taken together, our results demonstrated that Nur77 is a novel regulator of human ApoA5 gene expression and provide a new insight into the role of this orphan nuclear receptor in lipoprotein metabolism and triglyceride homeostasis.

  15. Phosphorylation-dependent down-regulation of apolipoprotein A5 by insulin

    SciTech Connect

    Nowak, Maxine; Helleboid-Chapman, Audrey; Jakel, Heidelinde; Rommens, Corinne; Martin, Genevieve; Duran-Sandoval, Daniel; Staels, Bart; Rubin, Edward M.; Pennacchio, Len A.; Taskinen, Marja-Riitta; Fruchart-Najib, Jamila; Fruchart, Jean-Charles

    2004-02-15

    The apolipoprotein A5 (APOA5) gene has been shown to be important in lowering plasma triglyceride levels. Since several studies have shown that hyperinsulinemia is associated with hypertriglyceridemia, we sought to determine whether APOA5 gene is regulated by insulin. We show here that cell and mouse treatments with insulin down-regulated APOA5 expression in a dose-dependent manner. Furthermore, we determined that insulin decreases APOA5 promoter activity and subsequent deletion analyses revealed an E-box-containing fragment. We showed that Upstream Stimulatory Factors, USF1/USF2, bind to the identified E-box in the APOA5 promoter. Moreover, in cotransfection studies, USF1 stimulates APOA5 promoter activity. The treatment with insulin reduces the binding of USF1/USF2 to APOA5 promoter. The inhibition of PI3K pathway with wortmannin abolished the insulin s effect on APOA5 gene transcription. Using oligoprecipitation method of USF from nuclear extracts, we demonstrated that phosphorylated USF1 failed to bind to APOA5 promoter. This indicates that the APOA5 gene transrepression by insulin involves a phosphorylation of USF through PI3K, that modulate their binding to APOA5 promoter and results in APOA5 down-regulation. The effect of exogenous hyperinsulinemia in healthy men shows a decrease of the plasma ApoAV level. These data suggest a potential mechanism involving APOA5 gene in hypertriglyceridemia associated with hyperinsulinemia.

  16. Apolipoprotein A5: A newly identified gene impacting plasmatriglyceride levels in humans and mice

    SciTech Connect

    Pennacchio, Len A.; Rubin, Edward M.

    2002-09-15

    Apolipoprotein A5 (APOA5) is a newly described member of theapolipoprotein gene family whose initial discovery arose from comparativesequence analysis of the mammalian APOA1/C3/A4 gene cluster. Functionalstudies in mice indicated that alteration in the level of APOA5significantly impacted plasma triglyceride concentrations. Miceover-expressing human APOA5 displayed significantly reducedtriglycerides, while mice lacking apoA5 had a large increase in thislipid parameter. Studies in humans have also suggested an important rolefor APOA5 in determining plasma triglyceride concentrations. In theseexperiments, polymorphisms in the human gene were found to define severalcommon haplotypes that were associated with significant changes intriglyceride concentrations in multiple populations. Several separateclinical studies have provided consistent and strong support for theeffect with 24 percent of Caucasians, 35 percent of African-Americans and53 percent of Hispanics carrying APOA5 haplotypes associated withincreased plasma triglyceride levels. In summary, APOA5 represents anewly discovered gene involved in triglyceride metabolism in both humansand mice whose mechanism of action remains to be deciphered.

  17. Association of apolipoprotein A5 concentration with serum insulin and triglyceride levels and coronary artery disease in Korean men

    Technology Transfer Automated Retrieval System (TEKTRAN)

    OBJECTIVE: Whereas the relation between apolipoprotein A5 (APOA5) gene polymorphisms and triglycerides (TG) levels is well established, the associations between apoA5 concentrations, TG and coronary artery disease (CAD) remain controversial. Therefore, we investigated these relations in the setting ...

  18. Two independent apolipoprotein A5 haplotypes influence human plasma triglyceride levels.

    PubMed

    Pennacchio, Len A; Olivier, Michael; Hubacek, Jaroslav A; Krauss, Ronald M; Rubin, Edward M; Cohen, Jonathan C

    2002-11-15

    The recently identified apolipoprotein A5 gene (APOA5) has been shown to play an important role in determining plasma triglyceride concentrations in humans and mice. We previously identified an APOA5 haplotype (designated APOA5*2) that is present in approximately 16% of Caucasians and is associated with increased plasma triglyceride concentrations. In this report we describe another APOA5 haplotype (APOA5*3) containing the rare allele of the single nucleotide polymorphism c.56C>G that changes serine to tryptophan at codon 19 and is independently associated with high plasma triglyceride levels in three different populations. In a sample of 264 Caucasian men and women with plasma triglyceride concentrations above the 90th percentile or below the 10th percentile, the APOA5*3 haplotype was more than three-fold more common in the group with high plasma triglyceride levels. In a second independently ascertained sample of Caucasian men and women (n=419) who were studied while consuming their self-selected diets as well as after high-carbohydrate diets and high-fat diets, the APOA5*3 haplotype was associated with increased plasma triglyceride levels on all three dietary regimens. In a third population comprising 2660 randomly selected individuals, the APOA5*3 haplotype was found in 12% of Caucasians, 14% of African-Americans and 28% of Hispanics and was associated with increased plasma triglyceride levels in both men and women in each ethnic group. These findings establish that the APOA5 locus contributes significantly to inter-individual variation in plasma triglyceride levels in humans. Together, the APOA5*2 and APOA5*3 haplotypes are found in 25-50% of African-Americans, Hispanics and Caucasians and support the contribution of common human variation to quantitative phenotypes in the general population.

  19. Two independent apolipoprotein a5 Haplotypes influence human plasma triglyceride levels

    SciTech Connect

    Pennacchio, Len A.; Olivier, Michael; Hubacek, Jaroslav A.; Krauss, Ronald M.; Rubin, Edward M.; Cohen, Jonathan C.

    2002-09-16

    The recently identified apolipoprotein A5 gene (APOA5) has been shown to play an important role in determining plasma triglyceride concentrations in humans and mice. We previously identified an APOA5 haplotype (designated APOA5*2) that is present in {approx}16 percent of Caucasians and is associated with increased plasma triglyceride concentrations. In this report we describe another APOA5 haplotype (APOA5*3) containing the rare allele of the single nucleotide polymorphism c.56C>G that changes serine to tryptophan at codon 19 and is independently associated with high plasma triglyceride levels in three different populations. In a sample of 264 Caucasian men and women with plasma triglyceride concentrations above the 90th percentile or below the 10th percentile, the APOA5*3 haplotype was more than three-fold more common in the group with high plasma triglyceride levels. In a second independently ascertained sample of Caucasian men and women (n 1/4 419) who were studied while consuming their self-selected diets as well as after high-carbohydrate diets and high-fat diets, the APOA5*3 haplotype was associated with increased plasma triglyceride levels on all three dietary regimens. In a third population comprising 2660 randomly selected individuals, the APOA5*3 haplotype was found in 12 percent of Caucasians, 14 percent of African-Americans and 28 percent of Hispanics and was associated with increased plasma triglyceride levels in both men and women in each ethnic group. These findings establish that the APOA5 locus contributes significantly to inter-individual variation in plasma triglyceride levels in humans. Together, the APOA5*2 and APOA5*3 haplotypes are found in 25 50 percent of African-Americans, Hispanics and Caucasians and support the contribution of common human variation to quantitative phenotypes in the general population.

  20. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.

    PubMed

    Do, Ron; Stitziel, Nathan O; Won, Hong-Hee; Jørgensen, Anders Berg; Duga, Stefano; Angelica Merlini, Pier; Kiezun, Adam; Farrall, Martin; Goel, Anuj; Zuk, Or; Guella, Illaria; Asselta, Rosanna; Lange, Leslie A; Peloso, Gina M; Auer, Paul L; Girelli, Domenico; Martinelli, Nicola; Farlow, Deborah N; DePristo, Mark A; Roberts, Robert; Stewart, Alexander F R; Saleheen, Danish; Danesh, John; Epstein, Stephen E; Sivapalaratnam, Suthesh; Hovingh, G Kees; Kastelein, John J; Samani, Nilesh J; Schunkert, Heribert; Erdmann, Jeanette; Shah, Svati H; Kraus, William E; Davies, Robert; Nikpay, Majid; Johansen, Christopher T; Wang, Jian; Hegele, Robert A; Hechter, Eliana; Marz, Winfried; Kleber, Marcus E; Huang, Jie; Johnson, Andrew D; Li, Mingyao; Burke, Greg L; Gross, Myron; Liu, Yongmei; Assimes, Themistocles L; Heiss, Gerardo; Lange, Ethan M; Folsom, Aaron R; Taylor, Herman A; Olivieri, Oliviero; Hamsten, Anders; Clarke, Robert; Reilly, Dermot F; Yin, Wu; Rivas, Manuel A; Donnelly, Peter; Rossouw, Jacques E; Psaty, Bruce M; Herrington, David M; Wilson, James G; Rich, Stephen S; Bamshad, Michael J; Tracy, Russell P; Cupples, L Adrienne; Rader, Daniel J; Reilly, Muredach P; Spertus, John A; Cresci, Sharon; Hartiala, Jaana; Tang, W H Wilson; Hazen, Stanley L; Allayee, Hooman; Reiner, Alex P; Carlson, Christopher S; Kooperberg, Charles; Jackson, Rebecca D; Boerwinkle, Eric; Lander, Eric S; Schwartz, Stephen M; Siscovick, David S; McPherson, Ruth; Tybjaerg-Hansen, Anne; Abecasis, Goncalo R; Watkins, Hugh; Nickerson, Deborah A; Ardissino, Diego; Sunyaev, Shamil R; O'Donnell, Christopher J; Altshuler, David; Gabriel, Stacey; Kathiresan, Sekar

    2015-02-01

    Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.

  1. Multiple rare alleles at LDLR and APOA5 confer risk for early-onset myocardial infarction

    PubMed Central

    Do, Ron; Stitziel, Nathan O.; Won, Hong-Hee; Jørgensen, Anders Berg; Duga, Stefano; Merlini, Pier Angelica; Kiezun, Adam; Farrall, Martin; Goel, Anuj; Zuk, Or; Guella, Illaria; Asselta, Rosanna; Lange, Leslie A.; Peloso, Gina M.; Auer, Paul L.; Girelli, Domenico; Martinelli, Nicola; Farlow, Deborah N.; DePristo, Mark A.; Roberts, Robert; Stewart, Alexander F.R.; Saleheen, Danish; Danesh, John; Epstein, Stephen E.; Sivapalaratnam, Suthesh; Hovingh, G. Kees; Kastelein, John J.; Samani, Nilesh J.; Schunkert, Heribert; Erdmann, Jeanette; Shah, Svati H.; Kraus, William E.; Davies, Robert; Nikpay, Majid; Johansen, Christopher T.; Wang, Jian; Hegele, Robert A.; Hechter, Eliana; Marz, Winfried; Kleber, Marcus E.; Huang, Jie; Johnson, Andrew D.; Li, Mingyao; Burke, Greg L.; Gross, Myron; Liu, Yongmei; Assimes, Themistocles L.; Heiss, Gerardo; Lange, Ethan M.; Folsom, Aaron R.; Taylor, Herman A.; Olivieri, Oliviero; Hamsten, Anders; Clarke, Robert; Reilly, Dermot F.; Yin, Wu; Rivas, Manuel A.; Donnelly, Peter; Rossouw, Jacques E.; Psaty, Bruce M.; Herrington, David M.; Wilson, James G.; Rich, Stephen S.; Bamshad, Michael J.; Tracy, Russell P.; Cupples, L. Adrienne; Rader, Daniel J.; Reilly, Muredach P.; Spertus, John A.; Cresci, Sharon; Hartiala, Jaana; Tang, W.H. Wilson; Hazen, Stanley L.; Allayee, Hooman; Reiner, Alex P.; Carlson, Christopher S.; Kooperberg, Charles; Jackson, Rebecca D.; Boerwinkle, Eric; Lander, Eric S.; Schwartz, Stephen M.; Siscovick, David S.; McPherson, Ruth; Tybjaerg-Hansen, Anne; Abecasis, Goncalo R.; Watkins, Hugh; Nickerson, Deborah A.; Ardissino, Diego; Sunyaev, Shamil R.; O’Donnell, Christopher J.; Altshuler, David; Gabriel, Stacey; Kathiresan, Sekar

    2014-01-01

    Summary Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance1,2. When MI occurs early in life, the role of inheritance is substantially greater1. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families3–8 whereas common variants at more than 45 loci have been associated with MI risk in the population9–15. Here, we evaluate the contribution of rare mutations to MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes where rare coding-sequence mutations were more frequent in cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare, damaging mutations (3.1% of cases versus 1.3% of controls) were at 2.4-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). This sequence-based estimate of the proportion of early MI cases due to LDLR mutations is remarkably similar to an estimate made more than 40 years ago using total cholesterol16. At apolipoprotein A-V (APOA5), carriers of rare nonsynonymous mutations (1.4% of cases versus 0.6% of controls) were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase15,17 and apolipoprotein C318,19. When combined, these observations suggest that, beyond LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk. PMID:25487149

  2. Association analysis of APOA5 rs662799 and rs3135506 polymorphisms with obesity in Moroccan patients.

    PubMed

    Lakbakbi El Yaagoubi, F; Charoute, H; Bakhchane, A; Ajjemami, M; Benrahma, H; Errouagui, A; Kandil, M; Rouba, H; Barakat, A

    2015-12-01

    The aim of the present study is to explore the association between the APOA5 polymorphisms and haplotypes with obesity in Moroccan patients. The study was performed in 459 subjects, Obese (n=164) and non-obese (n=295). All subjects were genotyped for the APOA5 -1131T>C (rs662799) and c.56C>G (rs3135506) polymorphisms. The contribution of APOA5 polymorphisms and haplotypes in the increased risk of obesity were explored using logistic regression analyses. The -1131T>C and c.56C>G polymorphisms were significantly associated with obesity. Both polymorphisms were strongly associated with increased BMI. Analysis of constructed haplotypes showed a significant association between CG haplotype and susceptibility to obesity (OR [95%CI]=3.09 [1.93-4.97]; P<0.001). These results support a potential role for APOA5 common variants and related haplotypes as risk factors for obesity.

  3. Increased risk of obesity related to total energy intake with the APOA5-1131T > C polymorphism in Korean premenopausal women.

    PubMed

    Lim, Hyo Hee; Choi, Miok; Kim, Ji Young; Lee, Jong Ho; Kim, Oh Yoen

    2014-10-01

    We hypothesized that triglyceride-raising apolipoprotein A5 (APOA5)-1131T > C may contribute to the increased risk of obesity associated with dietary intake in Korean premenopausal women whose minor allele frequency is higher than that in Western people. Genetically unrelated Korean premenopausal women (approximately 20-59 years, n = 1128) were genotyped for APOA5-1131T > C. Anthropometric, metabolic parameters and dietary intakes were analyzed. Odds ratios (ORs) for obesity risk (body mass index, ≥25.0 kg/m(2)) were calculated. Genotype distribution of APOA5-1131T > C of study subjects were like TT: 49.9%, TC: 40.8%, and CC: 9.3%. We found a significant interaction between APOA5-1131T > C and total energy intake (TEI) for obesity after adjusted for age, cigarette smoking, and alcohol consumption (P < .001). The risk of obesity in CC homozygotes compared with T carriers (TT + TC) was significantly increased, when the subjects consume higher TEI (≥2001 kcal/d (8372 kJ/d), median value of the population) (OR, 2.495; 95% confidence intervals, 1.325-4.696; P = .005), particularly, when they maintain negative balance between total energy expenditure and TEI (total energy expenditure/TEI, <1) (OR, 2.917; 95% confidence intervals, 1.451-5.864; P = .003). The contributions of APOA5-1131CC homozygotes to obesity risk in those who consume higher TEI were all significantly high regardless of percentage of energy intake from dietary macronutrients. Whereas, no significant association was observed in those who consume lower TEI (<2001 kcal/d). In addition, serum levels of triglyceride, high-density lipoprotein-cholesterol, and apolipoprotein A5 were associated with APOA5-1131T > C and TEI. These findings suggest that APOA5-1131CC homozygotes may influence the susceptibility of the individual to obesity, particularly, when they consume higher TEI, but the genetic effect may be attenuated, when people maintain low or adequate energy intake.

  4. Analysis of apolipoprotein A5, C3 and plasma triglyceride concentrations in genetically engineered mice

    SciTech Connect

    Baroukh, Nadine; Bauge, Eric; Akiyama, Jennifer; Chang, Jessie; Afzal, Veena; Fruchart, Jean-Charles; Rubin, Edward M.; Fruchart, Jamila; Pennacchio, Len A.

    2004-03-11

    To address the relationship between the apolipoprotein A5 and C3 genes, we generated independent lines of mice that either over-expressed or completely lacked both genes. We report both lines display normal triglyceride concentrations compared to over-expression or deletion of either gene alone. Together, these data support that APOA5 and APOC3 independently influence plasma triglyceride concentrations but in an opposing manner.

  5. Additive effects of LPL, APOA5 and APOE variant combinations on triglyceride levels and hypertriglyceridemia: results of the ICARIA genetic sub-study

    PubMed Central

    2010-01-01

    Background Hypertriglyceridemia (HTG) is a well-established independent risk factor for cardiovascular disease and the influence of several genetic variants in genes related with triglyceride (TG) metabolism has been described, including LPL, APOA5 and APOE. The combined analysis of these polymorphisms could produce clinically meaningful complementary information. Methods A subgroup of the ICARIA study comprising 1825 Spanish subjects (80% men, mean age 36 years) was genotyped for the LPL-HindIII (rs320), S447X (rs328), D9N (rs1801177) and N291S (rs268) polymorphisms, the APOA5-S19W (rs3135506) and -1131T/C (rs662799) variants, and the APOE polymorphism (rs429358; rs7412) using PCR and restriction analysis and TaqMan assays. We used regression analyses to examine their combined effects on TG levels (with the log-transformed variable) and the association of variant combinations with TG levels and hypertriglyceridemia (TG ≥ 1.69 mmol/L), including the covariates: gender, age, waist circumference, blood glucose, blood pressure, smoking and alcohol consumption. Results We found a significant lowering effect of the LPL-HindIII and S447X polymorphisms (p < 0.0001). In addition, the D9N, N291S, S19W and -1131T/C variants and the APOE-ε4 allele were significantly associated with an independent additive TG-raising effect (p < 0.05, p < 0.01, p < 0.001, p < 0.0001 and p < 0.001, respectively). Grouping individuals according to the presence of TG-lowering or TG-raising polymorphisms showed significant differences in TG levels (p < 0.0001), with the lowest levels exhibited by carriers of two lowering variants (10.2% reduction in TG geometric mean with respect to individuals who were homozygous for the frequent alleles of all the variants), and the highest levels in carriers of raising combinations (25.1% mean TG increase). Thus, carrying two lowering variants was protective against HTG (OR = 0.62; 95% CI, 0.39-0.98; p = 0.042) and having one single raising polymorphism (OR

  6. Effects of apolipoprotein A5 haplotypes on the ratio of triglyceride to high-density lipoprotein cholesterol and the risk for metabolic syndrome in Koreans

    PubMed Central

    2014-01-01

    Background Single-nucleotide polymorphisms (SNPs) around the apolipoprotein A5 gene (APOA5) have pleiotropic effects on the levels of triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C). APOA5 SNPs have also been associated with metabolic syndrome (MS). Here, we constructed haplotypes with SNPs spanning APOA5 and ZNF259, which are approximately 1.3 kb apart, to perform association analyses with the risk for MS and the levels of TG and HDL-C in terms of a TG:HDL-C ratio. Methods The effects of three constructed haplotypes (TAA, CGG, and CGA, in the order of rs662799, rs651821, and rs6589566) on the TG:HDL-C ratio and MS were estimated using multiple regression analyses in 2,949 Koreans and in each gender separately (1,082 men and 1,867 women). Results The haplotypes, CGG and CGA, were associated with the TG:HDL-C ratio and the risk of MS development in both genders. That is, the minor alleles of the rs662799 and rs651821 in APOA5, irrespective of which allele was present at rs6589566, had the marked effects. Interestingly, a C–G–A haplotype at these three SNPs had the most marked effects on the TG:HDL-C ratio and the risk of MS development in women. Conclusions We have identified the novel APOA5-ZNF259 haplotype manifesting sex-dependent effects on elevation of the TG:HDL-C ratio as well as the increased risk for MS. PMID:24618354

  7. Apolipoprotein A5, a crucial determinant of plasma triglyceridelevels, is highlyresponsive to PPARalpha activators

    SciTech Connect

    Vu-Dac, Ngoc; Gervois, Philippe; Jakel, Heidi; Nowak, Maxine; Bauge, Eric; Dehondt, Helene; Staels, Bart; Pennacchio, Len A.; Fruchart-Najib, Jamila; Fruchart, Jean-Charles

    2003-03-30

    The recently discovered APOA5 gene has been shown in humans and mice to be important in determining plasma triglycerides (TG) levels, a major cardiovascular disease risk factor. APOAV represents the first described apolipoprotein where over-expression lowers triglyceride levels. Since fibrates represent a commonly used therapy for lowering plasma triglycerides in humans, we investigated their ability to modulate APOA5 gene expression and consequently influence plasma TG levels. Human primary hepatocytes treated with Wy 14,643 or fenofibrate displayed a strong induction of APOA5 mRNA. Deletion and mutagenesis analyses of the proximal APOA5 promoter firmly demonstrate the presence of a functional PPAR response element. These findings demonstrate that APOA5 is a highly responsive PPARa target gene and support its role as a major mediator for how fibrates reduce plasma triglycerides in humans.

  8. Haplotypes in the APOA1-C3-A4-A5 gene cluster affect plasma lipids in both humans and baboons.

    PubMed

    Wang, Qian-fei; Liu, Xin; O'Connell, Jeff; Peng, Ze; Krauss, Ronald M; Rainwater, David L; VandeBerg, John L; Rubin, Edward M; Cheng, Jan-Fang; Pennacchio, Len A

    2004-05-15

    Genetic studies in non-human primates serve as a potential strategy for identifying genomic intervals where polymorphisms impact upon human disease-related phenotypes. It remains unclear, however, whether independently arising polymorphisms in orthologous regions of non-human primates leads to similar variation in a quantitative trait found in both species. To explore this paradigm, we studied a baboon apolipoprotein gene cluster (APOA1/C3/A4/A5) for which the human gene orthologs have well-established roles in influencing plasma HDL-cholesterol and triglyceride concentrations. Our extensive polymorphism analysis of this 68 kb gene cluster in 96 pedigreed baboons identified several haplotype blocks each with limited diversity, consistent with haplotype findings in humans. To determine whether baboons, like humans, also have particular haplotypes associated with lipid phenotypes, we genotyped 634 well-characterized baboons using 16 haplotype tagging SNPs. Genetic analysis of single SNPs, as well as haplotypes, revealed an association of APOA5 and APOC3 variants with HDL-cholesterol and triglyceride concentrations, respectively. Thus, independent variation in orthologous genomic intervals does associate with similar quantitative lipid traits in both species, supporting the possibility of uncovering human quantitative trait loci genes in a highly controlled non-human primate model.

  9. Haplotypes in the APOA1-C3-A4-A5 gene cluster affect plasma lipids in both humans and baboons

    SciTech Connect

    Wang, Qian-fei; Liu, Xin; O'Connell, Jeff; Peng, Ze; Krauss, Ronald M.; Rainwater, David L.; VandeBerg, John L.; Rubin, Edward M.; Cheng, Jan-Fang; Pennacchio, Len A.

    2003-09-15

    Genetic studies in non-human primates serve as a potential strategy for identifying genomic intervals where polymorphisms impact upon human disease-related phenotypes. It remains unclear, however, whether independently arising polymorphisms in orthologous regions of non-human primates leads to similar variation in a quantitative trait found in both species. To explore this paradigm, we studied a baboon apolipoprotein gene cluster (APOA1/C3/A4/A5) for which the human gene orthologs have well established roles in influencing plasma HDL-cholesterol and triglyceride concentrations. Our extensive polymorphism analysis of this 68 kb gene cluster in 96 pedigreed baboons identified several haplotype blocks each with limited diversity, consistent with haplotype findings in humans. To determine whether baboons, like humans, also have particular haplotypes associated with lipid phenotypes, we genotyped 634 well characterized baboons using 16 haplotype tagging SNPs. Genetic analysis of single SNPs, as well as haplotypes, revealed an association of APOA5 and APOC3 variants with HDL cholesterol and triglyceride concentrations, respectively. Thus, independent variation in orthologous genomic intervals does associate with similar quantitative lipid traits in both species, supporting the possibility of uncovering human QTL genes in a highly controlled non-human primate model.

  10. Linkage and association of haplotypes at the APOA1/C3/A4/A5 genecluster to familial combined hyperlipidemia

    SciTech Connect

    Eichenbaum-Voline, Sophie; Olivier, Michael; Jones, Emma L.; Naoumova, Rossitza P.; Jones, Bethan; Gau, Brian; Seed, Mary; Betteridge,D. John; Galton, David J.; Rubin, Edward M.; Scott, James; Shoulders,Carol C.; Pennacchio, Len A.

    2002-09-15

    Combined hyperlipidemia (CHL) is a common disorder of lipidmetabolism that leads to an increased risk of cardiovascular disease. Thelipid profile of CHL is characterised by high levels of atherogeniclipoproteins and low levels of high-density-lipoprotein-cholesterol.Apolipoprotein (APO) A5 is a newly discovered gene involved in lipidmetabolism located within 30kbp of the APOA1/C3/A4 gene cluster. Previousstudies have indicated that sequence variants in this cluster areassociated with increased plasma lipid levels. To establish whethervariation at the APOA5 gene contributes to the transmission of CHL, weperformed linkage and linkage disequilibrium (LD) tests on a large cohortof families (n=128) with familial CHL (FCHL). The linkage data producedevidence for linkage of the APOA1/C3/A4/A5 genomic interval to FCHL (NPL= 1.7, P = 0.042). The LD studies substantiated these data. Twoindependent rare alleles, APOA5c.56G and APOC3c.386G of this gene clusterwere over-transmitted in FCHL (P = 0.004 and 0.007, respectively), andthis was associated with a reduced transmission of the most commonAPOA1/C3/A4/A5 haplotype (frequency 0.4425) to affected subjects (P =0.013). The APOA5c.56G allele was associated with increased plasmatriglyceride levels in FCHL probands, whereas the second, andindependent, APOC3c.386G allele was associated with increased plasmatriglyceride levels in FCHL pedigree founders. Thus, this allele (or anallele in LD) may mark a quantitative trait associated with FCHL, as wellas representing a disease susceptibility locus for the condition. Thisstudy establishes that sequence variation in the APOA1/C3/A4/A5 genecluster contributes to the transmission of FCHL in a substantialproportion of affected families, and that these sequence variants mayalso contribute to the lipid abnormalities of the metabolic syndrome,which is present in up to 40 percent of persons with cardiovasculardisease.

  11. Single nucleotide polymorphisms in CETP, SLC46A1, SLC19A1, CD36, BCMO1, APOA5, and ABCA1 are significant predictors of plasma HDL in healthy adults

    PubMed Central

    2013-01-01

    Background In a marker-trait association study we estimated the statistical significance of 65 single nucleotide polymorphisms (SNP) in 23 candidate genes on HDL levels of two independent Caucasian populations. Each population consisted of men and women and their HDL levels were adjusted for gender and body weight. We used a linear regression model. Selected genes corresponded to folate metabolism, vitamins B-12, A, and E, and cholesterol pathways or lipid metabolism. Methods Extracted DNA from both the Sacramento and Beltsville populations was analyzed using an allele discrimination assay with a MALDI-TOF mass spectrometry platform. The adjusted phenotype, y, was HDL levels adjusted for gender and body weight only statistical analyses were performed using the genotype association and regression modules from the SNP Variation Suite v7. Results Statistically significant SNP (where P values were adjusted for false discovery rate) included: CETP (rs7499892 and rs5882); SLC46A1 (rs37514694; rs739439); SLC19A1 (rs3788199); CD36 (rs3211956); BCMO1 (rs6564851), APOA5 (rs662799), and ABCA1 (rs4149267). Many prior association trends of the SNP with HDL were replicated in our cross-validation study. Significantly, the association of SNP in folate transporters (SLC46A1 rs37514694 and rs739439; SLC19A1 rs3788199) with HDL was identified in our study. Conclusions Given recent literature on the role of niacin in the biogenesis of HDL, focus on status and metabolism of B-vitamins and metabolites of eccentric cleavage of β-carotene with lipid metabolism is exciting for future study. PMID:23656756

  12. Effects of a 3-year dietary intervention on age-related changes in triglyceride and apolipoprotein A-V levels in patients with impaired fasting glucose or new-onset type 2 diabetes as a function of the APOA5 -1131 T > C polymorphism

    PubMed Central

    2014-01-01

    Background The purpose of this study was to estimate the effects of a 3-year dietary intervention on age-related changes in triglyceride and apolipoprotein (apo A-V) levels in patients with impaired fasting glucose (IFG) or new-onset type 2 diabetes as a function of the APOA5 -1131 T > C polymorphism. Methods We genotyped the APOA5 -1131 T > C polymorphism in 203 Korean individuals with IFG or new-onset type 2 diabetes for the TT (n = 91), TC (n = 98), and CC (n = 14) alleles. Plasma apo A-V and triglyceride levels were evaluated at baseline and after a 3-year dietary intervention. Results Our results showed that HDL, glucose, insulin, HOMA-IR index, free fatty acids, and apo A-V decreased and brachial-ankle pulse wave velocity (ba-PWV) and malondialdehyde (MDA) increased at the 3-year follow-up visit compared with baseline. Plasma apo A-V levels were reduced in subjects with the C allele (TC or CC) (P = 0.036) and triglyceride levels were reduced in subjects with the TT allele (P = 0.047). Subjects with the C allele showed lower post-treatment apo A-V and higher post-treatment fasting triglyceride levels than subjects with the TT allele. Changes in apo A-V and triglyceride levels were negatively correlated in subjects with the TT allele and positively correlated in subjects with the C allele. Conclusions This study showed that the dietary intervention prevented an age-related increase in triglyceride levels in individuals with IFG or new-onset type 2 diabetes who possess the TT allele, but not the CT or CC allele, of the APOA5 -1131 T > C polymorphism. PMID:24775272

  13. Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

    SciTech Connect

    Kim, Sangsoo Daniel; Antenos, Monica; Squires, E. James; Kirby, Gordon M.

    2013-07-15

    Bilirubin (BR) has recently been identified as the first endogenous substrate for cytochrome P450 2A5 (CYP2A5) and it has been suggested that CYP2A5 plays a major role in BR clearance as an alternative mechanism to BR conjugation by uridine-diphosphate glucuronyltransferase 1A1. This study investigated the mechanisms of Cyp2a5 gene regulation by BR and the cytoprotective role of CYP2A5 in BR hepatotoxicity. BR induced CYP2A5 expression at the mRNA and protein levels in a dose-dependent manner in primary mouse hepatocytes. BR treatment also caused nuclear translocation of Nuclear factor-E2 p45-related factor 2 (Nrf2) in hepatocytes. In reporter assays, BR treatment of primary hepatocytes transfected with a Cyp2a5 promoter-luciferase reporter construct resulted in a 2-fold induction of Cyp2a5 reporter activity. Furthermore, cotransfection of the hepatocytes with a Nrf2 expression vector without BR treatment resulted in an increase in Cyp2a5 reporter activity of approximately 2-fold and BR treatment of Nrf2 cotransfectants further increased reporter activity by 4-fold. In addition, site-directed mutation of the ARE in the reporter construct completely abolished both the BR- and Nrf2-mediated increases in reporter activity. The cytoprotective role of CYP2A5 against BR-mediated apoptosis was also examined in Hepa 1–6 cells that lack endogenous CYP2A5. Transient overexpression of CYP2A5 partially blocked BR-induced caspase-3 cleavage in Hepa 1–6 cells. Furthermore, in vitro degradation of BR was increased by microsomes from Hepa 1–6 cells overexpressing CYP2A5 compared to control cells transfected with an empty vector. Collectively, these results suggest that Nrf2-mediated CYP2A5 transactivation in response to BR may provide an additional mechanism for adaptive cytoprotection against BR hepatotoxicity. - Highlights: • The mechanism of Cyp2a5 gene regulation by BR was investigated. • The cytoprotective role of CYP2A5 in BR hepatotoxicity was determined. • BR

  14. SLC7A5 act as a potential leukemic transformation target gene in myelodysplastic syndrome

    PubMed Central

    Ma, Yan; Song, Jing; Chen, Bobin; Xu, Xiaoping; Lin, Guowei

    2016-01-01

    Objective Myelodysplastic syndromes (MDS) are a heterogenous group of clonal hematopoietic stem cell disorders characterized by increased risk of leukemic transformation. This study identifies microRNAs(miRNA) and miRNA targets that might represent leukemic transformation markers for MDS. Methods Based on our previously established nested case-control study cohort of MDS patients, we chose paired patients to undergo Angilent 8 × 15K human miRNA microarrays. Target prediction analysis was administrated using targetscan 5.1 software. We further investigated the function of target gene in MDS cell line using siRNA method, including cell proliferation, cell apoptosis, cell cycle and electron microscope. Results Finally we screened a subset of 7 miRNAs to be significantly differentially expressed between the case (at the end of follow up with leukemic transformation) and control group (at the end of follow up without leukemic transformation). Target prediction analysis revealed SLC7A5 was the common target gene of these 7 miRNAs. Further study on the function of SLC7A5 gene in SKM-1 cell line showed that downregulation of SLC7A5 inhibited SKM-1 cells proliferation, increased apoptosis and caused cell cycle arrest in the G0/G1 stage. Conclusion Our data indicate that SLC7A5 gene may act as a potential leukemic transformation target gene in MDS. PMID:26657287

  15. Molecular diversity and population structure at the Cytochrome P450 3A5 gene in Africa

    PubMed Central

    2013-01-01

    Background Cytochrome P450 3A5 (CYP3A5) is an enzyme involved in the metabolism of many therapeutic drugs. CYP3A5 expression levels vary between individuals and populations, and this contributes to adverse clinical outcomes. Variable expression is largely attributed to four alleles, CYP3A5*1 (expresser allele); CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343) (low/non-expresser alleles). Little is known about CYP3A5 variability in Africa, a region with considerable genetic diversity. Here we used a multi-disciplinary approach to characterize CYP3A5 variation in geographically and ethnically diverse populations from in and around Africa, and infer the evolutionary processes that have shaped patterns of diversity in this gene. We genotyped 2538 individuals from 36 diverse populations in and around Africa for common low/non-expresser CYP3A5 alleles, and re-sequenced the CYP3A5 gene in five Ethiopian ethnic groups. We estimated the ages of low/non-expresser CYP3A5 alleles using a linked microsatellite and assuming a step-wise mutation model of evolution. Finally, we examined a hypothesis that CYP3A5 is important in salt retention adaptation by performing correlations with ecological data relating to aridity for the present day, 10,000 and 50,000 years ago. Results We estimate that ~43% of individuals within our African dataset express CYP3A5, which is lower than previous independent estimates for the region. We found significant intra-African variability in CYP3A5 expression phenotypes. Within Africa the highest frequencies of high-activity alleles were observed in equatorial and Niger-Congo speaking populations. Ethiopian allele frequencies were intermediate between those of other sub-Saharan African and non-African groups. Re-sequencing of CYP3A5 identified few additional variants likely to affect CYP3A5 expression. We estimate the ages of CYP3A5*3 as ~76,400 years and CYP3A5*6 as ~218,400 years. Finally we report that global CYP3A5 expression

  16. A 5.8S nuclear ribosomal RNA gene sequence database: applications to ecology and evolution

    NASA Technical Reports Server (NTRS)

    Cullings, K. W.; Vogler, D. R.

    1998-01-01

    We complied a 5.8S nuclear ribosomal gene sequence database for animals, plants, and fungi using both newly generated and GenBank sequences. We demonstrate the utility of this database as an internal check to determine whether the target organism and not a contaminant has been sequenced, as a diagnostic tool for ecologists and evolutionary biologists to determine the placement of asexual fungi within larger taxonomic groups, and as a tool to help identify fungi that form ectomycorrhizae.

  17. Linkage approach and direct COL4A5 gene mutation screening in Alport syndrome

    SciTech Connect

    Turco, A.E.; Rossetti, S.; Biasi, O.

    1994-09-01

    Alport Syndrome (AS) is transmitted as an X-linked dominant trait in the majority of families, the defective gene being COL4A5 at Xq22. In the remaining cases AS appears to be autosomally inherited. Recently, mutations in COL4A3 and COL4A4 genes at 2q35-q37 were identified in families with autosomal recessive AS. Mutation detection screening is being performed by non-radioactive single stand conformation polymorphism (SSCP), heteroduplex analysis, and automated DNA sequencing in over 170 AS patients enrolled in the ongoing Italian Multicenter Study on AS. So far twenty-five different mutations have been found, including missense, splicing, and frameshifts. Moreover, by using six tightly linked COL4A5 informative makers, we have also typed two larger AS families, and have shown compatible sex-linked transmission in one other, suggesting autosomal recessive inheritance. In this latter three-generation COL4A5-unlinked family we are now looking for linkage and for mutations in the candidate COL4A3 and COL4A4 genes on chromosome 2q.

  18. Single nucleotide polymorphisms in CETP, SLC46A1, SLC19A1, CD36, BCOM1, APOA5, and ABCA1 are significant predictors of plasma HDL in healthy adults

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In a marker-trait association study we estimated the statistical significance of 65 single nucleotide polymorphisms (SNP) in 23 candidate genes on HDL levels of two independent Caucasian populations. Each population consisted of men and women and their HDL levels were adjusted for gender and body we...

  19. Aberrant splicing of the COL4A5 gene in patients with Alport syndrome.

    PubMed

    Lemmink, H H; Kluijtmans, L A; Brunner, H G; Schröder, C H; Knebelmann, B; Jelínková, E; van Oost, B A; Monnens, L A; Smeets, H J

    1994-02-01

    A variety of mutations have been identified in the X-linked type IV collagen alpha 5 chain (COL4A5) gene in patients with Alport syndrome. A substantial number of these mutations were predicted to have an effect on RNA splicing. For 4 such mutations in our group of patients the effect of the DNA mutation on the COL4A5 mRNA structure and stability was analysed. An alteration of the invariant splice acceptor site of intron 41 resulted in a shift of the actual splicing to either a cryptic splice site within exon 42 or the normal splice site in the next intron. A single base substitution of the final nucleotide of exon 48 resulted in the removal of the entire exon. Two frameshift mutations, a 10 basepair duplication in exon 49 and a single base deletion in exon 41, were incorporated in the mRNA as such and resulted in a stretch of missense codons terminated by a premature stop codon. Exon skipping was occasionally observed in these samples, but not reproducibly in every experiment. In healthy controls exon skipping was never detected. Analysis of female carriers revealed that in only one case was the stability of the mutated mRNA reduced in comparison with the normal transcript. The extent to which the non-collagenous domain was predicted to be deleted correlated with the severeness of the disease. PMID:8004101

  20. Give me A5 for lipoprotein hydrolysis!

    PubMed

    Merkel, Martin; Heeren, Joerg

    2005-10-01

    APOA5 is a newly identified apolipoprotein that plays a crucial role in the regulation of plasma triglyceride levels. In several human studies, common APOA5 single nucleotide polymorphisms have been strongly associated with elevated plasma triglyceride levels. In this issue of the JCI, Marçais et al. report that the rare Q139X mutation in APOA5 leads to severe hypertriglyceridemia by exerting a dominant-negative effect on the plasma lipolytic system for triglyceride-rich lipoproteins. The presented data support the idea that the molecular mechanism of APOA5 function may include the enhancement of binding between lipoproteins and proteoglycans at the vascular wall and activation of proteoglycan-bound lipoprotein lipase.

  1. Histone H3 methylation at lysine 4 on the SLC2A5 gene in intestinal Caco-2 cells is involved in SLC2A5 expression.

    PubMed

    Inamochi, Yuko; Mochizuki, Kazuki; Osaki, Ayumi; Ishii, Takeshi; Nakayama, Tsutomu; Goda, Toshinao

    2010-01-29

    Histone H3 methylation at lysine 4 (K4) is associated with euchromatic regions and is thought to be important for the transcriptional activation of genes during differentiation. In this study, we found that di- and tri-methylation of histone H3 at K4 and acetylation of histones H3 and H4 from the promoter/enhancer to the transcribed region close to the transcription initiation site of the solute carrier family 2, member 5 (SLC2A5) gene, and its expression, were induced by differentiation of intestine-like Caco-2 cells. These effects were accompanied by contact inhibition of cell growth of these cells. Furthermore, these modifications were induced by co-treatment with a synthetic glucocorticoid hormone dexamethasone and a p44/42 mitogen-activated protein kinase inhibitor PD89059. Our results suggest that methylation of histone H3 at K4 and acetylation of histones H3 and H4 are involved in SLC2A5 gene induction associated with intestinal differentiation of Caco-2 cells.

  2. Improved genetic counseling in Alport syndrome by new variants of COL4A5 gene.

    PubMed

    Fernandez-Rosado, Francisco; Campos, Ana; Alvarez-Cubero, Maria Jesus; Ruiz, Ana; Entrala-Bernal, Carmen

    2015-07-01

    There are current requirements of using genetic databases for offering a better genetic assistance to patients of some syndromes, especially those with X-linked heredity patterns (like Alport Syndrome) for the high probability of having descendants affected by the disease. We describe the first reported case of COL4A5 gene missense c.1499 G>T mutation in a 16-year-old girl confirmed to be affected by Alport Syndrome after genetic counseling. Next Generation Sequencing procedures let discover this mutation and offer an accurate clinical treatment to this patient. Current scientific understanding of genetic syndromes suggests the high importance of updated databases and the inclusion of Variant of Unknown Significance related to clinical cases. All of this updating could enable patients to have a better opportunity of diagnosis and having genetic and clinical counseling. This event is even more important in women planning to start a family to have correct genetic counseling regarding the risk posed to offspring, and allowing the decision to undergo prenatal testing.

  3. Phenotype-Genotype Discrepancy Due to a 5.5-kb Deletion in the GALT Gene.

    PubMed

    González-del Angel, Ariadna; Velázquez-Aragón, José; Alcántara-Ortigoza, Miguel A; Vela-Amieva, Marcela; Hernández-Martínez, Nancy

    2012-01-01

    Classical galactosemia is an autosomal recessive inborn error of metabolism caused by a deficiency of the galactose-1-phosphate uridyltransferase (GALT). More than 200 mutations have been described in the GALT gene. A 5.5-kb GALT deletion, first described in patients of Ashkenazi Jewish ancestry, may lead either to an erroneous genotype assignment of classical galactosemia or to discrepancies with parental genotypes and the expected biochemical phenotype. The presence of the 5.5-kb deletion was examined in 27 Mexican nonrelated families with at least one child with reduced GALT activity in erythrocytes and it was detected in the 5.5% (n=3) of the 54 alleles tested. The first molecular studies in three of our families showed that the genotypes of the parents were inconsistent with those of their children, which were considered initially as homozygous p.N314D-Duarte 2, but after analyzing for the presence of the 5.5-kb deletion, were reassigned as compound heterozygotes [5.5-kb deletion]+[p.N314D-Duarte 2]. Identification of the 5.5-kb deletion in Mexican patients suggests that this mutation might not be exclusive to a given ethnic group and should be tested in other populations, especially when there is a discrepancy between the genotypes of patients and parents or by incongruence between biochemical phenotype and GALT genotype. Establishing a genotype-phenotype correlation for the 5.5-kb GALT deletion and determining the appropriate management will require additional studies in patients with a G/G genotype bearing the 5.5-kb GALT deletion.

  4. Identification of four novel mutations in the COL4A5 gene of patients with Alport syndrome

    SciTech Connect

    Lemmink, H.H.; Schroeder, C.H.; Brunner, H.G.; Nelen, M.R.; Van Oost, B.A.; Smeets, H.J.M. ); Zhou, Jing; Tryggvason, K. ); Haagsma-Schouten, W.A.G. ); Roodvoets, A.P. ); Rascher, W. )

    1993-08-01

    The type IV collagen [alpha]5 chain (COL4A5) genes of patients with Alport syndrome were tested for major gene rearrangements by Southern blot analysis, using COL4A5 cDNA clones as probes. In addition, individual exons were screened for small mutations by single-strand conformation polymorphism (SSCP) analysis. Four new COL4A5 mutations were detected. A duplication of the nine most 3[prime] located nucleotides of exon 49 and the first nucleotide of intron 49 was identified in the COL4A5 gene of one patient. Two patients displayed single base substitutions leading to, respectively, a proline to threonine and an arginine to glutamine substitution in the C-terminal end. Both substitutions involve amino acids conserved through evolution. In COL4A5 intron 41 a mutation changing the splice acceptor site from AG to AA was identified. All mutations cosegregate with the clinical phenotype of Alport syndrome in affected family members. In a control population of 50 individuals tested by PCR-SSCP these mutations were never identified. Together with two mutations reported previously, a total of six mutations were found in 26 patients with Alport syndrome (23%) after systematic screening of about 30% of the COL4A5 coding region. The clinical features of these six patients are described in detail. 21 refs., 2 figs., 3 tabs.

  5. Analysis of a 5S rRNA gene cloned from Euplotes eurstomus

    SciTech Connect

    Roberson, A.E.; Wolffe, A.; Olins, D.E.

    1987-05-01

    The macronucleus of the hypotrichous ciliated protozoan Euplotes eurystomus lends itself to the study of eukaryotic gene and chromatin structure because native macronuclear DNA exists as linear, gene-sized fragments between 400 and 20,000 bp in length. The macronuclear chromatin, while arranged in a typical nucleosomal structure, is freely soluble in low ionic strength buffers without treatment by nucleases. Thus, specific genes may be enriched as native, intact chromatin molecules. The 5S rRNA gene from Euplotes has been cloned to facilitate investigation of 5S gene-chromatin following characterization of the gene at the DNA level. It has been demonstrated that the gene, while in circular or linear form, can be transcribed in vitro by a Xenopus oocyte nuclear extract. The transcript generated in vitro is 120 nucleotides in length and is synthesized by RNA polymerase III. Anti-Xenopus TFIIIA antibodies recognize a Euplotes macronuclear chromatin-associated protein which is approx. 80 KD in size. It has been established that the sequence of the telomere flanking the 5S gene in Euplotes eurystomus is the same telomeric sequence published for Euplotes aediculatus.

  6. Structure and genetic mapping of the Cytochrome P450 gene (CYP1A5) in the turkey (Meleagris gallopavo).

    PubMed

    Reed, K M; Mendoza, K M; Coulombe, R A

    2007-01-01

    Cytochromes P450 (P450) are a superfamily of membrane-bound hemoproteins that oxidize a large number of endogenous and exogenous compounds. The recently cloned P450 gene (CYP1A5) encodes the primary protein responsible for epoxidation of aflatoxin B(1) (AFB(1)) in the turkey, an animal extremely sensitive to this mycotoxin. Hypersensitivity of turkeys to AFB(1) was first demonstrated by association with 'Turkey X Disease' which caused widespread deaths of turkeys and other poultry throughout Europe in the 1960s, later shown to be caused by AFB(1)-contaminated feed. In this study, comparative genomic approaches were used to selectively amplify and sequence the introns and 3' flanking region of CYP1A5. The structure of the CYP1A5 gene in the turkey is shown to be equivalent to that of the human CYP1A genes with seven exons of 38, 858, 127, 90, 124, 87 and 307 bp, respectively, and six introns. A single nucleotide polymorphism (SNP) in the 3' UTR was used to assign CYP1A5 to turkey linkage group M16 (equivalent to chicken chromosome 10). The results of this study provide the framework for identifying allelic variants of this biochemically important P450 gene in poultry.

  7. A 5-base insertion in the gammaC-crystallin gene is associated with autosomal dominant variable zonular pulverulent cataract.

    PubMed

    Ren, Z; Li, A; Shastry, B S; Padma, T; Ayyagari, R; Scott, M H; Parks, M M; Kaiser-Kupfer, M I; Hejtmancik, J F

    2000-05-01

    A seven-generation family with 30 members affected by highly variable autosomal dominant zonular pulverulent cataracts has been previously described. We have localized the cataracts to a 19-cM interval on chromosome 2q33-q35 including the gamma-crystallin gene cluster. Maximum lod scores are 4.56 (theta=0.02) with D2S157, 3.66 (theta=0.12) with D2S72, and 3.57 (theta=0.052) with CRYG. Sequencing and allele-specific oligonucleotide analysis of the pseudo gammaE-crystallin promoter region from individuals in the pedigree suggest that activation of the gammaE-crystallin pseudo gene is unlikely to cause the cataracts in the family. In addition, base changes in the TATA box but not the Sp1-binding site have been found in unaffected controls and can be excluded as a sole cause of cataracts. In order to investigate the underlying genetic mechanism of cataracts in this family further, exons of the highly expressed gammaC- and gammaD-crystallin genes have been sequenced. The gammaD-crystallin gene shows no abnormalities, but a 5-bp duplication within exon 2 of the gammaC-crystallin gene has been found in one allele of each affected family member and is absent from both unaffected family members and unaffected controls. This mutation disrupts the reading frame of the gammaC-crystallin coding sequence and is predicted to result in the synthesis of an unstable gammaC-crystallin with 38 amino acids of the first "Greek key" motif followed by 52 random amino acids. This finding suggests that the appropriate association of mutant betagamma-crystallins into oligomers is not necessary to cause cataracts and may give us new insights into the genetic mechanism of cataract formation.

  8. miR-199a-5p regulates the expression of metastasis-associated genes in B16F10 melanoma cells

    PubMed Central

    Zhou, Jianda; Liu, Rui; Wang, Yang; Tang, Jingtian; Tang, Shijie; Chen, Xiang; Xia, Kun; Xiong, Wei; Xu, Dan; Wang, Shaohua; He, Quanyong; Cao, Ke

    2014-01-01

    MicroRNAs are regulatory factors that play important roles in tumor development, invasion and metastasis. Previously, we showed that miR-199a is abnormally expressed in clinical melanoma specimens and expression was closely associated with clinical features of metastasis. However, the exact molecular mechanisms by which miR-199a-5p influences melanoma invasion and metastasis remains unclear. In this study, we investigated gene expression changes of metastasis-associated genes in B16F10 melanoma cells following targeted silencing or overexpression of miR-199a-5p, using mouse tumor metastasis PCR arrays. Comparison of gene expression changes in miR-199a-5p-silenced versus overexpressing cells identified a set of upregulated genes (> 2-fold) including Cd44, Cdh1, Cxcr4, Etv4, Fxyd5, Rpsa, Mmp3, Myc, Rb1, Tcf20, Hprt1, Actb1 and downregulated genes (> 2-fold) including Ctsk, Itga7 and Tnfsf10. Regulation of a subset of these genes (Myc, Tnfsf10 and Cd44) following miR-199a-5p silencing or overexpression was validated by reverse transcription-polymerase chain reaction (RT-PCR) and western blot. In conclusion, our study demonstrates that miR-199a-5p regulates melanoma metastasis-related genes, and may provide a basis for the development of novel, molecularly targeted drugs. PMID:25400815

  9. miR-199a-5p regulates the expression of metastasis-associated genes in B16F10 melanoma cells.

    PubMed

    Zhou, Jianda; Liu, Rui; Wang, Yang; Tang, Jingtian; Tang, Shijie; Chen, Xiang; Xia, Kun; Xiong, Wei; Xu, Dan; Wang, Shaohua; He, Quanyong; Cao, Ke

    2014-01-01

    MicroRNAs are regulatory factors that play important roles in tumor development, invasion and metastasis. Previously, we showed that miR-199a is abnormally expressed in clinical melanoma specimens and expression was closely associated with clinical features of metastasis. However, the exact molecular mechanisms by which miR-199a-5p influences melanoma invasion and metastasis remains unclear. In this study, we investigated gene expression changes of metastasis-associated genes in B16F10 melanoma cells following targeted silencing or overexpression of miR-199a-5p, using mouse tumor metastasis PCR arrays. Comparison of gene expression changes in miR-199a-5p-silenced versus overexpressing cells identified a set of upregulated genes (> 2-fold) including Cd44, Cdh1, Cxcr4, Etv4, Fxyd5, Rpsa, Mmp3, Myc, Rb1, Tcf20, Hprt1, Actb1 and downregulated genes (> 2-fold) including Ctsk, Itga7 and Tnfsf10. Regulation of a subset of these genes (Myc, Tnfsf10 and Cd44) following miR-199a-5p silencing or overexpression was validated by reverse transcription-polymerase chain reaction (RT-PCR) and western blot. In conclusion, our study demonstrates that miR-199a-5p regulates melanoma metastasis-related genes, and may provide a basis for the development of novel, molecularly targeted drugs. PMID:25400815

  10. Association between polymorphisms in genes involved in lipid metabolism and immunological status in chronically HIV-infected patients.

    PubMed

    Echeverria, Patricia; Guardiola, Montse; González, Marta; Vallvé, Joan Carles; Bonjoch, Anna; Puig, Jordi; Clotet, Bonaventura; Ribalta, Josep; Negredo, Eugènia

    2015-02-01

    Several studies have reported associations between lipid parameters and clinical progression of HIV infection. We performed a cross-sectional study including 468 antiretroviral-treated HIV-infected patients to investigate the impact of 13 polymorphisms of 9 genes affecting lipid metabolism and CD4 and CD8-T cell levels. Polymorphisms were identified in genes selected for their role in the development of atherogenic dyslipidemia, defined as triglycerides ⩾1.7mmol/L and high-density lipoprotein cholesterol (HDLc) <1.02 in women or 1.28mmol/L in men. Lipid and lipoprotein parameters were determined in all participants, as well as CD4 and CD8 T-cell counts. ANOVA was performed to compare the mean values of lipid and CD4 and CD8 T-cell count data. A Bonferroni correction for multiple comparisons was applied. 468 patients were included, 148 of them had a diagnosis of atherogenic dyslipidemia. The polymorphism rs3135506 in APOA5 was associated with a 9% increase in triglycerides (p=0.002), 10% and 21% decrease in HDLc (p=0.005), and CD4 T-cell count (p=0.024), respectively. APOA5 rs662799, was associated with a 19% increase in CD8 T-cell count (p=0.002). Carriers of LPL rs328 in the dyslipidemic group presented 11% higher levels of HDLc (p=0.015) and 14% higher levels of CD4 cells (p=0.038). In conclusion, polymorphisms in genes associated to the development of atherogenic dyslipidemia, especially variants in APOA5 gene (rs3135506 and rs662799), can influence the circulating CD4 T-cell levels in chronically HIV-infected patients. These data support previous reports on the effect of lipid metabolism on immunologic parameters in HIV+ individuals on antiretroviral therapy.

  11. Analysis of genetic variations in CYP2C9, CYP2C19, CYP2D6 and CYP3A5 genes using oligonucleotide microarray

    PubMed Central

    Dong, Yuanyuan; Xiao, Huasheng; Wang, Qi; Zhang, Chunxiu; Liu, Xiuming; Yao, Na; Sheng, Haihui; Li, Haiyan

    2015-01-01

    The cytochrome P450 enzymes play a critical role in the metabolism of many commonly prescribed drugs. Among them, the most important enzymes are highly polymorphic CYP2C9, CYP2C19, CYP2D6 and CYP3A5, which are responsible for about 40% of the metabolism of clinical used drugs. Here we developed a novel CYP450 oligonucleotide microarray that allow for detection of 32 known variations of CYP genes from a single multiplex reaction, including 19 polymorphisms of CYP2D6 gene, 8 polymorphisms of CYP2C9 gene, 4 polymorphisms of CYP2C19 gene and 1 polymorphism of CYP3A5 gene. 229 genomic DNA samples from unrelated Han subjects were analyzed. The microarray results showed to have high call rate and accuracy according to concordance with genotypes identified by independent bidirectional sequencing. Furthermore, we found that the major CYP2C9, CYP2C19, CYP2D6 and CYP3A5 alleles in Chinese Han population were CYP2C9*3 (allelic frequency of 10.7%), CYP2C9*2 (20.31%), CYP2C19*2 (5.68%), CYP2D6*10 (58.52%), CYP2D6*2 (13.76) and CYP3A5*3 (70.69%). With flexible DNA preparation, the microarray can significantly facilitates the process of detecting genetics variations in CYP2C9, CYP2C19, CYP2D6 and CYP3A5 gene and provide safe and effective therapy for individual patients. PMID:26770516

  12. A 5 S rRNA gene is present in the mitochondrial genome of the protist Reclinomonas americana but is absent from red algal mitochondrial DNA.

    PubMed

    Lang, B F; Goff, L J; Gray, M W

    1996-09-01

    Except in the case of land plants, mitochondrial ribosomes apparently lack a 5 S rRNA species, even though this small RNA is a component of all prokaryotic, chloroplast and eukaryotic cytosol ribosomes. In plants, the mitochondrial 5 S rRNA is encoded by mtDNA and differs in sequence from the 5 S rRNA specified by plant nuclear and chloroplast genomes. A distinctive 5 S rRNA component has not been found in the mitochondrial ribosomes of non-plant eukaryotes and, with the notable exception of the chlorophycean alga, Prototheca wickerhamii, a 5 S rRNA gene has not been identified in those non-plant mtDNAs characterized to date. Here, we report the presence of a 5 S rRNA gene in the mtDNA of the heterotrophic flagellate Reclinomonas americana. This unicellular eukaryote is a member of the jakobid flagellates, an early-diverging group of protists that share ultrastructural characteristics with the retortamonads, primitive protists that lack mitochondria. We report sequence data from the mtDNAs of the red algae Porphyra purpurea and Gracilariopsis lemaneiformis, which we use to evaluate a recent claim that a 5 S rRNA gene exists in the mtDNA of a third rhodophyte alga, Chondrus crispus. Our results lead us to the opposite conclusion: that a 5 S rRNA gene is not encoded by red algal mtDNA. In view of the accumulating evidence favoring a monophyletic origin of the mitochondrial genome, it is likely that a 5 S rRNA gene was present in an ancestral proto-mitochondrial genome, and that contemporary mtDNA-encoded 5 S rRNA genes have all descended from this ancestral gene. Considering the highly restricted phylogenetic distribution of identified mtDNA-encoded 5 S rRNA genes, it follows that the mitochondrial 5 S rRNA gene must have been lost multiple times during evolutionary diversification of the eukaryotic lineage.

  13. [CYP2D6, CYP3A5, and CYP3A4 gene polymorphism in Russian, Tatar, and Bashkir populations].

    PubMed

    Mustafina, O E; Tuktarova, I A; Karimov, D D; Somova, R sh; Nasibullin, T R

    2015-01-01

    The allele and genotype frequency distribution at polymorphic loci rs3892097 (184G>A) of CYP2D6 gene, rs776746 (6986A>G) of the CYP3A5 gene and rs2740574 (-392A>G) of the CYP3A4 gene in Russians, Tatars, and Bashkirs was examined. Samples were taken from residents of Bashkortostan Republic (1240 men and women aged from 20 to 109 years and consisted of 443 Russians, 517 Tatars, and 280 Bashkirs). Allele identification was conducted using PCR-RFLP or PCR with TaqMan probes. The "nonfunctional" allele rs3892097*A of the CYP2D6 gene was detected in populations of Russians, Tatars, and Bashkirs in 17.2, 9.5, and 7.1% cases, respectively. The rs776746*G allele of the CYP3A5 gene encoding the CYP3A5 isoenzyme with decreased activity was revealed with a frequency of 94.6% in populations of Russians, 94.3% in the Tatar population, and 91.5% in the Bashkir population. The share of the minor allele rs2740574*G of the CYP3A4 was 4.0% in populations of Russians, 0.5% in the Tatar population, and 0.9% in the Bashkir population. It has been previously shown that the rs3892097*A, rs776746*G, and rs2740574*G allele frequencies vary significantly in different world populations. Since allele variants of CYP2D6, CYP3A5, and CYP3A4 genes can play essential role in interindividual and in interethnic differences in the metabolism of many therapeutic agents, the obtained results could be used in the prognosis of pharmacotherapy efficacy in populations of Russians, Tatars, and Bashkirs.

  14. Mechanism of lipid lowering in mice expressing human apolipoprotein A5

    SciTech Connect

    Fruchart-Najib, Jamila; Bauge, Eric; Niculescu, Loredan-Stefan; Pham, Tatiana; Thomas, Benoit; Rommens, Corinne; Majd, Zouher; Brewer, Bryan; Rubin, Edward M.; Pennacchio, Len A.; Fruchart, Jean-Charles

    2004-01-15

    Recently, we reported that apoAV plays key role in triglycerides lowering. Here, we attempted to determine the mechanism underlying this hypotriglyceridemic effect. We showed that triglyceride turnover is faster in hAPOA5 transgenic compared to wild type mice. Moreover, both apoB and apoCIII are decreased and LPL activity is increased in postheparin plasma of hAPOA5 transgenic mice. These data suggest a decrease in size and number of VLDL. To further investigate the mechanism of hAPOA5 in hyperlipidemic background, we intercrossed hAPOA5 and hAPOC3 transgenic mice. The effect resulted in a marked decreased of VLDL triglyceride, cholesterol, apolipoproteins B and CIII. In postprandial state, the triglyceride response is abolished in hAPOA5 transgenic mice. We demonstrated that in response to the fat load in hAPOA5XhAPOC3 mice, apoAV shifted from HDL to VLDL, probably to limit the elevation of triglycerides. In vitro, apoAV activates lipoprotein lipase. However, apoAV does not interact with LPL but interacts physically with apoCIII. This interaction does not seem to displace apoCIII from VLDL but may induce conformational change in apoCIII and consequently change in its function leading the activation of lipoprotein lipase.

  15. Association of Polymorphisms of Genes Involved in Lipid Metabolism with Blood Pressure and Lipid Values in Mexican Hypertensive Individuals

    PubMed Central

    Ríos-González, Blanca Estela; Ibarra-Cortés, Bertha; Ramírez-López, Guadalupe; Sánchez-Corona, José; Magaña-Torres, María Teresa

    2014-01-01

    Hypertension and dyslipidemia exhibit an important clinical relationship because an increase in blood lipids yields an increase in blood pressure (BP). We analyzed the associations of seven polymorphisms of genes involved in lipid metabolism (APOA5 rs3135506, APOB rs1042031, FABP2 rs1799883, LDLR rs5925, LIPC rs1800588, LPL rs328, and MTTP rs1800591) with blood pressure and lipid values in Mexican hypertensive (HT) patients. A total of 160 HT patients and 160 normotensive individuals were included. Genotyping was performed through PCR-RFLP, PCR-AIRS, and sequencing. The results showed significant associations in the HT group and HT subgroups classified as normolipemic and hyperlipemic. The alleles FABP2 p.55T, LIPC −514T, and MTTP −493T were associated with elevated systolic BP. Five alleles were associated with lipids. LPL p.474X and FABP2 p.55T were associated with decreased total cholesterol and LDL-C, respectively; APOA5 p.19W with increased HDL-C; APOA5 p.19W and FABP2 p.55T with increased triglycerides; and APOB p.4181K and LDLR c.1959T with decreased triglycerides. The APOB p.E4181K polymorphism increases the risk for HT (OR = 1.85, 95% CI: 1.17–2.93; P = 0.001) under the dominant model. These findings indicate that polymorphisms of lipid metabolism genes modify systolic BP and lipid levels and may be important in the development of essential hypertension and dyslipidemia in Mexican HT patients. PMID:25587205

  16. Association of polymorphisms of genes involved in lipid metabolism with blood pressure and lipid values in mexican hypertensive individuals.

    PubMed

    Ríos-González, Blanca Estela; Ibarra-Cortés, Bertha; Ramírez-López, Guadalupe; Sánchez-Corona, José; Magaña-Torres, María Teresa

    2014-01-01

    Hypertension and dyslipidemia exhibit an important clinical relationship because an increase in blood lipids yields an increase in blood pressure (BP). We analyzed the associations of seven polymorphisms of genes involved in lipid metabolism (APOA5 rs3135506, APOB rs1042031, FABP2 rs1799883, LDLR rs5925, LIPC rs1800588, LPL rs328, and MTTP rs1800591) with blood pressure and lipid values in Mexican hypertensive (HT) patients. A total of 160 HT patients and 160 normotensive individuals were included. Genotyping was performed through PCR-RFLP, PCR-AIRS, and sequencing. The results showed significant associations in the HT group and HT subgroups classified as normolipemic and hyperlipemic. The alleles FABP2 p.55T, LIPC -514T, and MTTP -493T were associated with elevated systolic BP. Five alleles were associated with lipids. LPL p.474X and FABP2 p.55T were associated with decreased total cholesterol and LDL-C, respectively; APOA5 p.19W with increased HDL-C; APOA5 p.19W and FABP2 p.55T with increased triglycerides; and APOB p.4181K and LDLR c.1959T with decreased triglycerides. The APOB p.E4181K polymorphism increases the risk for HT (OR = 1.85, 95% CI: 1.17-2.93; P = 0.001) under the dominant model. These findings indicate that polymorphisms of lipid metabolism genes modify systolic BP and lipid levels and may be important in the development of essential hypertension and dyslipidemia in Mexican HT patients.

  17. The Arabidopsis thaliana MHX gene includes an intronic element that boosts translation when localized in a 5' UTR intron.

    PubMed

    Akua, Tsofit; Shaul, Orit

    2013-11-01

    The mechanisms that underlie the ability of some introns to increase gene expression, a phenomenon called intron-mediated enhancement (IME), are not fully understood. It is also not known why introns localized in the 5'-untranslated region (5' UTR) are considerably longer than downstream eukaryotic introns. It was hypothesized that this extra length results from the presence of some functional intronic elements. However, deletion analyses studies carried out thus far were unable to identify specific intronic regions necessary for IME. Using deletion analysis and a gain-of-function approach, an internal element that considerably increases translational efficiency, without affecting splicing, was identified in the 5' UTR intron of the Arabidopsis thaliana MHX gene. Moreover, the ability of this element to enhance translation was diminished by a minor downstream shift in the position of introns containing it from the 5' UTR into the coding sequence. These data suggest that some of the extra length of 5' UTR introns results from the presence of elements that enhance translation, and, moreover, from the ability of 5' UTR introns to provide preferable platforms for such elements over downstream introns. The impact of the identified intronic element on translational efficiency was augmented upon removal of neighbouring intronic elements. Interference between different intronic elements had not been reported thus far. This interference may support the bioinformatics-based idea that some of the extra sequence of 5' UTR introns is also necessary for separating different functional intronic elements.

  18. The mitochondrial solute carrier SLC25A5 at Xq24 is a novel candidate gene for non-syndromic intellectual disability.

    PubMed

    Vandewalle, Joke; Bauters, Marijke; Van Esch, Hilde; Belet, Stefanie; Verbeeck, Jelle; Fieremans, Nathalie; Holvoet, Maureen; Vento, Jodie; Spreiz, Ana; Kotzot, Dieter; Haberlandt, Edda; Rosenfeld, Jill; Andrieux, Joris; Delobel, Bruno; Dehouck, Marie-Bertille; Devriendt, Koen; Fryns, Jean-Pierre; Marynen, Peter; Goldstein, Amy; Froyen, Guy

    2013-10-01

    Loss-of-function mutations in several different neuronal pathways have been related to intellectual disability (ID). Such mutations often are found on the X chromosome in males since they result in functional null alleles. So far, microdeletions at Xq24 reported in males always have been associated with a syndromic form of ID due to the loss of UBE2A. Here, we report on overlapping microdeletions at Xq24 that do not include UBE2A or affect its expression, in patients with non-syndromic ID plus some additional features from three unrelated families. The smallest region of overlap, confirmed by junction sequencing, harbors two members of the mitochondrial solute carrier family 25, SLC25A5 and SLC25A43. However, identification of an intragenic microdeletion including SLC25A43 but not SLC25A5 in a healthy boy excluded a role for SLC25A43 in cognition. Therefore, our findings point to SLC25A5 as a novel gene for non-syndromic ID. This highly conserved gene is expressed ubiquitously with high levels in cortex and hippocampus, and a presumed role in mitochondrial exchange of ADP/ATP. Our data indicate that SLC25A5 is involved in memory formation or establishment, which could add mitochondrial processes to the wide array of pathways that regulate normal cognitive functions.

  19. Effects of variations in the APOA1/C3/A4/A5 gene cluster on different parameters of postprandial lipid metabolism in healthy young men.

    PubMed

    Delgado-Lista, Javier; Perez-Jimenez, Francisco; Ruano, Juan; Perez-Martinez, Pablo; Fuentes, Francisco; Criado-Garcia, Juan; Parnell, Laurence D; Garcia-Rios, Antonio; Ordovas, Jose M; Lopez-Miranda, Jose

    2010-01-01

    The APOA1/C3/A4/A5 gene cluster encodes important regulators of fasting lipids, but the majority of lipid metabolism takes place in the postprandial state and knowledge about gene regulation in this state is scarce. With the aim of characterizing possible regulators of lipid metabolism, we studied the effects of nine single nucleotide polymorphisms (SNPs) during postprandial lipid metabolism. Eighty-eight healthy young men were genotyped for APOA1 -2630 (rs613808), APOA1 -2803 (rs2727784), APOA1 -3012 (rs11216158), APOC3 -640 (rs2542052), APOC3 -2886 (rs2542051), APOC3 G34G (rs4520), APOA4 N147S (rs5104), APOA4 T29T (rs5092), and A4A5_inter (rs1263177) and were fed a saturated fatty acid-rich meal (1g fat/kg of weight with 60% fat, 15% protein and 25% carbohydrate). Serial blood samples were extracted for 11 h after the meal. Total cholesterol and fractions [HDL-cholesterol, LDL-cholesterol, trifacylglycerols (TGs) in plasma, TG-rich lipoproteins (TRLs) (large TRLs and small TRLs), apolipoprotein A-I and apolipoprotein B] were determined. APOA1 -2803 homozygotes for the minor allele and A4A5_inter carriers showed a limited degree of postprandial lipemia. Carriers of the rare alleles of APOA4 N147S and APOA4 T29T had lower APOA1 plasma concentration during this state. APOC3 -640 was associated with altered TG kinetics but not its magnitude. We have identified new associations between SNPs in the APOA1/C3/A4/A5 gene cluster and altered postprandial lipid metabolism.

  20. X-linked Alport syndrome: An SSCP-based mutation survey over all 51 exons of the COL4A5 gene

    SciTech Connect

    Renieri, A.; Bruttini, M.; Galli, L.; Ballabio, A.; De Marchi, M.

    1996-06-01

    The COL4A5 gene encodes the {alpha}5 (type IV) collagen chain and is defective in X-linked Alport syndrome (AS). Here, we report the first systematic analysis of all 51 exons of COL4A5 gene in a series of 201 Italian AS patients. We have previously reported nine major rearrangements, as well as 18 small mutations identified in the same patient series by SSCP analysis of several exons. After systematic analysis of all 51 exons of COL4A5, we have now identified 30 different mutations: 10 glycine substitutions in the triple helical domain of the protein, 9 frameshift mutations, 4 in-frame deletions, 1 start codon, 1 nonsense, and 5 splice-site mutations. These mutations were either unique or found in two unrelated families, thus excluding the presence of a common mutation in the coding part of the gene. Overall, mutations were detected in only 45% of individuals with a certain or likely diagnosis of X-linked AS. This finding suggests that mutations in noncoding segments of COL4A5 account for a high number of X-linked AS cases. An alternative hypothesis is the presence of locus heterogeneity, even within the X-linked form of the disease. A genotype/phenotype comparison enabled us to better substantiate a significant correlation between the degree of predicted disruption of the {alpha}5 chain and the severity of phenotype in affected male individuals. Our study has significant implications in the diagnosis and follow-up of AS patients. 44 refs., 3 figs., 4 tabs.

  1. X-linked Alport syndrome: an SSCP-based mutation survey over all 51 exons of the COL4A5 gene.

    PubMed Central

    Renieri, A.; Bruttini, M.; Galli, L.; Zanelli, P.; Neri, T.; Rossetti, S.; Turco, A.; Heiskari, N.; Zhou, J.; Gusmano, R.; Massella, L.; Banfi, G.; Scolari, F.; Sessa, A.; Rizzoni, G.; Tryggvason, K.; Pignatti, P. F.; Savi, M.; Ballabio, A.; De Marchi, M.

    1996-01-01

    The COL4A5 gene encodes the alpha5 (type IV) collagen chain and is defective in X-linked Alport syndrome (AS). Here, we report the first systematic analysis of all 51 exons of COL4A5 gene in a series of 201 Italian AS patients. We have previously reported nine major rearrangements, as well as 18 small mutations identified in the same patient series by SSCP analysis of several exons. After systematic analysis of all 51 exons of COL4A5, we have now identified 30 different mutations: 10 glycine substitutions in the triple helical domain of the protein, 9 frameshift mutations, 4 in-frame deletions, 1 start codon, 1 nonsense, and 5 splice-site mutations. These mutations were either unique or found in two unrelated families, thus excluding the presence of a common mutation in the coding part of the gene. Overall, mutations were detected in only 45% of individuals with a certain or likely diagnosis of X-linked AS. This finding suggests that mutations in noncoding segments of COL4A5 account for a high number of X-linked AS cases. An alternative hypothesis is the presence of locus heterogeneity, even within the X-linked form of the disease. A genotype/phenotype comparison enabled us to better substantiate a significant correlation between the degree of predicted disruption of the alpha5 chain and the severity of phenotype in affected male individuals. Our study has significant implications in the diagnosis and follow-up of AS patients. PMID:8651296

  2. Microsatellite allele A5.1 of MHC class I chain-related gene A is associated with latent autoimmune diabetes in adults in Latvia.

    PubMed

    Berzina, L; Shtauvere-Brameus, A; Rumba, I; Sanjeevi, C B

    2002-04-01

    NIDDM is one of the most common forms of diabetes. The diagnosis is based on WHO classification, which is a clinical classification and misses the autoimmune diabetes in adults. Therefore, among the clinically diagnosed NIDDM cases, there can be a certain number of patients with latent autoimmune diabetes in adults (LADA). The MICA gene is located in the MHC class I region and is expressed by monocytes, keratinocytes, and endothelial cells. Sequence determination of the MICA gene identifies trinucleotide repeat (GCT) microsatellite polymorphism, which identifies 5 alleles with 4, 5, 6, and 9 repetitions of GCT (A4, A5, A6, and A9) or 5 repetitions of GCT with 1 additional G insertion for allele A5.1. From our previous studies, we have shown that microsatellite allele A5 of MICA is associated with IDDM. The aim of this study was to test the hypothesis that certain MICA alleles are associated with LADA among clinically diagnosed NIDDM. Out of 100 clinically diagnosed NIDDM patients, 49 tested positive for GAD65 and IA-2 antibodies by use of 35S RIA. Samples from these 49 patients and 96 healthy controls were analyzed for MICA by PCR amplification, and fragment sizes were determined in an ABI prism DNA sequencer. Our results show that MICA allele A5.1 is significantly increased in antibody-positive (GAD65 or IA-2) NIDDM patients [35/49 (72%)] when compared to healthy controls [22/96 (23%)] (OR = 8.4; P < 0.0001). However, we do not see any association with each of the antibodies separately. From our study, we conclude that (a) MICA allele A5.1 is associated with LADA and (b) MICA may play an important role in the etiopathogenesis of LADA.

  3. Dietary capsanthin, the main carotenoid in paprika (Capsicum annuum), alters plasma high-density lipoprotein-cholesterol levels and hepatic gene expression in rats.

    PubMed

    Aizawa, Koichi; Inakuma, Takahiro

    2009-12-01

    The effects of dietary capsanthin, the main carotenoid in paprika (Capsicum annuum), on lipid metabolism were examined. Young male Wistar rats were fed diets containing paprika powder, paprika organic solvent extract, residue of paprika extract, and purified capsanthin. Administration of purified capsanthin for 2 weeks resulted in a significant increase in plasma HDL-cholesterol (P < 0.05) without detectable differences in plasma total cholesterol and TAG concentrations. A statistically significant correlation (r 0.567; P < 0.001) was found between dietary capsanthin concentrations and plasma HDL-cholesterol concentrations. Animals receiving diets containing two different capsanthin concentrations exhibited dose-dependent increases in plasma HDL-cholesterol (r 0.597; P < 0.005). While capsanthin was absent in the liver of animals fed the basal diet, it increased markedly in capsanthin-fed animals (P < 0.001). Quantitative analyses of hepatic mRNA levels revealed that capsanthin administration resulted in up-regulation of mRNA for apoA5 and lecithin cholesterol acyltransferase (LCAT), without significant differences in other mRNA levels related to HDL-cholesterol metabolism. These results suggest that capsanthin had an HDL-cholesterol-raising effect on plasma, and the potential to increase cholesterol efflux to HDL particles by increasing apoA5 levels and/or enhancement of LCAT activity.

  4. Induction by fructose force-feeding of histone H3 and H4 acetylation at their lysine residues around the Slc2a5 gene and its expression in mice.

    PubMed

    Honma, Kazue; Mochizuki, Kazuki; Goda, Toshinao

    2013-01-01

    It has been reported that fructose force-feeding rapidly induced jejunal Slc2a5 gene expression in rodents. We demonstrate in this study that acetylation at lysine (K) 9 of histone H3 and acetylation at K5 and K16 of histone H4 were more enhanced in the promoter/enhancer to transcribed regions of the Slc2a5 gene in fructose force-fed mice than in glucose force-fed mice. However, fructose force-feeding did not induce acetylation at K14 of histone H3, or at K8 and K12 of histone H4 around the Slc2a5 gene. These results suggest that fructose force-feeding induced selective histone acetylation, particularly of H3 and H4, around the jejunal Slc2a5 gene in mice.

  5. Increased serotonin-1A (5-HT1A) autoreceptor expression and reduced raphe serotonin levels in deformed epidermal autoregulatory factor-1 (Deaf-1) gene knock-out mice.

    PubMed

    Czesak, Margaret; Le François, Brice; Millar, Anne M; Deria, Mariam; Daigle, Mireille; Visvader, Jane E; Anisman, Hymie; Albert, Paul R

    2012-02-24

    Altered regulation of the serotonin-1A (5-HT1A) receptor gene is implicated in major depression and mood disorders. The functional human 5-HT1A C(-1019)G promoter polymorphism (rs6295), which prevents the binding of Deaf-1/NUDR leading to dysregulation of the receptor, has been associated with major depression. In cell models Deaf-1 displays dual activity, repressing 5-HT1A autoreceptor expression in serotonergic raphe cells while enhancing postsynaptic 5-HT1A heteroreceptor expression in nonserotonergic neurons. A functional Deaf-1 binding site on the mouse 5-HT1A promoter was recognized by Deaf-1 in vitro and in vivo and mediated dual activity of Deaf-1 on 5-HT1A gene transcription. To address regulation by Deaf-1 in vivo, Deaf-1 knock-out mice bred to a C57BL/6 background were compared with wild-type siblings for changes in 5-HT1A RNA and protein by quantitative RT-PCR, in situ hybridization, and immunofluorescence. In the dorsal raphe, Deaf-1 knock-out mice displayed increased 5-HT1A mRNA, protein, and 5-HT1A-positive cell counts but reduced 5-HT levels, whereas other serotonergic markers, such as tryptophan hydroxylase (TPH)- or 5-HT-positive cells and TPH2 RNA levels, were unchanged. By contrast, 5-HT1A mRNA and 5-HT1A-positive cells were reduced in the frontal cortex of Deaf-1-null mice, with no significant change in hippocampal 5-HT1A RNA, protein, or cell counts. The region-specific alterations of brain 5-HT1A gene expression and reduced raphe 5-HT content in Deaf-1(-/-) mice indicate the importance of Deaf-1 in regulation of 5-HT1A gene expression and provide insight into the role of the 5-HT1A G(-1019) allele in reducing serotonergic neurotransmission by derepression of 5-HT1A autoreceptors.

  6. Prevention of diet-induced hepatic steatosis and hepatic insulin resistance by second generation antisense oligonucleotides targeted to the longevity gene mIndy (Slc13a5).

    PubMed

    Pesta, Dominik H; Perry, Rachel J; Guebre-Egziabher, Fitsum; Zhang, Dongyan; Jurczak, Michael; Fischer-Rosinsky, Antje; Daniels, Martin A; Willmes, Diana M; Bhanot, Sanjay; Bornstein, Stefan R; Knauf, Felix; Samuel, Varman T; Shulman, Gerald I; Birkenfeld, Andreas L

    2015-12-01

    Reducing the expression of the Indy (I'm Not Dead Yet) gene in lower organisms extends life span by mechanisms resembling caloric restriction. Similarly, deletion of the mammalian homolog, mIndy (Slc13a5), encoding for a plasma membrane tricarboxylate transporter, protects from aging- and diet-induced adiposity and insulin resistance in mice. The organ specific contribution to this phenotype is unknown. We examined the impact of selective inducible hepatic knockdown of mIndy on whole body lipid and glucose metabolism using 2'-O-methoxyethyl chimeric anti-sense oligonucleotides (ASOs) in high-fat fed rats. 4-week treatment with 2'-O-methoxyethyl chimeric ASO reduced mIndy mRNA expression by 91% (P=0.001) compared to control ASO. Besides similar body weights between both groups, mIndy-ASO treatment lead to a 74% reduction in fasting plasma insulin concentrations as well as a 35% reduction in plasma triglycerides. Moreover, hepatic triglyceride content was significantly reduced by the knockdown of mIndy, likely mediating a trend to decreased basal rates of endogenous glucose production as well as an increased suppression of hepatic glucose production by 25% during a hyperinsulinemic-euglycemic clamp. Together, these data suggest that inducible liver-selective reduction of mIndy in rats is able to ameliorate hepatic steatosis and insulin resistance, conditions occurring with high calorie diets and during aging. PMID:26647160

  7. MiR-34a-5p promotes the multi-drug resistance of osteosarcoma by targeting the CD117 gene

    PubMed Central

    Wang, Haiyan; Cai, Wenjing; Gao, Jin; Li, Yinpeng; Cai, Shanbao

    2016-01-01

    An association has been reported between miR-34a-5p and several types of cancer. Specifically, in this study, using systematic observations of multi-drug sensitive (G-292 and MG63.2) and resistant (SJSA-1 and MNNG/HOS) osteosarcoma (OS) cell lines, we showed that miR-34a-5p promotes the multi-drug resistance of OS through the receptor tyrosine kinase CD117, a direct target of miR-34a-5p. Consistently, the siRNA-mediated repression of CD117 in G-292 and MG63.2 cells led to a similar phenotype that exhibited all of the miR-34a-5p mimic-triggered changes. In addition, the activity of the MEF2 signaling pathway was drastically altered by the forced changes in the miR-34a-5p or CD117 level in OS cells. Furthermore, si-CD117 suppressed the enhanced colony and sphere formation, which is in agreement with the characteristics of a cancer stem marker. Taken together, our data established CD117 as a direct target of miR-34-5p and demonstrated that this regulation interferes with several CD117-mediated effects on OS cells. In addition to providing new mechanistic insights, our results will provide an approach for diagnosing and chemotherapeutically treating OS. PMID:27056900

  8. Identification of a 5-Methylcytosine Site that may Regulate C/EBPβ Binding and Determine Tissue-Specific Expression of the BPI Gene in Piglets

    PubMed Central

    Sun, Li; Wang, Jing; Yin, Xuemei; Sun, Shouyong; Zi, Chen; Zhu, Guoqiang; Wu, Shenglong; Bao, Wenbin

    2016-01-01

    Bactericidal/permeability-increasing protein (BPI) plays an important role in innate immune defense in mammals. A previous study showed that BPI gene expression correlates to gram-negative bacteria resistance. However, this gene showed tissue-specific expression in piglets and strongly expressed only in the digestive tract. To investigate the mechanisms governing the tissue-specificity, bisulfite sequencing PCR and next generation sequencing were used for high accuracy methylation quantitation of CpG islands of BPI gene upstream in 11 different tissues from weaned Yorkshire piglets. Additionally, qPCR was used to examine mRNA levels of BPI gene as well as transcription factor. We additionally analyzed transcriptional regulation by studying key 5-methylcytosine sites and transcription factors. Results showed that BPI mRNA levels significantly correlated with the overall methylation as well as methylation at mC-15 which was non-CpG site, no significant correlation could be found between the BPI and transcription factor mRNA levels, EMSA test showed that C/EBPβ could interact with BPI wild-type promoter DNA, but not methylated DNA. So we confirmed that methylation of mC-15 residue could inhibit the ability of C/EBPβ binding to the BPI promoter and affect the expression, and this mechanism probably plays a role in the tissue specificity of BPI gene expression in weaned piglets. PMID:27338589

  9. Identification of a 5-Methylcytosine Site that may Regulate C/EBPβ Binding and Determine Tissue-Specific Expression of the BPI Gene in Piglets.

    PubMed

    Sun, Li; Wang, Jing; Yin, Xuemei; Sun, Shouyong; Zi, Chen; Zhu, Guoqiang; Wu, Shenglong; Bao, Wenbin

    2016-01-01

    Bactericidal/permeability-increasing protein (BPI) plays an important role in innate immune defense in mammals. A previous study showed that BPI gene expression correlates to gram-negative bacteria resistance. However, this gene showed tissue-specific expression in piglets and strongly expressed only in the digestive tract. To investigate the mechanisms governing the tissue-specificity, bisulfite sequencing PCR and next generation sequencing were used for high accuracy methylation quantitation of CpG islands of BPI gene upstream in 11 different tissues from weaned Yorkshire piglets. Additionally, qPCR was used to examine mRNA levels of BPI gene as well as transcription factor. We additionally analyzed transcriptional regulation by studying key 5-methylcytosine sites and transcription factors. Results showed that BPI mRNA levels significantly correlated with the overall methylation as well as methylation at mC-15 which was non-CpG site, no significant correlation could be found between the BPI and transcription factor mRNA levels, EMSA test showed that C/EBPβ could interact with BPI wild-type promoter DNA, but not methylated DNA. So we confirmed that methylation of mC-15 residue could inhibit the ability of C/EBPβ binding to the BPI promoter and affect the expression, and this mechanism probably plays a role in the tissue specificity of BPI gene expression in weaned piglets. PMID:27338589

  10. Predictors of heroin relapse: Personality traits, impulsivity, COMT gene Val158met polymorphism in a 5-year prospective study in Shanghai, China.

    PubMed

    Su, Hang; Li, Zhibin; Du, Jiang; Jiang, Haifeng; Chen, Zhikang; Sun, Haiming; Zhao, Min

    2015-12-01

    Relapse is a typical feature of heroin addiction and rooted in genetic and psychological determinants. The aim of this study was to evaluate the effect of personality traits, impulsivity, and COMT gene polymorphism (rs4680) on relapse to heroin use during 5-year follow up. 564 heroin dependent patients were enrolled in compulsory drug rehabilitation center. 12 months prior to their release, personality traits were measured by BIS-11 (Barratt Impulsiveness Scale-11) and Temperament and Character Inventory (TCI). The COMT gene rs4680 polymorphism was genotyped using a DNA sequence detection system. The heroin use status was evaluated for 5 years after discharged. Among the 564 heroin-dependent patients, 500 were followed for 5 years after discharge and 53.0% (n = 265) were considered as relapsed to heroin use according to a strict monitor system. Univariate analysis showed that age, having ever been in methadone maintenance treatment (MMT), the total scores and non-planning scores of BIS-11, and the COMT rs4680 gene variants were different between relapse and abstinent groups. Logistic regression analysis showed higher BIS total score, having ever been in MMT and younger first heroin use age are the predictors of relapse to heroin use during 5 years follow-up, and the COMT rs4680 gene had an interaction with BIS scores. Our findings indicated that the impulsive personality traits, methadone use history, and onset age could predict relapse in heroin-dependent patients during 5 year's follow up. The COMT gene showed a moderational effect in part the relationship of impulsivity with heroin relapse.

  11. Predictors of heroin relapse: Personality traits, impulsivity, COMT gene Val158met polymorphism in a 5-year prospective study in Shanghai, China.

    PubMed

    Su, Hang; Li, Zhibin; Du, Jiang; Jiang, Haifeng; Chen, Zhikang; Sun, Haiming; Zhao, Min

    2015-12-01

    Relapse is a typical feature of heroin addiction and rooted in genetic and psychological determinants. The aim of this study was to evaluate the effect of personality traits, impulsivity, and COMT gene polymorphism (rs4680) on relapse to heroin use during 5-year follow up. 564 heroin dependent patients were enrolled in compulsory drug rehabilitation center. 12 months prior to their release, personality traits were measured by BIS-11 (Barratt Impulsiveness Scale-11) and Temperament and Character Inventory (TCI). The COMT gene rs4680 polymorphism was genotyped using a DNA sequence detection system. The heroin use status was evaluated for 5 years after discharged. Among the 564 heroin-dependent patients, 500 were followed for 5 years after discharge and 53.0% (n = 265) were considered as relapsed to heroin use according to a strict monitor system. Univariate analysis showed that age, having ever been in methadone maintenance treatment (MMT), the total scores and non-planning scores of BIS-11, and the COMT rs4680 gene variants were different between relapse and abstinent groups. Logistic regression analysis showed higher BIS total score, having ever been in MMT and younger first heroin use age are the predictors of relapse to heroin use during 5 years follow-up, and the COMT rs4680 gene had an interaction with BIS scores. Our findings indicated that the impulsive personality traits, methadone use history, and onset age could predict relapse in heroin-dependent patients during 5 year's follow up. The COMT gene showed a moderational effect in part the relationship of impulsivity with heroin relapse. PMID:26345603

  12. Differential gene expression in Xylella fastidiosa 9a5c during co-cultivation with the endophytic bacterium Methylobacterium mesophilicum SR1.6/6.

    PubMed

    Dourado, Manuella Nóbrega; Santos, Daiene Souza; Nunes, Luiz Roberto; Costa de Oliveira, Regina Lúcia Batista da; de Oliveira, Marcus Vinicius; Araújo, Welington Luiz

    2015-12-01

    Xylella fastidiosa, the causal agent of citrus variegated chlorosis (CVC), colonizes plant xylem, reducing sap flow, and inducing internerval chlorosis, leaf size reduction, necrosis, and harder and smaller fruits. This bacterium may be transmitted from plant to plant by sharpshooter insects, including Bucephalogonia xanthopis. The citrus endophytic bacterium Methylobacterium mesophilicum SR1.6/6 colonizes citrus xylem and previous studies showed that this strain is also transferred from plant to plant by B. xanthopis (Insecta), suggesting that this endophytic bacterium may interact with X. fastidiosa in planta and inside the insect vector during co-transmission by the same insect vector. To better understand the X. fastidiosa behavior in the presence of M. mesophilicum, we evaluated the X. fastidiosa transcriptional profile during in vitro interaction with M. mesophilicum SR1.6/6. The results showed that during co-cultivation, X. fastidiosa down-regulated genes related to growth and up-regulated genes related to energy production, stress, transport, and motility, suggesting the existence of a specific adaptive response to the presence of M. mesophilicum in the culture medium.

  13. Fusarium oxysporum and its bacterial consortium promote lettuce growth and expansin A5 gene expression through microbial volatile organic compound (MVOC) emission.

    PubMed

    Minerdi, Daniela; Bossi, Simone; Maffei, Massimo E; Gullino, Maria Lodovica; Garibaldi, Angelo

    2011-05-01

    Fusarium oxysporum MSA 35 [wild-type (WT) strain] is a nonpathogenic Fusarium strain, which exhibits antagonistic activity to plant pathogenic F. oxysporum isolates. The fungus lives in association with a consortium of ectosymbiotic bacteria. The WT strain, when cured of the bacterial symbionts [the cured (CU) form], is pathogenic, causing wilt symptoms similar to those of pathogenic F. oxysporum f. sp. lactucae. Both WT and CU MSA 35 strains produce microbial volatile organic compounds (MVOCs), but with a different spectrum. In vitro dual culture assays were used to assess the effects of the MVOCs produced by WT and CU strains of F. oxysporum MSA 35 on the growth and expansin gene expression of lettuce seedlings. An increase in the root length (95.6%), shoot length (75.0%) and fresh weight (85.8%) was observed only after WT strain MVOCs exposure. Leaf chlorophyll content was significantly enhanced (68%) in WT strain MVOC-treated seedlings as compared with CU strain volatiles and nontreated controls. β-Caryophyllene was found to be one of the volatiles released by WT MSA 35 responsible for the plant growth promotion effect. Semi-quantitative and quantitative reverse transcription-PCR assays indicated a significant difference in the expansin gene expression level between leaf (6.7-fold) and roots (4.4-fold) exposed to WT strain volatiles when compared with the CU strain volatiles and those that were nonexposed.

  14. Differential gene expression in Xylella fastidiosa 9a5c during co-cultivation with the endophytic bacterium Methylobacterium mesophilicum SR1.6/6.

    PubMed

    Dourado, Manuella Nóbrega; Santos, Daiene Souza; Nunes, Luiz Roberto; Costa de Oliveira, Regina Lúcia Batista da; de Oliveira, Marcus Vinicius; Araújo, Welington Luiz

    2015-12-01

    Xylella fastidiosa, the causal agent of citrus variegated chlorosis (CVC), colonizes plant xylem, reducing sap flow, and inducing internerval chlorosis, leaf size reduction, necrosis, and harder and smaller fruits. This bacterium may be transmitted from plant to plant by sharpshooter insects, including Bucephalogonia xanthopis. The citrus endophytic bacterium Methylobacterium mesophilicum SR1.6/6 colonizes citrus xylem and previous studies showed that this strain is also transferred from plant to plant by B. xanthopis (Insecta), suggesting that this endophytic bacterium may interact with X. fastidiosa in planta and inside the insect vector during co-transmission by the same insect vector. To better understand the X. fastidiosa behavior in the presence of M. mesophilicum, we evaluated the X. fastidiosa transcriptional profile during in vitro interaction with M. mesophilicum SR1.6/6. The results showed that during co-cultivation, X. fastidiosa down-regulated genes related to growth and up-regulated genes related to energy production, stress, transport, and motility, suggesting the existence of a specific adaptive response to the presence of M. mesophilicum in the culture medium. PMID:26218710

  15. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.

    PubMed

    Thompson, Bryony A; Spurdle, Amanda B; Plazzer, John-Paul; Greenblatt, Marc S; Akagi, Kiwamu; Al-Mulla, Fahd; Bapat, Bharati; Bernstein, Inge; Capellá, Gabriel; den Dunnen, Johan T; du Sart, Desiree; Fabre, Aurelie; Farrell, Michael P; Farrington, Susan M; Frayling, Ian M; Frebourg, Thierry; Goldgar, David E; Heinen, Christopher D; Holinski-Feder, Elke; Kohonen-Corish, Maija; Robinson, Kristina Lagerstedt; Leung, Suet Yi; Martins, Alexandra; Moller, Pal; Morak, Monika; Nystrom, Minna; Peltomaki, Paivi; Pineda, Marta; Qi, Ming; Ramesar, Rajkumar; Rasmussen, Lene Juel; Royer-Pokora, Brigitte; Scott, Rodney J; Sijmons, Rolf; Tavtigian, Sean V; Tops, Carli M; Weber, Thomas; Wijnen, Juul; Woods, Michael O; Macrae, Finlay; Genuardi, Maurizio

    2014-02-01

    The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases.

  16. Correlation of HER2 overexpression with gene amplification and its relation to chromosome 17 aneuploidy: a 5-year experience with invasive ductal and lobular carcinomas.

    PubMed

    Nassar, Aziza; Khoor, Andras; Radhakrishnan, Reshmitha; Radhakrishnan, Anu; Cohen, Cynthia

    2014-01-01

    The HER2 oncogene shows expression or amplification, or both, in approximately 15% to 20% of breast cancers and has been associated with poor prognosis and a response to trastuzumab therapy. HER2 gene status determines the eligibility of breast cancer patients for trastuzumab therapy and a large fraction (41-56%) of these patients respond to targeted therapy. Several studies have related the increased expression of HER2 to an increased copy number of chromosome 17, rather than amplification of the HER2 gene. We compared the results of immunohistochemistry and fluorescence in situ hybridization in both invasive ductal and invasive lobular carcinomas, to determine the frequency of chromosome 17 aneuploidy associated with discordant results. In total, 390 invasive ductal carcinomas and 180 invasive lobular carcinomas diagnosed from January 2000 to December 2005 were included in the study only if results were available for immunohistochemistry (HercepTest; DAKO, Carpinteria, California) and fluorescence in situ hybridization (PathVysion HER2 DNA Probe Kit; Abbott Laboratories, Des Plaines, Illinois). Tumors classified as invasive ductal carcinomas were graded according to the Bloom-Richardson grading system. Correlation between the results of immunohistochemistry and fluorescence in situ hybridization was performed for all categories. Among invasive ductal carcinomas, 29% (115/390) showed chromosome 17 aneuploidy, mostly associated with grade 3/HER2 2+ (45%) or grade 2/HER2 3+ (55%) that were not amplified. Also, 34% (12/35) of invasive lobular carcinomas showed chromosome 17 aneuploidy; approximately one-third of these cases were HER2 2+ (33%) and HER2 3+ (37%) that were not amplified. Discordance between the results of immunohistochemistry and fluorescence in situ hybridization in both ductal and lobular carcinomas is largely associated with chromosome 17 aneuploidy.

  17. Structural polymorphism in the major groove of a 5S RNA gene complements the zinc finger domains of transcription factor IIIA.

    PubMed Central

    Huber, P W; Morii, T; Mei, H Y; Barton, J K

    1991-01-01

    Metal complexes that bind to DNA on the basis of shape-selection have been used to map the conformational features of the DNA binding site for transcription factor IIIA. Conformationally distinct segments are detected on the 5S rRNA gene that correspond closely to the binding sites identified for the individual zinc finger domains of the protein. The local conformations are characterized by a major groove opened because of a change in base pair inclination and/or displacement at a central 5'-pyrimidine-purine-3' step, flanked by a widened minor groove, as would arise at the junctions between alternating B- and A-like DNA segments. Docking experiments with a consensus structure of a zinc finger reveal that the mixed A-B binding site accommodates the peptide domain better than either canonical B- or A-DNA helices. The close structural matching of the conformational variations in the 5S rDNA both to the proposed sites of zinc finger binding and to the shape of an individual zinc finger domain points to DNA structural polymorphism as providing an important determinant in recognition. In particular, shape selection in the 5' half of the internal control region may orient the multiple finger domains. Images PMID:1961749

  18. Association of Polymorphisms within the Serotonin Receptor Genes 5-HTR1A, 5-HTR1B, 5-HTR2A and 5-HTR2C and Migraine Susceptibility in a Turkish Population

    PubMed Central

    Yücel, Yavuz; Coşkun, Salih; Cengiz, Beyhan; Özdemir, Hasan H.; Uzar, Ertuğrul; Çim, Abdullah; Camkurt, M. Akif; Aluclu, M. Ufuk

    2016-01-01

    Objective Migraine, a highly prevelant headache disorder, is regarded as a polygenic multifactorial disease. Serotonin (5-HT) and their respective receptors have been implicated in the patogenesis. Methods We investigated the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT2C receptor gene polymorphisms and their association with migraine in Turkish patients. The rs6295, rs1300060, rs1228814, rs6311, rs6313, rs6314, rs6318, rs3813929 (−759C/T) and rs518147 polymorphisms were analyzed in 135 patients with migraine and 139 healthy subjects, using a BioMark 96.96 dynamic array system. Results We found no difference in the frequency of the analyzed eight out of nine polymorpisms between migraine and control groups. However, a significant association was found between the rs3813929 polymorphism in the promoter region of 5-HTR2C gene and migraine. Also, the allele of rs3813929 was more common in the migraine group. Conclusion This result suggests that the 5-HTR2C rs3813929 polymorphism can be a genetic risk factor for migraine in a Turkish population. PMID:27489378

  19. A novel point mutation (G-1 to T) in a 5' splice donor site of intron 13 of the dystrophin gene results in exon skipping and is responsible for Becker muscular dystrophy.

    PubMed

    Hagiwara, Y; Nishio, H; Kitoh, Y; Takeshima, Y; Narita, N; Wada, H; Yokoyama, M; Nakamura, H; Matsuo, M

    1994-01-01

    The mutations in one-third of Duchenne and Becker muscular dystrophy patients remain unknown, as they do not involve gross rearrangements of the dystrophin gene. We now report a defect in the splicing of precursor mRNA (pre-mRNA), resulting from a maternally inherited mutation of the dystrophin gene in a patient with Becker muscular dystrophy. This defect results from a G-to-T transversion at the terminal nucleotide of exon 13, within the 5' splice site of intron 13, and causes complete skipping of exon 13 during processing of dystrophin pre-mRNA. The predicted polypeptide encoded by the aberrant mRNA is a truncated dystrophin lacking 40 amino acids from the amino-proximal end of the rod domain. This is the first report of an intraexon point mutation that completely inactivates a 5' splice donor site in dystrophin pre-mRNA. Analysis of the genomic context of the G-1-to-T mutation at the 5' splice site supports the exon-definition model of pre-mRNA splicing and contributes to the understanding of splice-site selection.

  20. A novel point mutation (G[sup [minus]1] to T) in a 5[prime] splice donor site of intron 13 of the dystrophin gene results in exon skipping and is responsible for Becker Muscular Dystrophy

    SciTech Connect

    Hagiwara, Yoko; Nishio, Hisahide; Kitoh, Yoshihiko; Takeshima, Yasuhiro; Narita, Naoko; Wada, Hiroko; Yokoyama, Mitsuhiro; Nakamura, Hajime; Matsuo, Masafumi )

    1994-01-01

    The mutations in one-third of Duchenne and Becker muscular dystrophy patients remain unknown, as they do not involve gross rearrangements of the dystrophin gene. The authors now report a defect in the splicing of precursor mRNA (pre-mRNA), resulting from a maternally inherited mutation of the dystrophin gene in a patient with Becker muscular dystrophy. This defect results from a G-to-T transversion at the terminal nucleotide of exon 13, within the 5[prime] splice site of intron 13, and causes complete skipping of exon 13 during processing of dystrophin pre-mRNA. The predicted polypeptide encoded by the aberrant mRNA is a truncated dystrophin lacking 40 amino acids from the amino-proximal end of the rod domain. This is the first report of an intraexon point mutation that completely inactivates a 5[prime] splice donor site in dystrophin pre-mRNA. Analysis of the genomic context of the G[sup [minus]1]-to-T mutation at the 5[prime] splice site supports the exon-definition model of pre-mRNA splicing and contributes to the understanding of splice-site selection. 48 refs., 5 figs.

  1. Polymorphisms in the cytochrome P450 genes CYP1A2, CYP1B1, CYP3A4, CYP3A5, CYP11A1, CYP17A1, CYP19A1 and colorectal cancer risk

    PubMed Central

    Bethke, Lara; Webb, Emily; Sellick, Gabrielle; Rudd, Matthew; Penegar, Stephen; Withey, Laura; Qureshi, Mobshra; Houlston, Richard

    2007-01-01

    Background Cytochrome P450 (CYP) enzymes have the potential to affect colorectal cancer (CRC) risk by determining the genotoxic impact of exogenous carcinogens and levels of sex hormones. Methods To investigate if common variants of CYP1A2, CYP1B1, CYP3A4, CYP3A5, CYP11A1, CYP17A1 and CYP19A1 influence CRC risk we genotyped 2,575 CRC cases and 2,707 controls for 20 single nucleotide polymorphisms (SNPs) that have not previously been shown to have functional consequence within these genes. Results There was a suggestion of increased risk, albeit insignificant after correction for multiple testing, of CRC for individuals homozygous for CYP1B1 rs162558 and heterozygous for CYP1A2 rs2069522 (odds ratio [OR] = 1.36, 95% confidence interval [CI]: 1.03–1.80 and OR = 1.34, 95% CI: 1.00–1.79 respectively). Conclusion This study provides some support for polymorphic variation in CYP1A2 and CYP1B1 playing a role in CRC susceptibility. PMID:17615053

  2. Gene expression profiles in human HepG2 cells treated with extracts of the Tamarindus indica fruit pulp.

    PubMed

    Razali, Nurhanani; Aziz, Azlina A; Junit, Sarni M

    2010-12-01

    Tamarindus indicaL. (T. indica) or locally known as asam jawa belongs to the family of Leguminosae. The fruit pulp had been reported to have antioxidant activities and possess hypolipidaemic effects. In this study, we attempted to investigate the gene expression patterns in human hepatoma HepG2 cell line in response to treatment with low concentration of the fruit pulp extracts. Microarray analysis using Affymetrix Human Genome 1.0 S.T arrays was used in the study. Microarray data were validated using semi-quantitative RT-PCR and real-time RT-PCR. Amongst the significantly up-regulated genes were those that code for the metallothioneins (MT1M, MT1F, MT1X) and glutathione S-transferases (GSTA1, GSTA2, GST02) that are involved in stress response. APOA4, APOA5, ABCG5 and MTTP genes were also significantly regulated that could be linked to hypolipidaemic activities of the T. indica fruit pulp.

  3. Independent effects of apolipoprotein AV and apolipoprotein CIII on plasma triglyceride concentrations

    SciTech Connect

    Baroukh, Nadine N.; Bauge, Eric; Akiyama, Jennifer; Chang, Jessie; Fruchart, Jean-Charles; Rubin, Edward M.; Fruchart, Jamila; Pennacchio, Len A.

    2003-08-15

    Both the apolipoprotein A5 and C3 genes have repeatedly been shown to play an important role in determining plasma triglyceride concentrations in humans and mice. In mice, transgenic and knockout experiments indicate that plasma triglyceride levels are negatively and positively correlated with APOA5 and APOC3 expression, respectively. In humans, common polymorphisms in both genes have also been associated with plasma triglyceride concentrations. The evolutionary relationship among these two apolipoprotein genes and their close proximity on human chromosome 11q23 have largely precluded the determination of their relative contribution to altered Both the apolipoprotein A5 and C3 genes have repeatedly been shown to play an important role in determining plasma triglyceride concentrations in humans and mice. In mice, transgenic and knockout experiments indicate that plasma triglyceride levels are negatively and positively correlated with APOA5 and APOC3 expression, respectively. In humans, common polymorphisms in both genes have also been associated with plasma triglyceride concentrations. The evolutionary relationship among these two apolipoprotein genes and their close proximity on human chromosome 11q23 have largely precluded the determination of their relative contribution to altered triglycerides. To overcome these confounding factors and address their relationship, we generated independent lines of mice that either over-expressed (''double transgenic'') or completely lacked (''double knockout'') both apolipoprotein genes. We report that both ''double transgenic'' and ''double knockout'' mice display intermedia tetriglyceride concentrations compared to over-expression or deletion of either gene alone. Furthermore, we find that human ApoAV plasma protein levels in the ''double transgenic'' mice are approximately 500-fold lower than human ApoCIII levels, supporting ApoAV is a potent triglyceride modulator despite its low concentration. Together, these data indicate

  4. Plantaricin IIA-1A5 from Lactobacillus plantarum IIA-1A5 displays bactericidal activity against Staphylococcus aureus.

    PubMed

    Arief, I Isnafia; Budiman, C; Jenie, B Sri Laksmi; Andreas, E; Yuneni, A

    2015-01-01

    Plantaricin IIA-1A5 is a bacteriocin produced by Lactobacillus plantarum IIA-1A5 isolated from Indonesian beef. This research aimed to identify the genes involved in plantaricin IIA-1A5 production and examine its mode of action against Staphylococcus aureus. It has been reported that a bacteriocin structural gene, plnW, is present in genome of L. plantarum IIA-1A5. Here, we reported the presence of additional genes responsible for plantaricin precursor (plnA and plnEF) and a gene encoding the quorum sensor of histidine kinase (plnB). It indicates that genes involved in production of plantaricin IIA-1A5 are organized in at least two bacteriocin operons (plnABCD, plnEFI) and a structural plnW gene. Purified plantaricin IIA-1A5 yielded a single band in SDS-PAGE with apparent size of 6.4 kDa. Amino acid composition of purified plantaricin IIA-1A5 was mainly composed of cationic glutamic acid and cysteine that allowed the formation of disulphide bonds, suggesting plantaricin IIA-1A5 belongs to the pediocin-subclass of class II bacteriocins. Plantaricin IIA-1A5 displayed remarkable antibacterial activity against S. aureus, which was initiated by the adsorption of plantaricin IIA-1A5 onto the cell membrane of S. aureus. The adsorption is hypothesised to be facilitated by non-ionic interactions as it is reduced by the presence of organic solvents or detergents. This adsorption promoted leakage of cellular metabolites through the cell membrane of S. aureus, as indicated by the release of genetic and proteinaceous material of S. aureus observed at 260 and 280 nm, respectively. The leakage also promoted the release of divalent (Ca(2+), Mg(2+)) and monovalent (K(+)) cations. The release of these intracellular components might be due to pores formed in the cell membrane of S. aureus by plantaricin IIA-1A5 as shown by scanning electron microscopy. Altogether, the mode of action of plantaricin IIA-1A5 against S. aureus seems to be bactericidal as indicated by lysis of the cell

  5. Apolipoprotein polymorphism is associated with pro-thrombotic profile in non-demented dyslipidemic subjects

    PubMed Central

    Ferreira, Cláudia N; Carvalho, Maria G; Gomes, Karina B; Reis, Helton J; Fernandes, Ana-Paula; Sousa, Marinez O

    2015-01-01

    Apolipoprotein gene polymorphism has an important role in lipid metabolism and in the development of cerebro- and cardio-vascular disease (CCVD), including dementia. Dyslipidemia and hemostatic abnormalities are key risk factors associated with athero-sclerotic events preceding CCVD. The aim of this study was to evaluate the possible relationships of various apolipoprotein-species with hemostatic parameters and cognitive function. Lipid profile, gene polymorphism, coagulation markers, and mini-mental state examination (MMSE) scores were assessed in 109 dys-lipidemic subjects and in 107 healthy control volunteers. Thrombin-activatable fibrinolysis inhibitor (TAFI) plasma levels were significantly higher in apolipoprotein-E2 (apoE2) patients when compared to other apoE forms. The apoA5 -1131T>C polymorphism was associated with elevated D-dimer concentration in dyslipidemic TT homozygous individuals. MMSE did not correlate with lipid or coagulation profile. These data suggest that apoE and apoA5 variants have an effect on hemostatic parameters, but they neither influence nor predict cognitive performance in non-demented individuals. PMID:25073959

  6. Apolipoprotein A1/C3/A5 haplotypes and serum lipid levels

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The association of single nucleotide polymorphisms (SNPs) in the apolipoprotein (Apo) A1/C3/A4/A5 gene cluster and serum lipid profiles is inconsistent. The present study was undertaken to detect the association between the ApoA1/C3/A5 gene polymorphisms and their haplotypes with serum lipid levels ...

  7. 42 CFR 59a.5 - Awards.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Awards. 59a.5 Section 59a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.5 Awards. (a) General. Within...

  8. 42 CFR 59a.5 - Awards.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Awards. 59a.5 Section 59a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.5 Awards. (a) General. Within...

  9. 42 CFR 59a.5 - Awards.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Awards. 59a.5 Section 59a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.5 Awards. (a) General. Within...

  10. 42 CFR 59a.5 - Awards.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Awards. 59a.5 Section 59a.5 Public Health PUBLIC... for Establishing, Expanding, and Improving Basic Resources § 59a.5 Awards. (a) General. Within the limits of funds available, the Secretary may award grants to those applicants whose proposals...

  11. 32 CFR 168a.5 - Responsibilities.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 1 2013-07-01 2013-07-01 false Responsibilities. 168a.5 Section 168a.5 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING NATIONAL DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.5 Responsibilities. (a) The Deputy Director,...

  12. 14 CFR 374a.5 - Exemption authority.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 4 2011-01-01 2011-01-01 false Exemption authority. 374a.5 Section 374a.5 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.5 Exemption authority....

  13. 14 CFR 374a.5 - Exemption authority.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 4 2014-01-01 2014-01-01 false Exemption authority. 374a.5 Section 374a.5 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.5 Exemption authority....

  14. 14 CFR 374a.5 - Exemption authority.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 4 2013-01-01 2013-01-01 false Exemption authority. 374a.5 Section 374a.5 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.5 Exemption authority....

  15. 14 CFR 374a.5 - Exemption authority.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 4 2012-01-01 2012-01-01 false Exemption authority. 374a.5 Section 374a.5 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.5 Exemption authority....

  16. 14 CFR 374a.5 - Exemption authority.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Exemption authority. 374a.5 Section 374a.5 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.5 Exemption authority....

  17. 32 CFR 352a.5 - Relationships.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 2 2013-07-01 2013-07-01 false Relationships. 352a.5 Section 352a.5 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.5 Relationships. (a) In the performance...

  18. 32 CFR 352a.5 - Relationships.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 2 2014-07-01 2014-07-01 false Relationships. 352a.5 Section 352a.5 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.5 Relationships. (a) In the performance...

  19. 32 CFR 352a.5 - Relationships.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 2 2011-07-01 2011-07-01 false Relationships. 352a.5 Section 352a.5 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.5 Relationships. (a) In the performance...

  20. 32 CFR 352a.5 - Relationships.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 2 2012-07-01 2012-07-01 false Relationships. 352a.5 Section 352a.5 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.5 Relationships. (a) In the performance...

  1. Apolipoprotein AV accelerates plasma hydrolysis of triglyceride-rich lipoproteins by interaction with proteoglycan-bound lipoprotein lipase.

    PubMed

    Merkel, Martin; Loeffler, Britta; Kluger, Malte; Fabig, Nathalie; Geppert, Gesa; Pennacchio, Len A; Laatsch, Alexander; Heeren, Joerg

    2005-06-01

    Apolipoprotein A5 (APOA5) is associated with differences in triglyceride levels and familial combined hyperlipidemia. In genetically engineered mice, apoAV plasma levels are inversely correlated with plasma triglycerides. To elucidate the mechanism by which apoAV influences plasma triglycerides, metabolic studies and in vitro assays resembling physiological conditions were performed. In human APOA5 transgenic mice (hAPOA5tr), catabolism of chylomicrons and very low density lipoprotein (VLDL) was accelerated due to a faster plasma hydrolysis of triglycerides by lipoprotein lipase (LPL). Hepatic VLDL and intestinal chylomicron production were not affected. The functional interplay between apoAV and LPL was further investigated by cross-breeding a human LPL transgene with the apoa5 knock-out and the hAPOA5tr to an lpl-deficient background. Increased LPL activity completely normalized hypertriglyceridemia of apoa5-deficient mice; however, overexpression of human apoAV modulated triglyceride levels only slightly when LPL was reduced. To reflect the physiological situation in which LPL is bound to cell surface proteoglycans, we examined hydrolysis in the presence or absence of proteoglycans. Without proteoglycans, apoAV derived either from triglyceride-rich lipoproteins, hAPOA5tr high density lipoprotein, or a recombinant source did not alter the LPL hydrolysis rate. In the presence of proteoglycans, however, apoAV led to a significant and dose-dependent increase in LPL-mediated hydrolysis of VLDL triglycerides. These results were confirmed in cell culture using a proteoglycan-deficient cell line. A direct interaction between LPL and apoAV was found by ligand blotting. It is proposed, that apoAV reduces triglyceride levels by guiding VLDL and chylomicrons to proteoglycan-bound LPL for lipolysis.

  2. Apolipoprotein AV Accelerates Plasma Hydrolysis OfTriglyceride-Rich Lipoproteins By Interaction With Proteoglycan BoundLipoprotein Lipase

    SciTech Connect

    Merkel, Martin; Loeffler, Britta; Kluger, Malte; Fabig, Nathalie; Geppert, Gesa; Pennacchio, Len A.; Laatsch, Alexander; Heeren, Joerg

    2005-02-22

    Apolipoprotein A5 (APOA5) is associated with differences intriglyceride levels and familial combined hyperlipidemia. In genetically engineered mice, apoAV plasma levels are inversely correlated with plasmatriglycerides. To elucidate the mechanism by which apoAV influences plasma triglycerides, metabolic studies and in vitro assays resembling physiological conditions were performed. In hAPOA5 transgenic mice(hAPOA5tr), catabolism of chylomicrons and VLDL was accelerated due to a faster plasma hydrolysis of triglycerides by lipoprotein lipase (LPL).Hepatic VLDL and intestinal chylomicron production were not affected. The functional interplay between apoAV and LPL was further investigated by crossbreeding a human LPL transgene with the apoa5 knockout, and the hAPOA5tr to an LPL deficient background. Increased LPL activity completely normalized hypertriglyceridemia of apoa5 deficient mice,however, over expression of human apoAV modulated triglyceride levels only slightly when LPL was reduced. To reflect the physiological situation in which LPL is bound to cell surface proteoglycans, we examined hydrolysis in the presence or absence of proteoglycans. Without proteoglycans, apoAV derived either from triglyceride-rich lipoproteins, hAPOA5tr HDL, or a recombinant source did not alter the LPL hydrolysis rate. In the presence of proteoglycans, however, apoAV led to a significant and dose-dependent increase in LPL mediated hydrolysis of VLDL triglycerides. These results were confirmed in cell culture using a proteoglycan-deficient cell line.A direct interaction between LPL and apoAV was found by ligand blotting.It is proposed, that apoAV reduces triglyceride levels by guiding VLDL and chylomicrons to proteoglycans bound LPL for lipolysis.

  3. 44 CFR Appendix A(5) to Part 61 - Appendix A(5) to Part 61

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 44 Emergency Management and Assistance 1 2010-10-01 2010-10-01 false Appendix A(5) to Part 61 A(5) Appendix A(5) to Part 61 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY, DEPARTMENT OF HOMELAND SECURITY INSURANCE AND HAZARD MITIGATION National Flood Insurance Program INSURANCE COVERAGE AND RATES Pt. 61, App....

  4. 32 CFR 168a.5 - Responsibilities.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.5 Responsibilities. (a) The Deputy Director, Defense Research and Engineering (Research and Advanced Technology) , shall: (1) Administer this part and issue DoD... representative of the Deputy Director, Defense Research and Engineering (Research and Advanced...

  5. 32 CFR 168a.5 - Responsibilities.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.5 Responsibilities. (a) The Deputy Director, Defense Research and Engineering (Research and Advanced Technology) , shall: (1) Administer this part and issue DoD... representative of the Deputy Director, Defense Research and Engineering (Research and Advanced...

  6. Genes and Gene Therapy

    MedlinePlus

    ... correctly, a child can have a genetic disorder. Gene therapy is an experimental technique that uses genes to ... or prevent disease. The most common form of gene therapy involves inserting a normal gene to replace an ...

  7. Gene-centric association signals for haemostasis and thrombosis traits identified with the HumanCVD BeadChip.

    PubMed

    Gaunt, T R; Zabaneh, D; Shah, S; Guyatt, A; Ladroue, C; Kumari, M; Drenos, F; Shah, T; Talmud, P J; Casas, J P; Lowe, G; Rumley, A; Lawlor, D A; Kivimaki, M; Whittaker, J; Hingorani, A D; Humphries, S E; Day, I N

    2013-11-01

    Coagulation phenotypes show strong intercorrelations, affect cardiovascular disease risk and are influenced by genetic variants. The objective of this study was to search for novel genetic variants influencing the following coagulation phenotypes: factor VII levels, fibrinogen levels, plasma viscosity and platelet count. We genotyped the British Women's Heart and Health Study (n=3,445) and the Whitehall II study (n=5,059) using the Illumina HumanCVD BeadArray to investigate genetic associations and pleiotropy. In addition to previously reported associations (SH2B3, F7/F10, PROCR, GCKR, FGA/FGB/FGG, IL5), we identified novel associations at GRK5 (rs10128498, p=1.30x10(-6)), GCKR (rs1260326, p=1.63x10(-6)), ZNF259-APOA5 (rs651821, p=7.17x10(-6)) with plasma viscosity; and at CSF1 (rs333948, p=8.88x10(-6)) with platelet count. A pleiotropic effect was identified in GCKR which associated with factor VII (p=2.16x10(-7)) and plasma viscosity (p=1.63x10(-6)), and, to a lesser extent, ZNF259-APOA5 which also associated with factor VII and fibrinogen (p<1.00x10-²) and plasma viscosity (p<1.00x10(-5)). Triglyceride associated variants were overrepresented in factor VII and plasma viscosity associations. Adjusting for triglyceride levels resulted in attenuation of associations at the GCKR and ZNF259-APOA5 loci. In addition to confirming previously reported associations, we identified four single nucleotide polymorphisms (SNPs) associated with plasma viscosity and platelet count and found evidence of pleiotropic effects with SNPs in GCKR and ZNF259-APOA5. These triglyceride-associated, pleiotropic SNPs suggest a possible causal role for triglycerides in coagulation.

  8. A Genome-Wide mQTL Analysis in Human Adipose Tissue Identifies Genetic Variants Associated with DNA Methylation, Gene Expression and Metabolic Traits.

    PubMed

    Volkov, Petr; Olsson, Anders H; Gillberg, Linn; Jørgensen, Sine W; Brøns, Charlotte; Eriksson, Karl-Fredrik; Groop, Leif; Jansson, Per-Anders; Nilsson, Emma; Rönn, Tina; Vaag, Allan; Ling, Charlotte

    2016-01-01

    Little is known about the extent to which interactions between genetics and epigenetics may affect the risk of complex metabolic diseases and/or their intermediary phenotypes. We performed a genome-wide DNA methylation quantitative trait locus (mQTL) analysis in human adipose tissue of 119 men, where 592,794 single nucleotide polymorphisms (SNPs) were related to DNA methylation of 477,891 CpG sites, covering 99% of RefSeq genes. SNPs in significant mQTLs were further related to gene expression in adipose tissue and obesity related traits. We found 101,911 SNP-CpG pairs (mQTLs) in cis and 5,342 SNP-CpG pairs in trans showing significant associations between genotype and DNA methylation in adipose tissue after correction for multiple testing, where cis is defined as distance less than 500 kb between a SNP and CpG site. These mQTLs include reported obesity, lipid and type 2 diabetes loci, e.g. ADCY3/POMC, APOA5, CETP, FADS2, GCKR, SORT1 and LEPR. Significant mQTLs were overrepresented in intergenic regions meanwhile underrepresented in promoter regions and CpG islands. We further identified 635 SNPs in significant cis-mQTLs associated with expression of 86 genes in adipose tissue including CHRNA5, G6PC2, GPX7, RPL27A, THNSL2 and ZFP57. SNPs in significant mQTLs were also associated with body mass index (BMI), lipid traits and glucose and insulin levels in our study cohort and public available consortia data. Importantly, the Causal Inference Test (CIT) demonstrates how genetic variants mediate their effects on metabolic traits (e.g. BMI, cholesterol, high-density lipoprotein (HDL), hemoglobin A1c (HbA1c) and homeostatic model assessment of insulin resistance (HOMA-IR)) via altered DNA methylation in human adipose tissue. This study identifies genome-wide interactions between genetic and epigenetic variation in both cis and trans positions influencing gene expression in adipose tissue and in vivo (dys)metabolic traits associated with the development of obesity and

  9. A Genome-Wide mQTL Analysis in Human Adipose Tissue Identifies Genetic Variants Associated with DNA Methylation, Gene Expression and Metabolic Traits

    PubMed Central

    Volkov, Petr; Olsson, Anders H.; Gillberg, Linn; Jørgensen, Sine W.; Brøns, Charlotte; Eriksson, Karl-Fredrik; Groop, Leif; Jansson, Per-Anders; Nilsson, Emma; Rönn, Tina; Vaag, Allan; Ling, Charlotte

    2016-01-01

    Little is known about the extent to which interactions between genetics and epigenetics may affect the risk of complex metabolic diseases and/or their intermediary phenotypes. We performed a genome-wide DNA methylation quantitative trait locus (mQTL) analysis in human adipose tissue of 119 men, where 592,794 single nucleotide polymorphisms (SNPs) were related to DNA methylation of 477,891 CpG sites, covering 99% of RefSeq genes. SNPs in significant mQTLs were further related to gene expression in adipose tissue and obesity related traits. We found 101,911 SNP-CpG pairs (mQTLs) in cis and 5,342 SNP-CpG pairs in trans showing significant associations between genotype and DNA methylation in adipose tissue after correction for multiple testing, where cis is defined as distance less than 500 kb between a SNP and CpG site. These mQTLs include reported obesity, lipid and type 2 diabetes loci, e.g. ADCY3/POMC, APOA5, CETP, FADS2, GCKR, SORT1 and LEPR. Significant mQTLs were overrepresented in intergenic regions meanwhile underrepresented in promoter regions and CpG islands. We further identified 635 SNPs in significant cis-mQTLs associated with expression of 86 genes in adipose tissue including CHRNA5, G6PC2, GPX7, RPL27A, THNSL2 and ZFP57. SNPs in significant mQTLs were also associated with body mass index (BMI), lipid traits and glucose and insulin levels in our study cohort and public available consortia data. Importantly, the Causal Inference Test (CIT) demonstrates how genetic variants mediate their effects on metabolic traits (e.g. BMI, cholesterol, high-density lipoprotein (HDL), hemoglobin A1c (HbA1c) and homeostatic model assessment of insulin resistance (HOMA-IR)) via altered DNA methylation in human adipose tissue. This study identifies genome-wide interactions between genetic and epigenetic variation in both cis and trans positions influencing gene expression in adipose tissue and in vivo (dys)metabolic traits associated with the development of obesity and

  10. 44 CFR Appendix A(5) to Part 61 - Appendix A(5) to Part 61

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... notice sent to you in conjunction with the community inspection procedure established under 44 CFR 59.30... procedure set forth in National Flood Insurance Program Regulations (44 CFR 59.30). During the several years... 44 Emergency Management and Assistance 1 2013-10-01 2013-10-01 false Appendix A(5) to Part 61...

  11. Vulnerability genes or plasticity genes?

    PubMed Central

    Belsky, J; Jonassaint, C; Pluess, M; Stanton, M; Brummett, B; Williams, R

    2009-01-01

    The classic diathesis–stress framework, which views some individuals as particularly vulnerable to adversity, informs virtually all psychiatric research on behavior–gene–environment (G × E) interaction. An alternative framework of ‘differential susceptibility' is proposed, one which regards those most susceptible to adversity because of their genetic make up as simultaneously most likely to benefit from supportive or enriching experiences—or even just the absence of adversity. Recent G × E findings consistent with this perspective and involving monoamine oxidase-A, 5-HTTLPR (5-hydroxytryptamine-linked polymorphic region polymorphism) and dopamine receptor D4 (DRD4) are reviewed for illustrative purposes. Results considered suggest that putative ‘vulnerability genes' or ‘risk alleles' might, at times, be more appropriately conceptualized as ‘plasticity genes', because they seem to make individuals more susceptible to environmental influences—for better and for worse. PMID:19455150

  12. MiR-30a-5p suppresses tumor growth in colon carcinoma by targeting DTL.

    PubMed

    Baraniskin, Alexander; Birkenkamp-Demtroder, Karin; Maghnouj, Abdelouahid; Zöllner, Hannah; Munding, Johanna; Klein-Scory, Susanne; Reinacher-Schick, Anke; Schwarte-Waldhoff, Irmgard; Schmiegel, Wolff; Hahn, Stephan A

    2012-04-01

    MicroRNAs (miRNAs) are small non-coding RNAs that are involved in different biological processes by suppressing target gene expression. Altered expression of miR-30a-5p has been reported in colon carcinoma. To elucidate its potential biological role in colon cancer, miR-30a-5p was overexpressed via a lentiviral vector system in two different colon cancer cell lines. This induced in both lines miR-30a-5p-mediated growth inhibition, attributable to a cell cycle arrest at the G(1) phase and an induction of apoptosis. Combining global gene expression analyses of miR-30a-5p transgenic line HCT116 with in silico miRNA target prediction, we identified the denticleless protein homolog (DTL) as a potential miRNA-30a-5p target. Subsequent reporter gene assays confirmed the predicted miR-30a-5p binding site in the 3'untranslated region of DTL. Importantly, overexpression of DTL in HCT116 cells partially rescued these cells from miR-30a-5p-mediated growth suppression. In addition, TP53 and CDKN1A expression were increased in miR-30a-5p-overexpressing HCT116 cells, suggesting that miR-30a-5p is able to modulate the cell cycle via a DTL-TP53-CDKN1A regulatory circuit. Finally, 379 colorectal cancer tissues were screened for DTL expression and DTL was found to be overexpressed in 95.8% of human colorectal cancers compared with normal colon mucosa. In conclusion, our data identified miR-30a-5p as a tumor-suppressing miRNA in colon cancer cells exerting its function via modulation of DTL expression, which is frequently overexpressed in colorectal cancer. Thus, our data suggest that restoring miR-30a-5p function may prove useful as therapeutic strategy for tumors with reduced miR-30a-5p expression.

  13. Distinctive Structure of the EphA3/Ephrin-A5 Complex Reveals a Dual Mode of Eph Receptor Interaction for Ephrin-A5

    PubMed Central

    Forse, Garry Jason; Uson, Maria Loressa; Nasertorabi, Fariborz; Kolatkar, Anand; Lamberto, Ilaria; Pasquale, Elena Bianca; Kuhn, Peter

    2015-01-01

    The Eph receptor tyrosine kinase/ephrin ligand system regulates a wide spectrum of physiological processes, while its dysregulation has been implicated in cancer progression. The human EphA3 receptor is widely upregulated in the tumor microenvironment and is highly expressed in some types of cancer cells. Furthermore, EphA3 is among the most highly mutated genes in lung cancer and it is also frequently mutated in other cancers. We report the structure of the ligand-binding domain of the EphA3 receptor in complex with its preferred ligand, ephrin-A5. The structure of the complex reveals a pronounced tilt of the ephrin-A5 ligand compared to its orientation when bound to the EphA2 and EphB2 receptors and similar to its orientation when bound to EphA4. This tilt brings an additional area of ephrin-A5 into contact with regions of EphA3 outside the ephrin-binding pocket thereby enlarging the size of the interface, which is consistent with the high binding affinity of ephrin-A5 for EphA3. This large variation in the tilt of ephrin-A5 bound to different Eph receptors has not been previously observed for other ephrins. PMID:25993310

  14. Genes and gene regulation

    SciTech Connect

    MacLean, N.

    1988-01-01

    Genetics has long been a central topic for biologists, and recent progress has captured the public imagination as well. This book addresses questions that are at the leading edge of this continually advancing discipline. In tune with the increasing emphasis on molecular biology and genetic engineering, this text emphasizes the molecular aspects of gene expression, and the evolution of gene sequence organization and control. It reviews the genetic material of viruses, bacteria, and of higher organisms. Cells and organisms are compared in terms of gene numbers, their arrangements within a cell, and the control mechanisms which regulate the activity of genes.

  15. 29 CFR 1912a.5 - Advice and recommendations.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 7 2010-07-01 2010-07-01 false Advice and recommendations. 1912a.5 Section 1912a.5 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.5 Advice...

  16. 38 CFR 18a.5 - Delegation to the General Counsel.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Counsel. 18a.5 Section 18a.5 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS (CONTINUED) DELEGATION OF RESPONSIBILITY IN CONNECTION WITH TITLE VI, CIVIL RIGHTS ACT OF 1964 § 18a.5 Delegation to the General Counsel. The General Counsel is delegated the responsibility, upon receipt...

  17. 38 CFR 18a.5 - Delegation to the General Counsel.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Counsel. 18a.5 Section 18a.5 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS (CONTINUED) DELEGATION OF RESPONSIBILITY IN CONNECTION WITH TITLE VI, CIVIL RIGHTS ACT OF 1964 § 18a.5 Delegation to the General Counsel. The General Counsel is delegated the responsibility, upon receipt...

  18. 38 CFR 18a.5 - Delegation to the General Counsel.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Counsel. 18a.5 Section 18a.5 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS (CONTINUED) DELEGATION OF RESPONSIBILITY IN CONNECTION WITH TITLE VI, CIVIL RIGHTS ACT OF 1964 § 18a.5 Delegation to the General Counsel. The General Counsel is delegated the responsibility, upon receipt...

  19. 38 CFR 18a.5 - Delegation to the General Counsel.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Counsel. 18a.5 Section 18a.5 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS (CONTINUED) DELEGATION OF RESPONSIBILITY IN CONNECTION WITH TITLE VI, CIVIL RIGHTS ACT OF 1964 § 18a.5 Delegation to the General Counsel. The General Counsel is delegated the responsibility, upon receipt...

  20. 38 CFR 18a.5 - Delegation to the General Counsel.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Counsel. 18a.5 Section 18a.5 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS (CONTINUED) DELEGATION OF RESPONSIBILITY IN CONNECTION WITH TITLE VI, CIVIL RIGHTS ACT OF 1964 § 18a.5 Delegation to the General Counsel. The General Counsel is delegated the responsibility, upon receipt...

  1. 32 CFR 242a.5 - Procedure for announcing meetings.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 2 2011-07-01 2011-07-01 false Procedure for announcing meetings. 242a.5 Section 242a.5 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) MISCELLANEOUS PUBLIC MEETING PROCEDURES OF THE BOARD OF REGENTS, UNIFORMED SERVICES UNIVERSITY OF THE HEALTH SCIENCES § 242a.5 Procedure...

  2. 26 CFR 1.56A-5 - Tax carryovers.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 1 2013-04-01 2013-04-01 false Tax carryovers. 1.56A-5 Section 1.56A-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY INCOME TAX INCOME TAXES Regulations Applicable to Taxable Years Beginning in 1969 and Ending in 1970 § 1.56A-5 Tax carryovers. (a) In...

  3. 26 CFR 1.56A-5 - Tax carryovers.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 1 2011-04-01 2009-04-01 true Tax carryovers. 1.56A-5 Section 1.56A-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY INCOME TAX INCOME TAXES Regulations Applicable to Taxable Years Beginning in 1969 and Ending in 1970 § 1.56A-5 Tax carryovers. (a) In...

  4. 26 CFR 1.56A-5 - Tax carryovers.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 1 2014-04-01 2013-04-01 true Tax carryovers. 1.56A-5 Section 1.56A-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY INCOME TAX INCOME TAXES Regulations Applicable to Taxable Years Beginning in 1969 and Ending in 1970 § 1.56A-5 Tax carryovers. (a) In...

  5. 26 CFR 1.56A-5 - Tax carryovers.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 1 2012-04-01 2012-04-01 false Tax carryovers. 1.56A-5 Section 1.56A-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY INCOME TAX INCOME TAXES Regulations Applicable to Taxable Years Beginning in 1969 and Ending in 1970 § 1.56A-5 Tax carryovers. (a) In...

  6. 32 CFR 242a.5 - Procedure for announcing meetings.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 2 2013-07-01 2013-07-01 false Procedure for announcing meetings. 242a.5 Section 242a.5 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) MISCELLANEOUS PUBLIC MEETING PROCEDURES OF THE BOARD OF REGENTS, UNIFORMED SERVICES UNIVERSITY OF THE HEALTH SCIENCES § 242a.5 Procedure...

  7. 32 CFR 242a.5 - Procedure for announcing meetings.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 2 2012-07-01 2012-07-01 false Procedure for announcing meetings. 242a.5 Section 242a.5 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) MISCELLANEOUS PUBLIC MEETING PROCEDURES OF THE BOARD OF REGENTS, UNIFORMED SERVICES UNIVERSITY OF THE HEALTH SCIENCES § 242a.5 Procedure...

  8. 32 CFR 242a.5 - Procedure for announcing meetings.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 2 2014-07-01 2014-07-01 false Procedure for announcing meetings. 242a.5 Section 242a.5 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) MISCELLANEOUS PUBLIC MEETING PROCEDURES OF THE BOARD OF REGENTS, UNIFORMED SERVICES UNIVERSITY OF THE HEALTH SCIENCES § 242a.5 Procedure...

  9. 7 CFR 1a.5 - Responsibility of the Inspector General.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 false Responsibility of the Inspector General. 1a.5 Section 1a.5 Agriculture Office of the Secretary of Agriculture LAW ENFORCEMENT AUTHORITIES § 1a.5 Responsibility of the Inspector General. The Inspector General shall: (a) Issue directives conforming to...

  10. 26 CFR 1.56A-5 - Tax carryovers.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 1 2010-04-01 2010-04-01 true Tax carryovers. 1.56A-5 Section 1.56A-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY INCOME TAX INCOME TAXES Regulations Applicable to Taxable Years Beginning in 1969 and Ending in 1970 § 1.56A-5 Tax carryovers. (a) In...

  11. 26 CFR 1.409A-5 - Funding. [Reserved

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 5 2012-04-01 2011-04-01 true Funding. 1.409A-5 Section 1.409A-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.409A-5 Funding....

  12. 26 CFR 1.409A-5 - Funding. [Reserved

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 5 2011-04-01 2011-04-01 false Funding. 1.409A-5 Section 1.409A-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.409A-5 Funding....

  13. 26 CFR 1.409A-5 - Funding. [Reserved

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Funding. 1.409A-5 Section 1.409A-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.409A-5 Funding....

  14. 26 CFR 1.409A-5 - Funding. [Reserved

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 5 2013-04-01 2013-04-01 false Funding. 1.409A-5 Section 1.409A-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.409A-5 Funding....

  15. 26 CFR 1.409A-5 - Funding. [Reserved

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 5 2014-04-01 2014-04-01 false Funding. 1.409A-5 Section 1.409A-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.409A-5 Funding....

  16. 49 CFR 178.33a-5 - Material.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 3 2012-10-01 2012-10-01 false Material. 178.33a-5 Section 178.33a-5 Transportation Other Regulations Relating to Transportation (Continued) PIPELINE AND HAZARDOUS MATERIALS SAFETY... Containers, and Linings § 178.33a-5 Material. (a) Uniform quality steel plate such as black plate,...

  17. 49 CFR 178.33a-5 - Material.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 3 2013-10-01 2013-10-01 false Material. 178.33a-5 Section 178.33a-5 Transportation Other Regulations Relating to Transportation (Continued) PIPELINE AND HAZARDOUS MATERIALS SAFETY... Containers, and Linings § 178.33a-5 Material. (a) Uniform quality steel plate such as black plate,...

  18. 49 CFR 178.33a-5 - Material.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 3 2011-10-01 2011-10-01 false Material. 178.33a-5 Section 178.33a-5 Transportation Other Regulations Relating to Transportation (Continued) PIPELINE AND HAZARDOUS MATERIALS SAFETY... Containers, and Linings § 178.33a-5 Material. (a) Uniform quality steel plate such as black plate,...

  19. 49 CFR 178.33a-5 - Material.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 3 2014-10-01 2014-10-01 false Material. 178.33a-5 Section 178.33a-5 Transportation Other Regulations Relating to Transportation (Continued) PIPELINE AND HAZARDOUS MATERIALS SAFETY... Containers, and Linings § 178.33a-5 Material. (a) Uniform quality steel plate such as black plate,...

  20. 42 CFR 52a.5 - How will NIH evaluate applications?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false How will NIH evaluate applications? 52a.5 Section 52a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.5 How will NIH evaluate applications? (a) NIH considers...

  1. 42 CFR 52a.5 - How will NIH evaluate applications?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false How will NIH evaluate applications? 52a.5 Section 52a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.5 How will NIH evaluate applications? (a) NIH considers...

  2. Studying Genes

    MedlinePlus

    ... Area What are genes? Genes are sections of DNA that contain instructions for making the molecules—many ... material in an organism. This includes genes and DNA elements that control the activity of genes. Does ...

  3. Impaired osteoblast differentiation in Annexin A2- and -A5-deficient cells

    SciTech Connect

    Genetos, Damian C.; Wong, Alice; Weber, Thomas J.; Karin, Norman J.; Yellowley, Clare E.

    2014-09-15

    Annexins are a class of calcium-binding proteins with diverse functions in the regulation of lipid rafts inflammation,fibrinolysis, transcriptional programming and ion transport. Within bone, they are well-characterized as components of mineralizing matrix vesicles, although little else is known as to their function during osteogenesis. We generated annexin A2 (AnxA2)- or annexin A5 (AnxA5)-knockdown pre-osteoblasts, and asked whether proliferation or osteogenic differentiation was altered in knockdown cells, compared to vector controls. We report that DNA content, a marker of proliferation, was significantly reduced in both AnxA2 and AnxA5 knockdown cells. Alkaline phosphatase expression and staining activity were also suppressed in AnxA2- or AnxA5-knockdown after 14 days of culture. The pattern of osteogenic gene expression was altered in knockdown cells, with Col1a1 expressed more rapidly in knock-down cells, compared to controls. In contrast, Runx2, Ibsp, and Bglap all revealed decreased expression after 14 days of culture. Using a murine fracture model, we demonstrate that AnxA2 and AnxA5 are rapidly expressed within the fracture callus. These data demonstrate that AnxA2 and AnxA5 can influence bone formation via regulation of osteoprogenitor proliferation and differentiation in addition to their well-studied function in matrix vesicles.

  4. A role for DNA methylation in regulation of EphA5 receptor expression in the mouse retina

    PubMed Central

    Petkova, Tihomira D.; Seigel, Gail M.; Otteson, Deborah C.

    2010-01-01

    Understanding the mechanisms regulating expression of retinal ganglion cell (RGC) specific and axon-guidance genes during development and in retinal stem cells will be critical for successful optic nerve regeneration. Müller glia have some characteristics of retinal stem cell properties, but in mammals have demonstrated limited potential to differentiate into RGCs. Chromatin remodeling through histone deacetylation and DNA methylation are a potential mechanism for silencing genes necessary for neuronal differentiation of glial cells. We investigated DNA methylation as a mechanism for regulating expression of mouse EphA5, one member of a large family of ephrin receptor genes that regulate patterning of the topographic connections of RGCs during visual system development. We analyzed spatial and age-related patterns of EphA5 promoter methylation by bisulfite sequencing and mRNA expression by quantitative RT-PCR in the mouse retina. The CpG island in the EphA5 promoter was hypomethylated in the retina and showed no change in overall methylation with age, despite a decline in EphA5 mRNA expression levels in the adult retina. In the nasal retina of post-natal day 0 mice, there was a modest, but statistically significant increase in methylation. Increased methylation corresponded with lower levels of receptor mRNA expression in the nasal retina. We cloned the EphA5 promoter and found that site-specific differences in methylation could preferentially activate or repress promoter activity in transient transfections of rat retinal progenitor cells (R28) using luciferase assays. In sphere cultures generated by EGF/FGF2 stimulation of conditionally immortalized mouse Müller glia (ImM10), EphA5 promoter was hypermethylated and EphA5 mRNA was not detected. Demethylation using 5-azadeoxycytidine (AzadC) resulted in a significant decrease of methylation of the EphA5 promoter and re-expression of the EphA5 mRNA. The inverse relationship between EphA5 promoter methylation and m

  5. 42 CFR 52a.5 - How will NIH evaluate applications?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false How will NIH evaluate applications? 52a.5 Section... INSTITUTES OF HEALTH CENTER GRANTS § 52a.5 How will NIH evaluate applications? (a) NIH considers the... statute or NIH policy, applications are reviewed by appropriate national advisory councils or...

  6. 42 CFR 52a.5 - How will NIH evaluate applications?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false How will NIH evaluate applications? 52a.5 Section... INSTITUTES OF HEALTH CENTER GRANTS § 52a.5 How will NIH evaluate applications? (a) NIH considers the... statute or NIH policy, applications are reviewed by appropriate national advisory councils or...

  7. 42 CFR 52a.5 - How will NIH evaluate applications?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false How will NIH evaluate applications? 52a.5 Section... INSTITUTES OF HEALTH CENTER GRANTS § 52a.5 How will NIH evaluate applications? (a) NIH considers the... statute or NIH policy, applications are reviewed by appropriate national advisory councils or...

  8. 42 CFR 54a.5 - Religious character and independence.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Religious character and independence. 54a.5 Section 54a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS CHARITABLE... DISCRETIONARY FUNDING UNDER TITLE V OF THE PUBLIC HEALTH SERVICE ACT, 42 U.S.C. 290aa, ET SEQ., FOR...

  9. 15 CFR 4a.5 - Duration of classification.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 15 Commerce and Foreign Trade 1 2010-01-01 2010-01-01 false Duration of classification. 4a.5 Section 4a.5 Commerce and Foreign Trade Office of the Secretary of Commerce CLASSIFICATION..., except as provided in § 1.6(d) of E.O. 12958. Under E.O. 12958, information may be exempted...

  10. 49 CFR 178.33a-5 - Material.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 2 2010-10-01 2010-10-01 false Material. 178.33a-5 Section 178.33a-5 Transportation Other Regulations Relating to Transportation PIPELINE AND HAZARDOUS MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION HAZARDOUS MATERIALS REGULATIONS SPECIFICATIONS FOR...

  11. 42 CFR 68a.5 - Who is ineligible to participate?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Who is ineligible to participate? 68a.5 Section 68a... INDIVIDUALS FROM DISADVANTAGED BACKGROUNDS (CR-LRP) § 68a.5 Who is ineligible to participate? The following... Government, a State, or other entity, unless a deferral is granted for the length of his/her...

  12. 42 CFR 65a.5 - How to apply.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false How to apply. 65a.5 Section 65a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC RESEARCH AND TRAINING...

  13. 42 CFR 65a.5 - How to apply.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false How to apply. 65a.5 Section 65a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC RESEARCH AND TRAINING...

  14. 42 CFR 65a.5 - How to apply.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false How to apply. 65a.5 Section 65a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC RESEARCH AND TRAINING...

  15. 42 CFR 65a.5 - How to apply.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false How to apply. 65a.5 Section 65a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC RESEARCH AND TRAINING...

  16. 42 CFR 65a.5 - How to apply.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false How to apply. 65a.5 Section 65a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC RESEARCH AND TRAINING...

  17. SLC24A5 and ASIP as phenotypic predictors in Brazilian population for forensic purposes.

    PubMed

    Lima, F A; de Araújo Lima, Felícia; Gonçalves, F T; de Toledo Gonçalves, Fernanda; Fridman, C; Fridman, Cintia

    2015-07-01

    Pigmentation is a variable and complex trait in humans and it is determined by the interaction of environmental factors, age, disease, hormones, exposure to ultraviolet radiation and genetic factors, including pigmentation genes. Many polymorphisms of these genes have been associated with phenotypic diversity of skin, eyes and hair color in homogeneous populations. Phenotype prediction from biological samples using genetic information has benefited forensic area in some countries, leading some criminal investigations. Herein, we evaluated the association between polymorphisms in the genes SLC24A5 (rs1426654) and ASIP (rs6058017) with skin, eyes and hair colors, in 483 healthy individuals from Brazilian population for attainable use in forensic practice. The volunteers answered a questionnaire where they self-reported their skin, eye and hair colors. The polymorphic homozygous genotype of rs1426654∗A and rs6058017∗A in SLC24A5 and ASIP respectively, showed strongest association with fairer skin (OR 47.8; CI 14.1-161.6 and OR 8.6; CI 2.5-29.8); SLC24A5 alone showed associations with blue eyes (OR 20.7; CI 1.2-346.3) and blond hair (OR 26.6; CI 1.5-460.9). Our data showed that polymorphic genotypes (AA), in both genes, are correlated with characteristics of light pigmentation, while the ancestral genotype (GG) is related to darker traits, corroborating with previous studies in European and African populations. These associations show that specific molecular information of an individual may be useful to access some phenotypic features in an attempt to help forensic investigations, not only on crime scene samples but also in cases of face reconstructions in unknown bodies.

  18. CYP3A5 mediates bioactivation and cytotoxicity of tetrandrine.

    PubMed

    Tian, Ye; Shen, Shuijie; Jiang, Yan; Shen, Qi; Zeng, Su; Zheng, Jiang

    2016-07-01

    Tetrandrine is a diaryl ether-type bisbenzylisoquinoline alkaloid and has shown multiple pharmacological activities. Our early work demonstrated that tetrandrine produced acute pulmonary toxicity and that tetrandrine was biotransformed to a quinone methide-derived metabolite mediated by CYP3A enzymes. The formation of the reactive intermediate is suggested to be responsible for the pulmonary toxicity induced by tetrandrine. In the present study, a WI-38-based Cyp3a5 transgenic cell line (WI-38/Cyp3a5) was established to investigate the role of CYP3A5 in tetrandrine-induced cytotoxicity. The transgenic cells were found to be more susceptible to the cytotoxicity of tetrandrine than the wild-type cells (WI-38/Vector). WI-38/Cyp3a5 cells showed higher cellular ROS levels, higher LDH activities in culture media, but lower cellular GSH contents than those observed in WI-38/Vector cells after exposure to tetrandrine. And severer apoptosis were observed in WI-38/Cyp3a5 cells after treatment with tetrandrine: WI-38/Cyp3a5 cells had higher proportion of early and late apoptotic cells, higher expression levels of caspase-3, but lower level of Bcl-2 than WI-38/Vector cells. This study provided strong evidence that CYP3A5 participated in tetrandrine-induced cytotoxicity. PMID:26302866

  19. Pharmacogenetic biomarkers: cytochrome P450 3A5.

    PubMed

    MacPhee, Iain A M

    2012-09-01

    The immunosuppressive drugs used for solid organ transplantation all have a narrow therapeutic index with wide variation between individuals in the blood concentration achieved by a given dose. Therapeutic drug monitoring is employed routinely but may not allow optimisation of drug exposure during the critical period two to three days following transplantation. A key factor in the inter-individual variability for tacrolimus, and probably sirolimus, is whether an individual is genetically predicted to express the drug metabolising enzyme cytochrome P450 3A5 (CYP3A5). Individuals predicted to express CYP3A5 by possession of at least one wild-type CYP3A5*1 allele require 1.5-2 times higher doses of tacrolimus to achieve target blood concentrations than individuals homozygous for the CYP3A5*3 allele who are functional non-expressers of CYP3A5. Planning the initial tacrolimus dose based on the CYP3A5 genotype has been shown to allow more rapid achievement of target blood concentrations after transplantation than a standard dose given to all patients. However, it remains to be demonstrated that use of this approach as an adjunct to therapeutic drug monitoring can reduce either efficacy failure (transplant rejection) or toxicity. Use of a pharmacogenetic approach to dosing sirolimus awaits testing and it is unlikely to be useful for ciclosporin or everolimus.

  20. A COL4A5 mutation with glomerular disease and signs of chronic thrombotic microangiopathy.

    PubMed

    Wuttke, Matthias; Seidl, Maximilian; Malinoc, Angelica; Prischl, Friedrich C; Kuehn, E Wolfgang; Walz, Gerd; Köttgen, Anna

    2015-12-01

    COL4A5 mutations are a known cause of Alport syndrome, which typically manifests with haematuria, hearing loss and ocular symptoms. Here we report on a 16-year-old male patient with a negative family history who presented with proteinuria, progressive renal failure and haemolysis, but without overt haematuria or hearing loss. A renal biopsy revealed features of atypical IgA nephropathy, while a second biopsy a year later showed features of focal segmental glomerulosclerosis, but was finally diagnosed as chronic thrombotic microangiopathy. Targeted sequencing of candidate genes for steroid-resistant nephrotic syndrome and congenital thrombotic microangiopathy was negative. Despite all therapeutic efforts, including angiotensin-converting enzyme inhibition, immunosuppressive therapy, plasma exchanges and rituximab, the patient progressed to end-stage renal disease. When a male cousin presented with nephrotic syndrome years later, whole-exome sequencing identified a shared disruptive COL4A5 mutation (p.F222C) that showed X-linked segregation. Thus, mutations in COL4A5 give rise to a broader spectrum of clinical presentation than commonly suspected, highlighting the benefits of comprehensive rather than candidate genetic testing in young patients with otherwise unexplained glomerular disease. Our results are in line with an increasing number of atypical presentations of single-gene disorders identified through genome-wide sequencing.

  1. A COL4A5 mutation with glomerular disease and signs of chronic thrombotic microangiopathy

    PubMed Central

    Wuttke, Matthias; Seidl, Maximilian; Malinoc, Angelica; Prischl, Friedrich C.; Kuehn, E. Wolfgang; Walz, Gerd; Köttgen, Anna

    2015-01-01

    COL4A5 mutations are a known cause of Alport syndrome, which typically manifests with haematuria, hearing loss and ocular symptoms. Here we report on a 16-year-old male patient with a negative family history who presented with proteinuria, progressive renal failure and haemolysis, but without overt haematuria or hearing loss. A renal biopsy revealed features of atypical IgA nephropathy, while a second biopsy a year later showed features of focal segmental glomerulosclerosis, but was finally diagnosed as chronic thrombotic microangiopathy. Targeted sequencing of candidate genes for steroid-resistant nephrotic syndrome and congenital thrombotic microangiopathy was negative. Despite all therapeutic efforts, including angiotensin-converting enzyme inhibition, immunosuppressive therapy, plasma exchanges and rituximab, the patient progressed to end-stage renal disease. When a male cousin presented with nephrotic syndrome years later, whole-exome sequencing identified a shared disruptive COL4A5 mutation (p.F222C) that showed X-linked segregation. Thus, mutations in COL4A5 give rise to a broader spectrum of clinical presentation than commonly suspected, highlighting the benefits of comprehensive rather than candidate genetic testing in young patients with otherwise unexplained glomerular disease. Our results are in line with an increasing number of atypical presentations of single-gene disorders identified through genome-wide sequencing. PMID:26613025

  2. 42 CFR 54a.5 - Religious character and independence.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... DISCRETIONARY FUNDING UNDER TITLE V OF THE PUBLIC HEALTH SERVICE ACT, 42 U.S.C. 290aa, et seq., FOR SUBSTANCE ABUSE PREVENTION AND TREATMENT SERVICES § 54a.5 Religious character and independence. A...

  3. 42 CFR 54a.5 - Religious character and independence.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... DISCRETIONARY FUNDING UNDER TITLE V OF THE PUBLIC HEALTH SERVICE ACT, 42 U.S.C. 290aa, ET SEQ., FOR SUBSTANCE ABUSE PREVENTION AND TREATMENT SERVICES § 54a.5 Religious character and independence. A...

  4. 42 CFR 54a.5 - Religious character and independence.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... DISCRETIONARY FUNDING UNDER TITLE V OF THE PUBLIC HEALTH SERVICE ACT, 42 U.S.C. 290aa, ET SEQ., FOR SUBSTANCE ABUSE PREVENTION AND TREATMENT SERVICES § 54a.5 Religious character and independence. A...

  5. 42 CFR 54a.5 - Religious character and independence.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... DISCRETIONARY FUNDING UNDER TITLE V OF THE PUBLIC HEALTH SERVICE ACT, 42 U.S.C. 290aa, et seq., FOR SUBSTANCE ABUSE PREVENTION AND TREATMENT SERVICES § 54a.5 Religious character and independence. A...

  6. MicroRNA-548a-5p promotes proliferation and inhibits apoptosis in hepatocellular carcinoma cells by targeting Tg737

    PubMed Central

    Zhao, Ge; Wang, Ting; Huang, Qi-Ke; Pu, Meng; Sun, Wei; Zhang, Zhuo-Chao; Ling, Rui; Tao, Kai-Shan

    2016-01-01

    AIM: To investigate whether Tg737 is regulated by microRNA-548a-5p (miR-548a-5p), and correlates with hepatocellular carcinoma (HCC) cell proliferation and apoptosis. METHODS: Assays of loss of function of Tg737 were performed by the colony formation assay, CCK assay and cell cycle assay in HCC cell lines. The interaction between miR-548a-5p and its downstream target, Tg737, was evaluated by a dual-luciferase reporter assay and quantitative real-time polymerase chain reaction. Tg737 was then up-regulated in HCC cells to evaluate its effect on miR-548a-5p regulation. HepG2 cells stably overexpressing miR-548a-5p or miR-control were also subcutaneously inoculated into nude mice to evaluate the effect of miR-548a-5p up-regulation on in vivo tumor growth. As the final step, the effect of miR-548a-5p on the apoptosis induced by cisplatin was evaluated by flow cytometry. RESULTS: Down-regulation of Tg737, which is a target gene of miR-548a-5p, accelerated HCC cell proliferation, and miR-548a-5p promoted HCC cell proliferation in vitro and in vivo. Like the down-regulation of Tg737, overexpression of miR-548a-5p in HCC cell lines promoted cell proliferation, increased colony forming ability and hampered cell apoptosis. In addition, miR-548a-5p overexpression increased HCC cell growth in vivo. MiR-548a-5p down-regulated Tg737 expression through direct contact with its 3’ untranslated region (UTR), and miR-548a-5p expression was negatively correlated with Tg737 levels in HCC specimens. Restoring Tg737 (without the 3’UTR) significantly hampered miR-548a-5p induced cell proliferation, and rescued the miR-548a-5p induced cell proliferation inhibition and apoptosis induced by cisplatin. CONCLUSION: MiR-548a-5p negatively regulates the tumor inhibitor gene Tg737 and promotes tumorigenesis in vitro and in vivo, indicating its potential as a novel therapeutic target for HCC. PMID:27340352

  7. ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis.

    PubMed

    Schaap, Frank G; Rensen, Patrick C N; Voshol, Peter J; Vrins, Carlos; van der Vliet, Hendrik N; Chamuleau, Robert A F M; Havekes, Louis M; Groen, Albert K; van Dijk, Ko Willems

    2004-07-01

    ApoAV has been discovered recently as a novel modifier of triglyceride (TG) metabolism, but the pathways involved are currently unknown. To gain insight into the function of apoAV, adenovirus-mediated gene transfer of murine apoa5 to C57Bl/6 mice was employed. The injection of low doses of Ad-apoa5 (1-5 x 10(8) plaqueforming units/mouse) dose-dependently reduced plasma very low density lipoprotein (VLDL)-TG levels. First, we evaluated whether a reduced hepatic VLDL production contributed to the TG-lowering effect. Ad-apoa5 treatment dose-dependently diminished (29-37%) the VLDL-TG production rate without affecting VLDL particle production, suggesting that apoAV impairs the lipidation of apoB. Second, Ad-apoa5 treatment dose-dependently reduced (68-88%) the postprandial hypertriglyceridemia following an intragastric fat load, suggesting that apoAV also stimulates the lipoprotein lipase (LPL)-dependent clearance of TG-rich lipoproteins. Indeed, recombinant apoAV was found to dose-dependently stimulate LPL activity up to 2.3-fold in vitro. Accordingly, intravenously injected VLDL-like TG-rich emulsions were cleared at an accelerated rate concomitant with the increased uptake of emulsion TG-derived fatty acids by skeletal muscle and white adipose tissue in Ad-apoa5-treated mice. From these data, we conclude that apoAV is a potent stimulator of LPL activity. Thus, apoAV lowers plasma TG by both reducing the hepatic VLDL-TG production rate and by enhancing the lipolytic conversion of TG-rich lipoproteins.

  8. MicroRNA-125a-5p regulates cancer cell proliferation and migration through NAIF1 in prostate carcinoma

    PubMed Central

    Fu, Yi; Cao, Fuhua

    2015-01-01

    Background We investigated the functional roles of microRNA-125a-5p in regulating human prostate carcinoma. Methods Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was conducted to evaluate the gene expression levels of miR-125a-5p in eight prostate cancer cell lines and nine biopsy specimens from patients with prostate cancer. miR-125a-5p was genetically knocked down in prostate cancer cell lines, DU145 and VCaP cells by lentiviral transduction. The effects of miR-125a-5p downregulation on prostate cancer cell proliferation and migration were evaluated by MTT assay and transwell assay, respectively. Direct regulation of miR-125a-5p on its downstream targets, NAIF1, and apoptotic gene caspase-3 were evaluated through dual-luciferase reporter assay, qRT-PCR, and Western blot, respectively. NAIF1 was then ectopically overexpressed in DU145 and VCaP cells to modulate prostate cancer cell proliferation and migration. Finally, the effects of miR-125a-5p downregulation or NAIF1 overexpression on the growth of in vivo prostate cancer xenograft were evaluated. Results miR-125a-5p was upregulated in prostate cancer cell lines and human prostate carcinomas. Lentivirus induced miR-125a-5p downregulation in DU145 and VCaP cells inhibited prostate cancer cell proliferation or migration. NAIF1 was the direct target of miR-125a-5p, as both gene and protein expression levels of NAIF1, as well as caspase-3 were upregulated by miR-125a-5p. Forced overexpression of NAIF1 had similar antitumor effects as miR-125a-5p downregulation on prostate cancer cell proliferation and migration. In vivo prostate xenograft assay confirmed the tumor-suppressive effect of miR-125a-5p downregulation or NAIF1 overexpression. Conclusion miR-125a-5p regulates prostate cancer cell proliferation and migration through NAIF1. PMID:26719710

  9. MicroRNA-125a-5p modulates human cervical carcinoma proliferation and migration by targeting ABL2

    PubMed Central

    Qin, Xian; Wan, Yajun; Wang, Saiying; Xue, Min

    2016-01-01

    Background In this study, we intended to understand the regulatory mechanisms of microRNA-125a-5p (miR-125a-5p) in human cervical carcinoma. Methods The gene expressions of miR-125a-5p in seven cervical carcinoma cell lines and 12 human cervical carcinoma samples were evaluated by quantitative real-time reverse transcription polymerase chain reaction. Ca-Ski and HeLa cells were transduced with lentivirus carrying miR-125a-5p mimics, and the effects of lentivirus-induced miR-125a-5p upregulation on cervical carcinoma proliferation and migration were examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and transwell assays, respectively. In additional, HeLa cells were inoculated into null mice to evaluate the effect of miR-125a-5p upregulation on in vivo cervical carcinoma growth. The direct regulation of miR-125a-5p on its target gene, ABL proto-oncogene 2 (ABL2), in cervical carcinoma was evaluated by quantitative real-time reverse transcription polymerase chain reaction, Western blotting and luciferase reporter assays, respectively. ABL2 was then downregulated by small interfering RNA to examine its effect on cervical carcinoma proliferation and migration. Results miR-125a-5p was downregulated in both cervical carcinoma cell lines and human cervical carcinomas. In Ca-Ski and HeLa cells, lentivirus-mediated miR-125a-5p upregulation inhibited cancer proliferation and migration in vitro and cervical carcinoma transplantation in vivo. ABL2 was shown to be directly targeted by miR-125a-5p. In cervical carcinoma, ABL2 gene and protein levels were both downregulated by miR-125a-5p. Small interfering RNA-mediated ABL2 downregulation also had tumor-suppressive effects on cervical carcinoma proliferation and migration. Conclusion The molecular pathway of miR-125a-5p/ABL2 plays an important role in human cervical carcinoma. Targeting miR-125a-5p/ABL2 pathway may provide a new treatment strategy for patients with cervical carcinoma. PMID:26766902

  10. Ephrin-A5 promotes bovine muscle progenitor cell migration before mitotic activation.

    PubMed

    Li, J; Johnson, S E

    2013-03-01

    Satellite cells are the resident stem cell population of adult skeletal muscle tissue that is responsible for growth and regeneration. The cells typically congregate near the tips of the muscle fibers and in close proximity to the neural muscular junction (NMJ). Ephrin-A5 is a chemotactic molecule that participates in the correct positioning and formation of the NMJ. The objective of the experiment was to examine the effects of ephrin-A5 signaling on bovine satellite cell (BSC) biology. Primary cultures of BSC demonstrate changes in velocity with time in culture that is unique to the Paired box protein 7 (Pax7):Myogenic factor 5 (Myf5) subpopulation. Treatment of the BSC with ephrin-A5 causes a reduction (P < 0.05) in velocity with a concomitant increase (P < 0.05) in directed migration. The chemoattractant properties of ephrin-A5 occur before myogenic differentiation 1 (MyoD) expression in the myogenic precursors and are abrogated after their differentiation to committed myoblasts. Ephrin-A5 induced migration appears to require components of the Ras homolog gene family member A (RhoA) and Rho-associated protein kinase (ROCK) signaling machinery. Supplementation of culture media with a chemical ROCK inhibitor suppressed (P < 0.05) ephrin-A5 initiated BSC migration. These results contrast with treatment of BSC with hepatocyte growth factor (HGF), a key modulator of myogenic and motogenic activity. Treatment of BSC with HGF had no effect on cell motility or migration immediately after culture establishment. Twenty-four hours after culture establishment, BSC demonstrated an increase (P < 0.05) in transwell migration toward HGF. These results document that temporal and spatial gradients of chemokines and growth factors participate in the localization of BSC within the niche.

  11. Coactivator PGC-1{alpha} regulates the fasting inducible xenobiotic-metabolizing enzyme CYP2A5 in mouse primary hepatocytes

    SciTech Connect

    Arpiainen, Satu; Jaervenpaeae, Sanna-Mari; Manninen, Aki; Viitala, Pirkko; Lang, Matti A.; Pelkonen, Olavi; Hakkola, Jukka

    2008-10-01

    The nutritional state of organisms and energy balance related diseases such as diabetes regulate the metabolism of xenobiotics such as drugs, toxins and carcinogens. However, the mechanisms behind this regulation are mostly unknown. The xenobiotic-metabolizing cytochrome P450 (CYP) 2A5 enzyme has been shown to be induced by fasting and by glucagon and cyclic AMP (cAMP), which mediate numerous fasting responses. Peroxisome proliferator-activated receptor {gamma} coactivator (PGC)-1{alpha} triggers many of the important hepatic fasting effects in response to elevated cAMP levels. In the present study, we were able to show that cAMP causes a coordinated induction of PGC-1{alpha} and CYP2A5 mRNAs in murine primary hepatocytes. Furthermore, the elevation of the PGC-1{alpha} expression level by adenovirus mediated gene transfer increased CYP2A5 transcription. Co-transfection of Cyp2a5 5' promoter constructs with the PGC-1{alpha} expression vector demonstrated that PGC-1{alpha} is able to activate Cyp2a5 transcription through the hepatocyte nuclear factor (HNF)-4{alpha} response element in the proximal promoter of the Cyp2a5 gene. Chromatin immunoprecipitation assays showed that PGC-1{alpha} binds, together with HNF-4{alpha}, to the same region at the Cyp2a5 proximal promoter. In conclusion, PGC-1{alpha} mediates the expression of CYP2A5 induced by cAMP in mouse hepatocytes through coactivation of transcription factor HNF-4{alpha}. This strongly suggests that PGC-1{alpha} is the major factor mediating the fasting response of CYP2A5.

  12. 26 CFR 1.408A-5 - Recharacterized contributions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... April 1, 2003, edition of 26 CFR part 1). Q-3. What is the effect of recharacterizing a contribution... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Recharacterized contributions. 1.408A-5 Section... Recharacterized contributions. This section sets forth the following questions and answers that provide...

  13. 42 CFR 68a.5 - Who is ineligible to participate?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... INDIVIDUALS FROM DISADVANTAGED BACKGROUNDS (CR-LRP) § 68a.5 Who is ineligible to participate? The following individuals are ineligible for CR-LRP participation: (a) Persons who are not eligible applicants as specified... obligation under the CR-LRP. The following are examples of programs which have a service...

  14. 7 CFR 15a.5 - Effect of other requirements.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... FROM FEDERAL FINANCIAL ASSISTANCE Introduction § 15a.5 Effect of other requirements. (a) Effect of...); and any other act of Congress or Federal regulation. (b) Effect of State or local law or other requirements. The obligation to comply with this part is not obviated or alleviated by any State or local...

  15. Role of miR-181a-5p and endoplasmic reticulum stress in the regulation of myogenic differentiation.

    PubMed

    Wei, Yingying; Tao, Xuelian; Xu, Huaming; Chen, Yan; Zhu, Li; Tang, Guoqing; Li, Mingzhou; Jiang, Anan; Shuai, Surong; Ma, Jideng; Jin, Long; Wen, Anxiang; Wang, Qin; Zhu, Guangxiang; Xie, Meng; Wu, Jiayun; He, Tao; Jiang, Yanzhi; Li, Xuewei

    2016-10-30

    Accumulating evidence has indicated that microRNAs (miRNAs) and endoplasmic reticulum (ER) stress play critical roles in myoblast differentiation. However, the regulation roles of miRNAs and ER stress in myogenic differentiation have not been fully revealed and need to be further studied. Here, we discovered that the expression levels of miR-181a-5p were strongly upregulated during C2C12 cell differentiation. miR-181a-5p overexpression promoted ER stress and differentiation of C2C12 cells, which was accompanied by increasing expression levels of marker genes related to ER stress-mediated apoptosis and myogenic differentiation. Opposite results were observed after inhibition of the miR-181a-5p expression. The gain- and loss-of-function experiments on C2C12 cells showed that miR-181a-5p affected the development of muscle fiber type, but had no significant influence on C2C12 cell proliferation. In the ER-stressed C2C12 cells induced by thapsigargin (Tg), the expression levels of both miR-181a-5p and marker genes related to ER stress and myogenesis were upregulated. In the ER-stressed C2C12 cells and porcine muscle fibroblast (PMF) cells pretreated with Tg, we found that miR-181a-5p targeted glucose-regulated protein, 78kDa/binding immunoglobulin protein (GRP78/BIP), and influenced cell apoptosis. In conclusion, these results indicate that miR-181a-5p and ER stress have positive synergistic effects on myogenic differentiation by increasing the expression levels of myogenic differentiation key genes and activating the ER stress-mediated apoptosis signaling pathway.

  16. Role of miR-181a-5p and endoplasmic reticulum stress in the regulation of myogenic differentiation.

    PubMed

    Wei, Yingying; Tao, Xuelian; Xu, Huaming; Chen, Yan; Zhu, Li; Tang, Guoqing; Li, Mingzhou; Jiang, Anan; Shuai, Surong; Ma, Jideng; Jin, Long; Wen, Anxiang; Wang, Qin; Zhu, Guangxiang; Xie, Meng; Wu, Jiayun; He, Tao; Jiang, Yanzhi; Li, Xuewei

    2016-10-30

    Accumulating evidence has indicated that microRNAs (miRNAs) and endoplasmic reticulum (ER) stress play critical roles in myoblast differentiation. However, the regulation roles of miRNAs and ER stress in myogenic differentiation have not been fully revealed and need to be further studied. Here, we discovered that the expression levels of miR-181a-5p were strongly upregulated during C2C12 cell differentiation. miR-181a-5p overexpression promoted ER stress and differentiation of C2C12 cells, which was accompanied by increasing expression levels of marker genes related to ER stress-mediated apoptosis and myogenic differentiation. Opposite results were observed after inhibition of the miR-181a-5p expression. The gain- and loss-of-function experiments on C2C12 cells showed that miR-181a-5p affected the development of muscle fiber type, but had no significant influence on C2C12 cell proliferation. In the ER-stressed C2C12 cells induced by thapsigargin (Tg), the expression levels of both miR-181a-5p and marker genes related to ER stress and myogenesis were upregulated. In the ER-stressed C2C12 cells and porcine muscle fibroblast (PMF) cells pretreated with Tg, we found that miR-181a-5p targeted glucose-regulated protein, 78kDa/binding immunoglobulin protein (GRP78/BIP), and influenced cell apoptosis. In conclusion, these results indicate that miR-181a-5p and ER stress have positive synergistic effects on myogenic differentiation by increasing the expression levels of myogenic differentiation key genes and activating the ER stress-mediated apoptosis signaling pathway. PMID:27461948

  17. Evaluation of annexin A5 as a biomarker for Alzheimer's disease and dementia with lewy bodies

    PubMed Central

    Sohma, Hitoshi; Imai, Shin-ichi; Takei, Norio; Honda, Hirohito; Matsumoto, Kyoichi; Utsumi, Kumiko; Matsuki, Kayo; Hashimoto, Eri; Saito, Toshikazu; Kokai, Yasuo

    2013-01-01

    Background: Alzheimer's disease (AD) differs from other forms of dementia in its relation to amyloid beta peptide (Aβ42). Using a cell culture model we previously identified annexin A5, a Ca2+, and phospholipid binding protein, as an AD biomarker. Plasma level of annexin A5 was significantly higher in AD patients compared to that in a control group. On the other hand, AD has been identified to share a number of clinical and pathological features with Dementia with Lewy bodies (DLB). The present study was done to examine whether or not plasma annexin A5 is a specific marker for AD, when being compared with the levels of DLB patients. As Apolipoprotein E (ApoE) gene subtype ε4 (ApoE-ε4) has been noticed as the probable genetic factor for AD, we also examined and compared ApoE genotype in both AD and DLB. Methods: Blood samples were obtained from 150 patients with AD (aged 77.6 ± 6.5 years), 50 patients of DLB (79.4 ± 5.0) and 279 community-dwelling healthy elderly individuals of comparable age and sex (75.6 ± 8.1). All AD patients met NINCDS-ADRDA criteria and all DLB patients were diagnosed as probable DLB according to the latest consensus diagnostic criteria. Quantification was done using the Chemiluminescent Enzyme Immunoassay (CLEIA) Technique (SphereLight assay) using the monoclonal antibodies against annexin A5. DNA genotyping of ApoE was performed by distinguishing unique combinations of Hha1 fragments of PCR-amplified genomic DNA products. Results: The plasma level of annexin A5 was significantly higher in AD patients than in the healthy individuals (control) (P < 0.0001). The plasma annexin A5 level was also significantly higher in DLB patients than in the control group (P < 0.0001). From the ROC curves with plasma annexin A5 concentrations, the mean areas under the curve were 0.863 and 0.838 for the AD/control and DLB/control, respectively. The rate of ApoE4 carrier status and the frequency of the ε4 allele were significantly higher in AD or DLB than

  18. Lepton mixing in A 5 family symmetry and generalized CP

    NASA Astrophysics Data System (ADS)

    Li, Cai-Chang; Ding, Gui-Jun

    2015-05-01

    We study lepton mixing patterns which can be derived from the A 5 family symmetry and generalized CP. We find five phenomenologically interesting mixing patterns for which one column of the PMNS matrix is (the first column of the golden ratio mixing), (the second column of the golden ratio mixing), or . The three lepton mixing angles are determined in terms of a single real parameter θ, and agreement with experimental data can be achieved for certain values of θ. The Dirac CP violating phase is predicted to be trivial or maximal while Majorana phases are trivial. We construct a supersymmetric model based on A 5 family symmetry and generalized CP. The lepton mixing is exactly the golden ratio pattern at leading order, and the mixing patterns of case III and case IV are reproduced after higher order corrections are considered.

  19. Tracheobronchopathia osteochondroplastica in a 5 year-old girl.

    PubMed

    Sant'Anna, Clemax Couto; Pires-de-Mello, Paulo; Morgado, Maria de Fátima; March, Maria de Fátima Pombo

    2012-12-01

    Tracheobronchopathia osteochondroplastica (TO) is considered an orphan disease with exceptional occurrence in children. We report a 5 year old female child who was referred to us with chronic cough and recurrent pneumonia. After several investigations, bronchoscopy showed multiple nodules in the tracheobronchial lumen, whose distribution was consistent with TO. The patient was followed for four years, with no change in the pattern of the disease.

  20. Child with Sotos phenotype and a 5:15 translocation

    SciTech Connect

    Maround, C.; Schmerler, S.; Hutcheon, R.G.

    1994-04-15

    The authors report on a 4-year-old girl with Sotos phenotype and a de novo balanced translocation between the long arms of chromosome 5 and chromosome 15 [46,XX,t(5,15)(q35;q22)]. They suggest a relationship between genetic material at 5q35 or 15q22 and the expression of an autosomal dominant gene. 18 refs., 2 figs.

  1. Neutrino masses and mixing in A5 with flavor antisymmetry

    NASA Astrophysics Data System (ADS)

    Joshipura, Anjan S.; Nath, Newton

    2016-08-01

    We discuss the consequences of assuming that the (Majorana) neutrino mass matrix Mν and the charged lepton mass matrix Ml satisfy SνTMνSν=-Mν and Tl†MlMl†Tl=MlMl† with respect to some discrete groups Sν and Tl contained in A5. These assumptions lead to a neutrino mass spectrum with two degenerate and one massless neutrino and also constrain mixing among them. We derive possible mixing patterns following from the choices Sν=Z2 , Z2×Z2 , and Tl=Z2,Z2×Z2,Z3,Z5 as subgroups of A5. One predicts the maximal atmospheric neutrino mixing angle θ23 and μ -τ reflection symmetry in a large number of cases, but it is also possible to obtain nonmaximal values for θ23. Only the third column of the neutrino mixing matrix can be obtained at the leading order due to degeneracy in masses of two of the neutrinos. We take up a specific example within the A5 group and identify Higgs vacuum expectation values which realize the above assumptions. Nonleading terms present in this example are shown to lead to splitting among degenerate pairs and a consistent description of both neutrino masses and mixing angles.

  2. Gene doping.

    PubMed

    Harridge, Stephen D R; Velloso, Cristiana P

    2008-01-01

    Gene doping is the misuse of gene therapy to enhance athletic performance. It has recently been recognised as a potential threat and subsequently been prohibited by the World Anti-Doping Agency. Despite concerns with safety and efficacy of gene therapy, the technology is progressing steadily. Many of the genes/proteins which are involved in determining key components of athletic performance have been identified. Naturally occurring mutations in humans as well as gene-transfer experiments in adult animals have shown that altered expression of these genes does indeed affect physical performance. For athletes, however, the gains in performance must be weighed against the health risks associated with the gene-transfer process, whereas the detection of such practices will provide new challenges for the anti-doping authorities.

  3. Differential roles of miR-199a-5p in radiation-induced autophagy in breast cancer cells.

    PubMed

    Yi, Heqing; Liang, Bing; Jia, Jie; Liang, Nan; Xu, Huiying; Ju, Guizhi; Ma, Shumei; Liu, Xiaodong

    2013-03-01

    Autophagy is a self-degrading process that is triggered by diverse stimuli including ionizing radiation. In this study we show novel phenomena in which transfection of miR-199a-5p mimic significantly suppresses IR-induced autophagy in MCF7 cells, and up-regulates basal and IR-induced autophagy in MDA-MB-231 breast cancer cells. We also identify DRAM1 and Beclin1 as novel target genes for miR-199a-5p. Overexpression of miR-199a-5p inhibits DRAM1 and Beclin1 expression in MCF7 cells, while it enhances expression of these genes in MDA-MB-231 cells. Furthermore, we show that miR-199a-5p sensitizes MDA-MB-231 cells to irradiation. Therefore, our data identify miR-199a-5p as a novel and unique regulator of autophagy, which plays an important role in cancer biology and cancer therapy. PMID:23337876

  4. MiRNA-125a-5p inhibits glioblastoma cell proliferation and promotes cell differentiation by targeting TAZ

    SciTech Connect

    Yuan, Jian; Xiao, Gelei; Peng, Gang; Liu, Dingyang; Wang, Zeyou; Liao, Yiwei; Liu, Qing; Wu, Minghua; Yuan, Xianrui

    2015-02-06

    Highlights: • Expression of miR-125a-5p is inversely correlated with that of TAZ in glioma cells. • MiR-125a-5p represses TAZ expression in glioma cells. • MiR-125a-5p directly targets the 3′ UTR of TAZ mRNA and promotes its degradation. • MiR-125a-5p represses CTGF and survivin via TAZ, and inhibits glioma cell growth. • MiR-125a-5p inhibits the stem cell features of HFU-251 MG cells. - Abstract: Glioblastoma (GBM) is the most lethal brain tumor due to the resistance to conventional therapies, such as radiotherapy and chemotherapy. TAZ, an important mediator of the Hippo pathway, was found to be up-regulated in diverse cancers, including in GBM, and plays important roles in tumor initiation and progression. However, little is known about the regulation of TAZ expression in tumors. In this study, we found that miR-125a-5p is an important regulator of TAZ in glioma cells by directly targeting the TAZ 3′ UTR. MiR-125a-5p levels are inversely correlated with that of TAZ in normal astrocytes and a panel of glioma cell lines. MiR-125a-5p represses the expression of TAZ target genes, including CTGF and survivin, and inhibits cell proliferation and induces the differentiation of GBM cells; whereas over-expression of TAZ rescues the effects of miR-125a-5p. This study revealed a mechanism for TAZ deregulation in glioma cells, and also demonstrated a tumor suppressor role of miR-125a-5p in glioblastoma cells.

  5. Electromagnetic energy dispersion in a 5D universe

    SciTech Connect

    Hartnett, John G.

    2010-06-15

    Electromagnetism is analyzed in a 5D expanding universe. Compared to the usual 4D description of electrodynamics it can be viewed as adding effective charge and current densities to the universe that are static in time. These lead to effective polarization and magnetization of the vacuum, which is most significant at high redshift. Electromagnetic waves propagate but group and phase velocities are dispersive. This introduces a new energy scale to the cosmos. And as a result electromagnetic waves propagate with superluminal speeds but no energy is transmitted faster than the canonical speed of light c.

  6. Pineal anlage tumor in a 5-month-old boy.

    PubMed

    Olaya, Joffre E; Raghavan, Ravi; Totaro, Laura; Zouros, Alexander

    2010-06-01

    Pineal tumors are rare neoplasms that are categorized into pineoblastomas, pineocytomas, and pineal parenchymal tumors of intermediate differentiation. Pineal anlage tumors are primary pineal tumors with neuroepithelial and ectomesenchymal differentiation and without endodermal differentiation. The authors review the literature and report the case of a 5-month-old boy with a pineal anlage tumor. This is only the sixth case of a pineal anlage tumor reported in the English-language literature adding to the understanding of this tumor's presentation, immunomorphological and molecular characteristics, embryological origin, radiological appearance, treatment outcome, and prognosis.

  7. 75 FR 9140 - Airworthiness Directives; International Aero Engines AG (IAE) V2500-A1, V2522-A5, V2524-A5, V2525...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-01

    ...- 7117, fax: (781) 238-7199. SUPPLEMENTARY INFORMATION: On February 12, 2010 (75 FR 6860), we published a proposed AD, FR Doc. 2010-2999, in the Federal Register. That AD applies to IAE V2500-A1, V2522-A5, V2524... Engines AG (IAE) V2500-A1, V2522-A5, V2524-A5, V2525-D5, V2527-A5, V2527E-A5, V2527M-A5, V2528-D5,...

  8. A 5-D hyperchaotic Rikitake dynamo system with hidden attractors

    NASA Astrophysics Data System (ADS)

    Vaidyanathan, S.; Pham, V.-T.; Volos, C. K.

    2015-07-01

    This paper presents a 5-D hyperchaotic Rikitake dynamo system with three positive Lyapunov exponents which is derived by adding two state feedback controls to the famous 3-D Rikitake two-disk dynamo system. It is noted that the proposed hyperchaotic system has no equilibrium points and hence it exhibits hidden attractors. In addition, the qualitative properties, as well as the adaptive synchronization of the hyperchaotic Rikitake dynamo system with unknown system parameters, are discussed in details. The main results are proved using Lyapunov stability theory and numerical simulations are shown using MATLAB. Moreover, an electronic circuit realization in SPICE has been detailed to confirm the feasibility of the theoretical 5-D hyperchaotic Rikitake dynamo model.

  9. HDAC Inhibitors Target HDAC5, Upregulate MicroRNA-125a-5p, and Induce Apoptosis in Breast Cancer Cells

    PubMed Central

    Hsieh, Tsung-Hua; Hsu, Chia-Yi; Tsai, Cheng-Fang; Long, Cheng-Yu; Wu, Chin-Hu; Wu, Deng-Chyang; Lee, Jau-Nan; Chang, Wei-Chun; Tsai, Eing-Mei

    2015-01-01

    Histone deacetylase inhibitors (HDACi) are novel clinical anticancer drugs that inhibit HDAC gene expression and induce cell apoptosis in human cancers. Nevertheless, the detailed mechanism or the downstream HDAC targets by which HDACi mediates apoptosis in human breast cancer cells remains unclear. Here, we show that HDACi reduce tumorigenesis and induce intrinsic apoptosis of human breast cancer cells through the microRNA miR-125a-5p in vivo and in vitro. Intrinsic apoptosis was activated by the caspase 9/3 signaling pathway. In addition, HDACi mediated the expression of miR-125a-5p by activating RUNX3/p300/HDAC5 complex. Subsequently, miR-125a-5p silenced HDAC5 post-transcriptionally in the cells treated with HDACi. Thus, a regulatory loop may exist in human breast cancer cells involving miR-125a-5p and HDAC5 that is controlled by RUNX3 signaling. Silencing of miR-125a-5p and RUNX3 inhibited cancer progression and activated apoptosis, but silencing of HDAC5 had a converse effect. In conclusion, we demonstrate a possible new mechanism by which HDACi influence tumorigenesis and apoptosis via downregulation of miR-125a-5p expression. This study provides clinical implications in cancer chemotherapy using HDACi. PMID:25531695

  10. Trichoderma genes

    SciTech Connect

    Foreman, Pamela; Goedegebuur, Frits; Van Solingen, Pieter; Ward, Michael

    2012-06-19

    Described herein are novel gene sequences isolated from Trichoderma reesei. Two genes encoding proteins comprising a cellulose binding domain, one encoding an arabionfuranosidase and one encoding an acetylxylanesterase are described. The sequences, CIP1 and CIP2, contain a cellulose binding domain. These proteins are especially useful in the textile and detergent industry and in pulp and paper industry.

  11. [Gene therapy].

    PubMed

    Rodríguez-Fragoso, L

    1997-01-01

    In the last years there has been much progress in our understanding of molecular mechanisms in the pathogenesis of disease. In this review we provide an overview of gene therapy, its most actualized techniques for gene delivery, and we give specific examples of laboratory and clinical achievements to date. The development of methods for delivering genes to mammalian cells has stimulated great interest in the possibility of treating human disease by gene-based therapies. As a result, concepts and methods that would have been considered purely science fiction 50 years ago are now used in the treatment of diseases. The widespread application of gene therapy technology to many diseases is already breaking down the traditional boundaries of modern medicine. However, despite its progress, several key technical drawbacks need to be overcome before gene therapy can be used safely and effectively in clinical settings. Technological developments, particularly in the areas of gene delivery and cell transplantation, will be critical for the successful practice of gene therapy.

  12. Gene Therapy

    PubMed Central

    Baum, Bruce J

    2014-01-01

    Applications of gene therapy have been evaluated in virtually every oral tissue, and many of these have proved successful at least in animal models. While gene therapy will not be used routinely in the next decade, practitioners of oral medicine should be aware of the potential of this novel type of treatment that doubtless will benefit many patients with oral diseases. PMID:24372817

  13. Curcumin exerts inhibitory effects on undifferentiated nasopharyngeal carcinoma by inhibiting the expression of miR-125a-5p.

    PubMed

    Gao, Wei; Chan, Jimmy Yu-Wai; Wong, Thian-Sze

    2014-11-01

    Curcumin suppresses proliferation, migration, invasion, metastasis and angiogenesis and induces apoptosis by regulating multiple signalling pathways and miRNAs in a wide variety of human malignancies. miRNAs play crucial roles in various steps of carcinogenesis in nasopharyngeal carcinoma (NPC); thus, they could serve as critical therapeutic targets for NPC treatment. Curcumin could provide a novel strategy to block or induce specific miRNAs for miRNA-based gene therapies. Nevertheless, there are no reports to date on the miRNAs regulated by curcumin in NPC. In the present study, we have carried out an miRNA microarray to identify the miRNAs regulated by curcumin in NPC. Curcumin treatment down-regulated the expression of hsa-miR-125a-5p, hsa-miR-574-3p and hsa-miR-210 as determined by miRNA microarray analysis and qPCR (real-time quantitative reverse transcription-PCR). Forced expression of miR-125a-5p enhanced proliferation, migration and invasion of HONE1 cells. Primary NPC exhibited a significantly higher expression level of miR-125a-5p than healthy controls. miR-125a-5p inhibited the expression of tumour protein 53 (TP53), and curcumin treatment up-regulated the expression of TP53. Taken together, these results indicate that curcumin exerted inhibitory effects on NPC by inhibiting the expression of miR-125a-5p and, subsequently, enhancing the expression of TP53. Curcumin could provide a novel strategy to block miR-125a-5p for miRNA-based gene therapies in NPC. PMID:24896104

  14. 75 FR 71373 - Airworthiness Directives; International Aero Engines V2500-A1, V2522-A5, V2524-A5, V2525-D5...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-23

    ..., 2000 (65 FR 19477-78). Examining the AD Docket You may examine the AD docket on the Internet at http... ``significant rule'' under the DOT Regulatory Policies and Procedures (44 FR 11034, February 26, 1979); and 3... Aero Engines (IAE) V2500-A1, V2522-A5, V2524-A5, V2525-D5, V2527-A5, V2527E-A5, V2527M-A5,...

  15. 75 FR 12971 - Airworthiness Directives; International Aero Engines (IAE) V2500-A1, V2522-A5, V2524-A5, V2525-D5...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-18

    ... (74 FR 19904), and a supplemental proposed AD on December 23, 2009 (74 FR 68192). That action proposed... 12866; (2) Is not a ``significant rule'' under DOT Regulatory Policies and Procedures (44 FR 11034... Engines (IAE) V2500- A1, V2522-A5, V2524-A5, V2525-D5, V2527-A5, V2527E-A5, V2527M-A5, V2528-D5,...

  16. Metabolism of a 5-nitroimidazole in susceptible and resistant isogenic strains of Bacteroides fragilis.

    PubMed Central

    Carlier, J P; Sellier, N; Rager, M N; Reysset, G

    1997-01-01

    We investigated the metabolism of dimetridazole (1,2-dimethyl-5-nitroimidazole) (DMZ) by the resting cell method in a susceptible strain of Bacteroides fragilis and in the same strain containing the nimA gene, which conferred resistance to 5-nitroimidazole drugs. In both cases, under strict anaerobic conditions DMZ was metabolized without major ring cleavage or nitrate formation. However, one of two distinct metabolic pathways is involved, depending on the susceptibility of the strain. In the susceptible strain, the classical reduction pathway of nitroaromatic compounds is followed at least as far as the nitroso-radical anion, with further formation of the azo-dimer: 5,5'-azobis-(1,2-dimethylimidazole). In the resistant strain, DMZ is reduced to the amine derivative, namely, 5-amino-1,2-dimethylimidazole, preventing the formation of the toxic form of the drug. The specificity of the six-electron reduction of the nitro group, which is restricted to 4- and 5-nitroimidazole, suggests an enzymatic reaction. We thus conclude that nimA and related genes may encode a 5-nitroimidazole reductase. PMID:9210672

  17. Annexin A5 multitasking: a potentially novel antiatherothrombotic agent?

    PubMed

    Cederholm, Anna; Frostegård, Johan

    2007-06-01

    Atherothrombosis, formed on an underlying atherosclerotic plaque, is the key pathogenic mechanism behind the majority of clinically evident cardiovascular ischemic diseases including acute coronary artery disease, cerebrovascular and peripheral arterial occlusion. Annexin A5 (ANXA5; previously annexin V), a member of the annexin superfamily, is a protein with potent and unique antithrombotic properties. The antithrombotic effect exerted by ANXA5 is thought to be mediated mainly by mechanical shielding of phospholipids, phosphatidylserine in particular, thereby reducing their availability for coagulation reactions. However, other intriguing properties of ANXA5 potentially contributing to its antithrombotic function, especially downregulation of surface expressed tissue factor, or interaction with additional ligands involved in hemostasis such as sulfatide and heparin, as well as upregulation of urokinase-type plasminogen activator were reported. The biological significance of ANXA5 as a member of endogenous antithrombotic system in vivo has been suggested recently for the large vasculature and for placental microcirculation. Antiatherothrombotic potential of ANXA5 deserves further attention and careful studies in order to determine its true physiological impact as well as its possible therapeutic applications.

  18. Natural history of alcoholic myopathy: a 5-year study.

    PubMed

    Estruch, R; Sacanella, E; Fernández-Solá, J; Nicolás, J M; Rubin, E; Urbano-Márquez, A

    1998-12-01

    Chronic myopathy is a common complication of alcoholism, but its natural history has not been well described. We, therefore, studied muscle structure and function in a 5-year study of 30 chronic alcoholics who became abstinent and 20 who relapsed, and 40 control subjects. The mean strength of the abstaining alcoholics increased from 18.6 to 23.2 kg; but, after 5 years, they were still substantially weaker than controls. In a subset who showed histological myopathy, the strength of half of the patients remained two standard deviations below that of controls. Alcoholics who relapsed tended to become progressively weaker (21.7 kg vs. 18.2 kg) and develop histological evidence of myopathy. Thus, continued alcohol abuse was generally reflected in deterioration of muscle strength and the appearance of histological injury to muscle. Importantly, almost half of the sober patients did not recover to normal levels, indicating that alcoholic myopathy is only partially reversible. We also unexpectedly found that, in some alcoholics, a substantial reduction in the amount of alcohol consumed may be as effective as complete abstinence in improving muscle strength or preventing its deterioration.

  19. Nearly free electrons in a 5d delafossite oxide metal

    PubMed Central

    Kushwaha, Pallavi; Sunko, Veronika; Moll, Philip J. W.; Bawden, Lewis; Riley, Jonathon M.; Nandi, Nabhanila; Rosner, Helge; Schmidt, Marcus P.; Arnold, Frank; Hassinger, Elena; Kim, Timur K.; Hoesch, Moritz; Mackenzie, Andrew P.; King, Phil D. C.

    2015-01-01

    Understanding the role of electron correlations in strong spin-orbit transition-metal oxides is key to the realization of numerous exotic phases including spin-orbit–assisted Mott insulators, correlated topological solids, and prospective new high-temperature superconductors. To date, most attention has been focused on the 5d iridium-based oxides. We instead consider the Pt-based delafossite oxide PtCoO2. Our transport measurements, performed on single-crystal samples etched to well-defined geometries using focused ion beam techniques, yield a room temperature resistivity of only 2.1 microhm·cm (μΩ-cm), establishing PtCoO2 as the most conductive oxide known. From angle-resolved photoemission and density functional theory, we show that the underlying Fermi surface is a single cylinder of nearly hexagonal cross-section, with very weak dispersion along kz. Despite being predominantly composed of d-orbital character, the conduction band is remarkably steep, with an average effective mass of only 1.14me. Moreover, the sharp spectral features observed in photoemission remain well defined with little additional broadening for more than 500 meV below EF, pointing to suppressed electron-electron scattering. Together, our findings establish PtCoO2 as a model nearly-free–electron system in a 5d delafossite transition-metal oxide. PMID:26601308

  20. Clinicopathological role of miR-30a-5p in hepatocellular carcinoma tissues and prediction of its function with bioinformatics analysis

    PubMed Central

    Huang, Wen-Ting; Chen, Zu-xuan; He, Rong-quan; Wu, Yu-zhuang; Yin, Shu-ya; Liang, Xiao-na; Chen, Gang; Yang, Hong; Peng, Zhi-gang; Yang, Li-hua

    2016-01-01

    Background It has been reported that deregulation or dysfunction of microRNAs (miRNAs) plays an essential part in the hepatocarcinogenesis. However, the contribution and mechanism of microRNA-30a-5p (miR-30a-5p) in hepatocellular carcinoma (HCC) remains largely unknown. Therefore, our aim was to investigate the clinicopathological role of miR-30a-5p in HCC tissues and explore its potential pathways in this study. Methods The expression of miR-30a-5p was measured in 95 HCC and adjacent noncancer tissues by real-time reverse transcription quantitative polymerase chain reaction. The relationship between miR-30a-5p expression levels and clinicopathological parameters was also analyzed. Furthermore, the potential target genes of miR-30a-5p were collected via online prediction and literature searching. Gene ontology and pathway enrichment analyses were used to identify the possible function of miR-30a-5p in HCC. Results Compared with adjacent noncancer tissues (2.23±0.77), expression level of miR-30a-5p was significantly lower in HCC tissues (1.26±0.66, P<0.001). MiR-30a-5p expression was evidently correlated with tumor nodes, metastasis, tumor–node–metastasis stage, portal vein tumor embolus, vascular invasion, and status of tumor capsule (all P<0.05). A total of 878 genes were finally used for the biological informatics analyses. These prospective target genes were highly enriched in various key pathways, for instance, Ubiquitin-mediated proteolysis, Axon guidance, Neurotrophin signaling pathway, Amyotrophic lateral sclerosis, and ErbB signaling pathway. Conclusion In conclusion, this study clarifies that the downregulation of miRNA-30a-5p might play a vital part in the incidence and progression of HCC via targeting various prospective genes and pathways. Future validation is required to further explore the prospective molecular mechanism of miR-30a-5p in HCC. PMID:27574447

  1. Characterization of the psychrotolerant acetogen strain SyrA5 and the emended description of the species Acetobacterium carbinolicum.

    PubMed

    Paarup, Maiken; Friedrich, Michael W; Tindall, Brian J; Finster, Kai

    2006-01-01

    A psychrotolerant, obligate anaerobic, acetogenic bacterium designated strain SyrA5 was isolated from black anoxic sediment of a brackish fjord. Cells were Gram-positive, non-sporeforming rods. The isolate utilized H(2)/CO(2), CO, fructose, glucose, ethanol, ethylene glycol, glycerol, pyruvate, lactate, betaine and the methyl-groups of several methoxylated benzoic derivatives such as syringate, trimethoxybenzoate and vallinate. The optimum temperature for growth was 29 degrees C, whilst slow growth occurred at 2 degrees C. The strain grew optimally with NaCl concentrations below 2.7% (w/v), but growth occurred up to 4.3% (w/v) NaCl. Growth was observed in the range from pH 5.9 to 8.5, optimum at pH 8. The G+C content was 44.1 mol%. Based upon 16S rRNA gene sequence analysis and DNA-DNA reassociation studies, the organism was classified in the genus Acetobacterium. Strain SyrA5 shared a 16S rRNA sequence similarity with A. carbinolicum of 100%, a fthfs gene (which codes for the N5,N10 tetrahydrofolate synthetase) sequence identity of 98.5-98.7% (amino acid sequence similarities were 99.4-100%) and a RNA-DNA hybridization homology of 64-68%. Despite a number of phenotypic differences between strain SyrA5 and A. carbinolicum we propose including strain SyrA5 as a subspecies of A. carbinolicum for which we propose the name Acetobacterium carbinolicum subspecies kysingense. The type strain is SyrA5 (=DSM 16427(T), ATCC BAA-990).

  2. Genetic polymorphisms of the drug-metabolizing enzyme cytochrome P450 3A5 in a Uyghur Chinese population.

    PubMed

    Chen, Zhengshuai; Li, Jingjie; Chen, Peng; Wang, Fengjiao; Zhang, Ning; Yang, Min; Jin, Tianbo; Chen, Chao

    2016-09-01

    1.  Detection of CYP3A5 variant alleles, and knowledge about their allelic frequency in Uyghur ethnic groups, is important to establish the clinical relevance of screening for these polymorphisms to optimize pharmacotherapy. 2. We used DNA sequencing to investigate the promoter, exons and surrounding introns, and 3'-untranslated region of the CYP3A5 gene in 96 unrelated healthy Uyghur individuals. We also used SIFT and PolyPhen-2 to predict the protein function of the novel non-synonymous mutation in CYP3A5 coding regions. 3. We found 24 different CYP3A5 polymorphisms in the Uyghur population, three of which were novel: the synonymous mutation 43C > T in exon 1, two mutations 32120C > G and 32245T > C in 3'-untranslated region, and we detected the allele frequencies of CYP3A5*1 and *3 as 64.58% and 35.42%, respectively. While no subjects with CYP3A5*6 were identified. Other identified genotypes included the heterozygous genotype 1A/3A (59.38%) and 1A/3E (11.46%), which lead to decreased enzyme activity. In addition, the frequency of haplotype "TTAGGT" was the most prevalent with 0.781. 4. Our data provide new information regarding CYP3A5 genetic polymorphisms in Uyghur individuals, which may help to improve individualization of drug therapy and offer a preliminary basis for more rational use of drugs. PMID:26739429

  3. Genetic polymorphisms of the drug-metabolizing enzyme cytochrome P450 3A5 in a Uyghur Chinese population.

    PubMed

    Chen, Zhengshuai; Li, Jingjie; Chen, Peng; Wang, Fengjiao; Zhang, Ning; Yang, Min; Jin, Tianbo; Chen, Chao

    2016-09-01

    1.  Detection of CYP3A5 variant alleles, and knowledge about their allelic frequency in Uyghur ethnic groups, is important to establish the clinical relevance of screening for these polymorphisms to optimize pharmacotherapy. 2. We used DNA sequencing to investigate the promoter, exons and surrounding introns, and 3'-untranslated region of the CYP3A5 gene in 96 unrelated healthy Uyghur individuals. We also used SIFT and PolyPhen-2 to predict the protein function of the novel non-synonymous mutation in CYP3A5 coding regions. 3. We found 24 different CYP3A5 polymorphisms in the Uyghur population, three of which were novel: the synonymous mutation 43C > T in exon 1, two mutations 32120C > G and 32245T > C in 3'-untranslated region, and we detected the allele frequencies of CYP3A5*1 and *3 as 64.58% and 35.42%, respectively. While no subjects with CYP3A5*6 were identified. Other identified genotypes included the heterozygous genotype 1A/3A (59.38%) and 1A/3E (11.46%), which lead to decreased enzyme activity. In addition, the frequency of haplotype "TTAGGT" was the most prevalent with 0.781. 4. Our data provide new information regarding CYP3A5 genetic polymorphisms in Uyghur individuals, which may help to improve individualization of drug therapy and offer a preliminary basis for more rational use of drugs.

  4. Apolipoprotein A-V: a potential modulator of plasma triglyceride levels in Turks.

    PubMed

    Hodoglugil, Ugur; Tanyolaç, Sinan; Williamson, David W; Huang, Yadong; Mahley, Robert W

    2006-01-01

    The apolipoprotein A-V gene (APOA5) plays an important role in determining plasma triglyceride levels. We studied the effects of APOA5 polymorphisms on plasma triglyceride levels in Turks, a population with low levels of HDL cholesterol and a high prevalence of coronary artery disease. We found 15 polymorphisms, three of which were novel. Seven haplotype-tagging single nucleotide polymorphisms (SNPs) were chosen and genotyped in approximately 3,000 subjects. The rare alleles of the -1464T>C, -1131T>C, S19W, and 1259T>C SNPs were significantly associated with increased triglyceride levels (19-86 mg/dl; P < 0.05) and had clear gene-dose effects. Haplotype analysis of the nine common APOA5 haplotypes revealed significant effects on triglyceride levels (P < 0.001). Detailed analysis of haplotypes clearly showed that the -1464T>C polymorphism had no effect by itself but was a marker for the -1131T>C, S19W, and 1259T>C polymorphisms. The -1131T>C and 1259T>C polymorphisms were in a strong but incomplete linkage disequilibrium and appeared to have independent effects. Thus, the APOA5 -1131T>C, S19W, and 1259T>C rare alleles were associated with significant increases in plasma triglyceride levels. At least one of these alleles was present in approximately 40% of the Turks. Similar associations were observed for -1131T>C and S19W in white Americans living in San Francisco, California.

  5. Association between urinary 6β-hydroxycortisol/cortisol ratio and CYP3A5 genotypes in a normotensive population.

    PubMed

    Rais, Naushad; Hussain, Arif; Chawla, Yogesh Kumar; Kohli, Krishan K

    2013-02-01

    Genetic polymorphism of genes involved in renal salt handling and arterial vessel tone is considered to be one of the causes of hypertension. Numerous reports suggest that cytochrome P4503A5 (CYP3A5) catalyzes 6β-hydroxylation of endogenous cortisol (CS), which is associated with sodium and water retention in the kidney and involved in the regulation of blood pressure. The purpose of the present study was to study the associations of single nucleotide polymorphisms in the CYP3A5 gene with the urinary 6β-hydroxycortisol/cortisol (6β-OH-CS/CS) ratio considered as quantitative phenotypes. CS measurements of three hundred (n=300) healthy, normotensive North Indian individuals was performed on morning spot urine samples by high-performance liquid chromatography. Furthermore, genotyping for CYP3A5*3 and CYP3A5*6 was performed by PCR-RFLP. The results indicated a unimodal distribution of CYP3A phenotypes in the North Indian population. In further analysis, all the phenotypes were distributed into three groups, demonstrating low (n=75), intermediate (n=150) and high CYP3A activity (n=75) based on CS and 6β-OH-CS levels and log 6β-OH-CS/CS ratios. The subjects in the low and high activity groups were genotyped for the CYP3A5*3 and *6 alleles. The present study demonstrated that the allele frequencies of CYP3A5*1 and *3 were 0.29 (95% CI, 0.22-0.36) and 0.71 (95% CI, 0.64-0.78), respectively. Notably, the frequency of normal homozygotes (CYP3A5*1/*1) was significantly higher in the high activity than the low activity group (11% vs. 5%). Similarly, the frequency of mutant homozygotes (CYP3A5*3/*3) was significantly higher in the low activity group than the high activity group (57% vs. 44%). The allele frequency of CYP3A5*3 was significantly higher in the low activity group (0.76) than the high activity group (0.67). The mean 6β-OH-CS/CS ratios were 110, 76 and 69 in wild-type homozygotes (n=12), heterozygotes (n=62) and mutant homozygotes (n=76), respectively. The

  6. Association between urinary 6β-hydroxycortisol/cortisol ratio and CYP3A5 genotypes in a normotensive population

    PubMed Central

    RAIS, NAUSHAD; HUSSAIN, ARIF; CHAWLA, YOGESH KUMAR; KOHLI, KRISHAN K.

    2013-01-01

    Genetic polymorphism of genes involved in renal salt handling and arterial vessel tone is considered to be one of the causes of hypertension. Numerous reports suggest that cytochrome P4503A5 (CYP3A5) catalyzes 6β-hydroxylation of endogenous cortisol (CS), which is associated with sodium and water retention in the kidney and involved in the regulation of blood pressure. The purpose of the present study was to study the associations of single nucleotide polymorphisms in the CYP3A5 gene with the urinary 6β-hydroxycortisol/cortisol (6β-OH-CS/CS) ratio considered as quantitative phenotypes. CS measurements of three hundred (n=300) healthy, normotensive North Indian individuals was performed on morning spot urine samples by high-performance liquid chromatography. Furthermore, genotyping for CYP3A5*3 and CYP3A5*6 was performed by PCR-RFLP. The results indicated a unimodal distribution of CYP3A phenotypes in the North Indian population. In further analysis, all the phenotypes were distributed into three groups, demonstrating low (n=75), intermediate (n=150) and high CYP3A activity (n=75) based on CS and 6β-OH-CS levels and log 6β-OH-CS/CS ratios. The subjects in the low and high activity groups were genotyped for the CYP3A5*3 and *6 alleles. The present study demonstrated that the allele frequencies of CYP3A5*1 and *3 were 0.29 (95% CI, 0.22–0.36) and 0.71 (95% CI, 0.64–0.78), respectively. Notably, the frequency of normal homozygotes (CYP3A5*1/*1) was significantly higher in the high activity than the low activity group (11% vs. 5%). Similarly, the frequency of mutant homozygotes (CYP3A5*3/*3) was significantly higher in the low activity group than the high activity group (57% vs. 44%). The allele frequency of CYP3A5*3 was significantly higher in the low activity group (0.76) than the high activity group (0.67). The mean 6β-OH-CS/CS ratios were 110, 76 and 69 in wild-type homozygotes (n=12), heterozygotes (n=62) and mutant homozygotes (n=76), respectively. The

  7. Amerindian-specific regions under positive selection harbour new lipid variants in Latinos

    PubMed Central

    Ko, Arthur; Cantor, Rita M.; Weissglas-Volkov, Daphna; Nikkola, Elina; Reddy, Prasad M. V. Linga; Sinsheimer, Janet S.; Pasaniuc, Bogdan; Brown, Robert; Alvarez, Marcus; Rodriguez, Alejandra; Rodriguez-Guillen, Rosario; Bautista, Ivette C.; Arellano-Campos, Olimpia; Muñoz-Hernández, Linda L.; Salomaa, Veikko; Kaprio, Jaakko; Jula, Antti; Jauhiainen, Matti; Heliövaara, Markku; Raitakari, Olli; Lehtimäki, Terho; Eriksson, Johan G.; Perola, Markus; Lohmueller, Kirk E.; Matikainen, Niina; Taskinen, Marja-Riitta; Rodriguez-Torres, Maribel; Riba, Laura; Tusie-Luna, Teresa; Aguilar-Salinas, Carlos A.; Pajukanta, Päivi

    2014-01-01

    Dyslipidemia and obesity are especially prevalent in populations with Amerindian backgrounds, such as Mexican–Americans, which predispose these populations to cardiovascular disease. Here we design an approach, known as the cross-population allele screen (CPAS), which we conduct prior to a genome-wide association study (GWAS) in 19,273 Europeans and Mexicans, in order to identify Amerindian risk genes in Mexicans. Utilizing CPAS to restrict the GWAS input variants to only those differing in frequency between the two populations, we identify novel Amerindian lipid genes, receptor-related orphan receptor alpha (RORA) and salt-inducible kinase 3 (SIK3), and three loci previously unassociated with dyslipidemia or obesity. We also detect lipoprotein lipase (LPL) and apolipoprotein A5 (APOA5) harbouring specific Amerindian signatures of risk variants and haplotypes. Notably, we observe that SIK3 and one novel lipid locus underwent positive selection in Mexicans. Furthermore, after a high-fat meal, the SIK3 risk variant carriers display high triglyceride levels. These findings suggest that Amerindian-specific genetic architecture leads to a higher incidence of dyslipidemia and obesity in modern Mexicans. PMID:24886709

  8. Amerindian-specific regions under positive selection harbour new lipid variants in Latinos.

    PubMed

    Ko, Arthur; Cantor, Rita M; Weissglas-Volkov, Daphna; Nikkola, Elina; Reddy, Prasad M V Linga; Sinsheimer, Janet S; Pasaniuc, Bogdan; Brown, Robert; Alvarez, Marcus; Rodriguez, Alejandra; Rodriguez-Guillen, Rosario; Bautista, Ivette C; Arellano-Campos, Olimpia; Muñoz-Hernández, Linda L; Salomaa, Veikko; Kaprio, Jaakko; Jula, Antti; Jauhiainen, Matti; Heliövaara, Markku; Raitakari, Olli; Lehtimäki, Terho; Eriksson, Johan G; Perola, Markus; Lohmueller, Kirk E; Matikainen, Niina; Taskinen, Marja-Riitta; Rodriguez-Torres, Maribel; Riba, Laura; Tusie-Luna, Teresa; Aguilar-Salinas, Carlos A; Pajukanta, Päivi

    2014-01-01

    Dyslipidemia and obesity are especially prevalent in populations with Amerindian backgrounds, such as Mexican-Americans, which predispose these populations to cardiovascular disease. Here we design an approach, known as the cross-population allele screen (CPAS), which we conduct prior to a genome-wide association study (GWAS) in 19,273 Europeans and Mexicans, in order to identify Amerindian risk genes in Mexicans. Utilizing CPAS to restrict the GWAS input variants to only those differing in frequency between the two populations, we identify novel Amerindian lipid genes, receptor-related orphan receptor alpha (RORA) and salt-inducible kinase 3 (SIK3), and three loci previously unassociated with dyslipidemia or obesity. We also detect lipoprotein lipase (LPL) and apolipoprotein A5 (APOA5) harbouring specific Amerindian signatures of risk variants and haplotypes. Notably, we observe that SIK3 and one novel lipid locus underwent positive selection in Mexicans. Furthermore, after a high-fat meal, the SIK3 risk variant carriers display high triglyceride levels. These findings suggest that Amerindian-specific genetic architecture leads to a higher incidence of dyslipidemia and obesity in modern Mexicans. PMID:24886709

  9. MiR-193a-5p Targets the Coding Region of AP-2α mRNA and Induces Cisplatin Resistance in Bladder Cancers

    PubMed Central

    Zhou, Ji; Duan, Huaxin; Xie, Yu; Ning, Yichong; Zhang, Xing; Hui, Na; Wang, Chunqing; Zhang, Jian; Zhou, Jianlin

    2016-01-01

    Transcription factor AP-2 alpha (AP-2α or TFAP2A) is a newly identified prognostic marker of chemotherapy; its expression is positively correlated with chemosensitivity and survival of cancer patients. Using computational programs, we predicted that the coding region of AP-2α gene contains a potential miRNA response element (MRE) of miR-193a-5p, and the single nucleotide polymorphism (SNP) site (c.497A>G, rs111681798) resides within the predicted MRE. The results of luciferase assays and Western blot analysis demonstrated that miR-193a-5p negatively regulated the expression of AP-2α proteins, but have no influence on the mutant AP-2α (c.497A>G). Infection with lentiviral AP-2α gene or miR-193a-5p inhibitor in the bladder cancer cells decreased migration and cisplatin resistance, while knockdown of AP-2α gene or overexpression of miR-193a-5p in the urothelial cell line SV-HUC-1 increased migration and cisplatin resistances. We concluded that miR-193a-5p induced cisplatin resistance by repressing AP-2α expression in bladder cancer cells. PMID:27698912

  10. MiR-193a-5p Targets the Coding Region of AP-2α mRNA and Induces Cisplatin Resistance in Bladder Cancers

    PubMed Central

    Zhou, Ji; Duan, Huaxin; Xie, Yu; Ning, Yichong; Zhang, Xing; Hui, Na; Wang, Chunqing; Zhang, Jian; Zhou, Jianlin

    2016-01-01

    Transcription factor AP-2 alpha (AP-2α or TFAP2A) is a newly identified prognostic marker of chemotherapy; its expression is positively correlated with chemosensitivity and survival of cancer patients. Using computational programs, we predicted that the coding region of AP-2α gene contains a potential miRNA response element (MRE) of miR-193a-5p, and the single nucleotide polymorphism (SNP) site (c.497A>G, rs111681798) resides within the predicted MRE. The results of luciferase assays and Western blot analysis demonstrated that miR-193a-5p negatively regulated the expression of AP-2α proteins, but have no influence on the mutant AP-2α (c.497A>G). Infection with lentiviral AP-2α gene or miR-193a-5p inhibitor in the bladder cancer cells decreased migration and cisplatin resistance, while knockdown of AP-2α gene or overexpression of miR-193a-5p in the urothelial cell line SV-HUC-1 increased migration and cisplatin resistances. We concluded that miR-193a-5p induced cisplatin resistance by repressing AP-2α expression in bladder cancer cells.

  11. Designer Genes.

    ERIC Educational Resources Information Center

    Miller, Judith; Miller, Mark

    1983-01-01

    Genetic technologies may soon help fill some of the most important needs of humanity from food to energy to health care. The research of major designer genes companies and reasons why the initial mad rush for biotechnology has slowed are reviewed. (SR)

  12. Attention Genes

    ERIC Educational Resources Information Center

    Posner, Michael I.; Rothbart, Mary K.; Sheese, Brad E.

    2007-01-01

    A major problem for developmental science is understanding how the cognitive and emotional networks important in carrying out mental processes can be related to individual differences. The last five years have seen major advances in establishing links between alleles of specific genes and the neural networks underlying aspects of attention. These…

  13. Genomewide Association Study of Tacrolimus Concentrations in African American Kidney Transplant Recipients Identifies Multiple CYP3A5 Alleles

    PubMed Central

    Oetting, W. S.; Schladt, D. P.; Guan, W.; Miller, M. B.; Remmel, R. P.; Dorr, C.; Sanghavi, K.; Mannon, R. B.; Herrera, B.; Matas, A. J.; Salomon, D. R.; Kwok, P.-Y.; Keating, B. J.; Israni, A. K.; Jacobson, P. A.

    2016-01-01

    We previously reported that tacrolimus (TAC) trough blood concentrations for African American (AA) kidney allograft recipients were lower than those observed in white patients. Subtherapeutic TAC troughs may be associated with acute rejection (AR) and AR-associated allograft failure. This variation in TAC troughs is due, in part, to differences in the frequency of the cytochrome P450 CYP3A5*3 allele (rs776746, expresses nonfunctional enzyme) between white and AA recipients; however, even after accounting for this variant, variability in AA-associated troughs is significant. We conducted a genomewide association study of TAC troughs in AA kidney allograft recipients to search for additional genetic variation. We identified two additional CYP3A5 variants in AA recipients independently associated with TAC troughs: CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343). All three variants and clinical factors account for 53.9% of the observed variance in troughs, with 19.8% of the variance coming from demographic and clinical factors including recipient age, glomerular filtration rate, anti-cytomegalovirus drug use, simultaneous pancreas-kidney transplant and antibody induction. There was no evidence of common genetic variants in AA recipients significantly influencing TAC troughs aside from the CYP3A gene. These results reveal that additional and possibly rare functional variants exist that account for the additional variation. PMID:26485092

  14. Genes and Hearing Loss

    MedlinePlus

    ... Meeting Calendar Find an ENT Doctor Near You Genes and Hearing Loss Genes and Hearing Loss Patient ... mutation may only have dystopia canthorum. How Do Genes Work? Genes are a road map for the ...

  15. Downregulation of miR-199a-5p Disrupts the Developmental Potential of In Vitro-Fertilized Mouse Blastocysts.

    PubMed

    Tan, Kun; Wang, Xiaodong; Zhang, Zhenni; Miao, Kai; Yu, Yong; An, Lei; Tian, Jianhui

    2016-09-01

    Although in vitro fertilization (IVF), one of the most effective and successful assisted reproductive technologies, is widely used for treating infertility and in animal breeding, increasing evidence indicates that IVF offspring are linked to various short- or long-term consequences. Erroneous epigenetic modifications induced by IVF are suspected of contributing to these consequences. Among these epigenetic modifications, microRNAs may affect embryo implantation and early postimplantation development. Here, we performed comparative microRNA profiling between in vivo-fertilized (IVO group) and in vitro-fertilized (IVF group) mouse embryos at Embryonic Day 3.5 (E3.5) and E7.5. Our dynamic analyses showed that the dysregulated microRNAs were mainly associated with the regulation of genes involved in carcinogenesis, genetic information processing, glucose metabolism, cytoskeleton organization, and neurogenesis. Further analysis showed that miR-199a-5p was consistently downregulated in IVF embryos compared with their IVO counterparts. Through gain- and loss-of-function experiments, we demonstrated that IVF-induced downregulation of miR-199a-5p results in a higher glycolytic rate and lower developmental potential of IVF blastocysts, including cell lineage misallocation and lower fetal survival post implantation. Therefore, preventing downregulation of miR-199a-5p may become an effective strategy for improving the development of IVF peri-implantation embryos in the future. PMID:27488027

  16. Arabidopsis gene expression patterns during spaceflight

    NASA Astrophysics Data System (ADS)

    Paul, A.-L.; Ferl, R. J.

    The exposure of Arabidopsis thaliana (Arabidopsis) plants to spaceflight environments resulted in the differential expression of hundreds of genes. A 5 day mission on orbiter Columbia in 1999 (STS-93) carried transgenic Arabidopsis plants engineered with a transgene composed of the alcohol dehydrogenase (Adh) gene promoter linked to the β -Glucuronidase (GUS) reporter gene. The plants were used to evaluate the effects of spaceflight on two fronts. First, expression patterns visualized with the Adh/GUS transgene were used to address specifically the possibility that spaceflight induces a hypoxic stress response, and to assess whether any spaceflight response was similar to control terrestrial hypoxia-induced gene expression patterns. (Paul et al., Plant Physiol. 2001, 126:613). Second, genome-wide patterns of native gene expression were evaluated utilizing the Affymetrix ATH1 GeneChip? array of 8,000 Arabidopsis genes. As a control for the veracity of the array analyses, a selection of genes identified with the arrays was further characterized with quantitative Real-Time RT PCR (ABI - TaqmanTM). Comparison of the patterns of expression for arrays of hybridized with RNA isolated from plants exposed to spaceflight compared to the control arrays revealed hundreds of genes that were differentially expressed in response to spaceflight, yet most genes that are hallmarks of hypoxic stress were unaffected. These results will be discussed in light of current models for plant responses to the spaceflight environment, and with regard to potential future flight opportunities.

  17. Signalling properties and pharmacology of a 5-HT7 -type serotonin receptor from Tribolium castaneum.

    PubMed

    Vleugels, R; Lenaerts, C; Vanden Broeck, J; Verlinden, H

    2014-04-01

    In the last decade, genome sequence data and gene structure information on invertebrate receptors has been greatly expanded by large sequencing projects and cloning studies. This information is of great value for the identification of receptors; however, functional and pharmacological data are necessary for an accurate receptor classification and for practical applications. In insects, an important group of neurotransmitter and neurohormone receptors, for which ample sequence information is available but pharmacological information is missing, are the biogenic amine G protein-coupled receptors (GPCRs). In the present study, we investigated the sequence information, pharmacology and signalling properties of a 5-HT7 -type serotonin receptor from the red flour beetle, Tribolium castaneum (Trica5-HT7 ). The receptor encoding cDNA shows considerable sequence similarity with cognate 5-HT7 receptors and phylogenetic analysis also clusters the receptor within this 5-HT receptor group. Real-time reverse transcription PCR demonstrated high expression levels in the brain, indicating the possible importance of this receptor in neural processes. Trica5-HT7 was dose-dependently activated by 5-HT, which induced elevated intracellular cyclic AMP levels but had no effect on calcium signalling. The synthetic agonists, α-methyl 5-HT, 5-methoxytryptamine, 5-carboxamidotryptamine and 8-hydroxy-2-(dipropylamino)tetralin hydrobromide, showed a response, although with a much lower potency and efficacy than 5-HT. Ketanserin and methiothepin were the most potent antagonists. Both showed characteristics of competitive inhibition on Trica5-HT7 . The signalling pathway and pharmacological profile offer important information that will facilitate functional and comparative studies of 5-HT receptors in insects and other invertebrates. The pharmacology of invertebrate 5-HT receptors differs considerably from that of vertebrates. The present study may therefore contribute to establishing a more

  18. Candidate genetic analysis of plasma high-density lipoprotein-cholesterol and severity of coronary atherosclerosis

    PubMed Central

    Chen, Suet Nee; Cilingiroglu, Mehmet; Todd, Josh; Lombardi, Raffaella; Willerson, James T; Gotto, Antonio M; Ballantyne, Christie M; Marian, AJ

    2009-01-01

    Background Plasma level of high-density lipoprotein-cholesterol (HDL-C), a heritable trait, is an important determinant of susceptibility to atherosclerosis. Non-synonymous and regulatory single nucleotide polymorphisms (SNPs) in genes implicated in HDL-C synthesis and metabolism are likely to influence plasma HDL-C, apolipoprotein A-I (apo A-I) levels and severity of coronary atherosclerosis. Methods We genotyped 784 unrelated Caucasian individuals from two sets of populations (Lipoprotein and Coronary Atherosclerosis Study- LCAS, N = 333 and TexGen, N = 451) for 94 SNPs in 42 candidate genes by 5' nuclease assays. We tested the distribution of the phenotypes by the Shapiro-Wilk normality test. We used Box-Cox regression to analyze associations of the non-normally distributed phenotypes (plasma HDL-C and apo A-I levels) with the genotypes. We included sex, age, body mass index (BMI), diabetes mellitus (DM), and cigarette smoking as covariates. We calculated the q values as indicators of the false positive discovery rate (FDR). Results Plasma HDL-C levels were associated with sex (higher in females), BMI (inversely), smoking (lower in smokers), DM (lower in those with DM) and SNPs in APOA5, APOC2, CETP, LPL and LIPC (each q ≤0.01). Likewise, plasma apo A-I levels, available in the LCAS subset, were associated with SNPs in CETP, APOA5, and APOC2 as well as with BMI, sex and age (all q values ≤0.03). The APOA5 variant S19W was also associated with minimal lumen diameter (MLD) of coronary atherosclerotic lesions, a quantitative index of severity of coronary atherosclerosis (q = 0.018); mean number of coronary artery occlusions (p = 0.034) at the baseline and progression of coronary atherosclerosis, as indicated by the loss of MLD. Conclusion Putatively functional variants of APOA2, APOA5, APOC2, CETP, LPL, LIPC and SOAT2 are independent genetic determinants of plasma HDL-C levels. The non-synonymous S19W SNP in APOA5 is also an independent determinant of plasma

  19. 26 CFR 1.643(a)-5 - Tax-exempt interest.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Tax-exempt interest. 1.643(a)-5 Section 1.643(a)-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Estates, Trusts, and Beneficiaries § 1.643(a)-5 Tax-exempt interest. (a) There...

  20. 42 CFR 63a.5 - How to apply for a training grant.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false How to apply for a training grant. 63a.5 Section 63a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.5 How to apply for a training...

  1. 42 CFR 63a.5 - How to apply for a training grant.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false How to apply for a training grant. 63a.5 Section 63a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.5 How to apply for a training...

  2. 42 CFR 63a.5 - How to apply for a training grant.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false How to apply for a training grant. 63a.5 Section 63a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.5 How to apply for a training...

  3. 42 CFR 63a.5 - How to apply for a training grant.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false How to apply for a training grant. 63a.5 Section 63a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.5 How to apply for a training...

  4. 42 CFR 63a.5 - How to apply for a training grant.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false How to apply for a training grant. 63a.5 Section 63a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.5 How to apply for a training...

  5. 26 CFR 1.643(a)-5 - Tax-exempt interest.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Tax-exempt interest. 1.643(a)-5 Section 1.643(a)-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Estates, Trusts, and Beneficiaries § 1.643(a)-5 Tax-exempt interest....

  6. Compare Gene Profiles

    SciTech Connect

    2014-05-31

    Compare Gene Profiles (CGP) performs pairwise gene content comparisons among a relatively large set of related bacterial genomes. CGP performs pairwise BLAST among gene calls from a set of input genome and associated annotation files, and combines the results to generate lists of common genes, unique genes, homologs, and genes from each genome that differ substantially in length from corresponding genes in the other genomes. CGP is implemented in Python and runs in a Linux environment in serial or parallel mode.

  7. Dioxin activation of CYP1A5 promoter/enhancer regions from two avian species, common cormorant (Phalacrocorax carbo) and chicken (Gallus gallus): Association with aryl hydrocarbon receptor 1 and 2 isoforms

    SciTech Connect

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

    2009-01-01

    The present study focuses on the molecular mechanism and interspecies differences in susceptibility of avian aryl hydrocarbon receptor (AHR)-cytochrome P4501A (CYP1A) signaling pathway. By the cloning of 5'-flanking regions of CYP1A5 gene from common cormorant (Phalacrocorax carbo) and chicken (Gallus gallus), seven putative xenobiotic response elements (XREs) were identified within 2.7 kb upstream region of common cormorant CYP1A5 (ccCYP1A5), and six XREs were found within 0.9 kb of chicken CYP1A5 (ckCYP1A5). Analysis of sequential deletion and mutagenesis of the binding sites in avian CYP1A5 genes by in vitro reporter gene assays revealed that two XREs at -613 bp and -1585 bp in ccCYP1A5, and one XRE at -262 bp in ckCYP1A5 conferred TCDD-responsiveness. The binding of AHR1 with AHR nuclear translocator 1 (ARNT1) to the functional XRE in a TCDD-dependent manner was verified with gel shift assays, suggesting that avian CYP1A5 is induced by TCDD through AHR1/ARNT1 signaling pathway as well as mammalian CYP1A1 but through a distinct pathway from mammalian CYP1A2, an ortholog of the CYP1A5. TCDD-EC{sub 50} for the transcriptional activity in both cormorant AHR1- and AHR2-ccCYP1A5 reporter construct was 10-fold higher than that in chicken AHR1-ckCYP1A5 reporter construct. In contrast, chicken AHR2 showed no TCDD-dependent response. The TCDD-EC{sub 50} for CYP1A5 transactivation was altered by switching AHR1 between the two avian species, irrespective of the species from which the regulatory region of CYP1A5 gene originates. Therefore, the structural difference in AHR, not the CYP1A5 regulatory region may be a major factor to account for the dioxin susceptibility in avian species.

  8. Cis-Acting Sequence Elements and Upstream Open Reading Frame in Mouse Utrophin-A 5'-UTR Repress Cap-Dependent Translation

    PubMed Central

    Ghosh, Trinath; Basu, Utpal

    2015-01-01

    Utrophin, the autosomal homologue of dystrophin can functionally compensate for dystrophin deficiency. Utrophin upregulation could therefore be a therapeutic strategy in Duchenne Muscular Dystrophy (DMD) that arises from mutation in dystrophin gene. In contrast to its transcriptional regulation, mechanisms operating at post-transcriptional level of utrophin expression have not been well documented. Although utrophin-A 5'-UTR has been reported with internal ribosome entry site (IRES), its inhibitory effect on translation is also evident. In the present study we therefore aimed to compare relative contribution of cap-independent and cap-dependent translation with mouse utrophin-A 5'-UTR through m7G-capped and A-capped mRNA transfection based reporter assay. Our results demonstrate that cap-independent translation with utrophin-A 5'-UTR is not as strong as viral IRES. However, cap-independent mode has significant contribution as cap-dependent translation is severely repressed with utrophin-A 5'-UTR. We further identified two sequence elements and one upstream open reading frame in utrophin-A 5'-UTR responsible for repression. The repressor elements in utrophin-A 5'-UTR may be targeted for utrophin upregulation. PMID:26230628

  9. Gene gymnastics

    PubMed Central

    Vijayachandran, Lakshmi S; Thimiri Govinda Raj, Deepak B; Edelweiss, Evelina; Gupta, Kapil; Maier, Josef; Gordeliy, Valentin; Fitzgerald, Daniel J; Berger, Imre

    2013-01-01

    Most essential activities in eukaryotic cells are catalyzed by large multiprotein assemblies containing up to ten or more interlocking subunits. The vast majority of these protein complexes are not easily accessible for high resolution studies aimed at unlocking their mechanisms, due to their low cellular abundance and high heterogeneity. Recombinant overproduction can resolve this bottleneck and baculovirus expression vector systems (BEVS) have emerged as particularly powerful tools for the provision of eukaryotic multiprotein complexes in high quality and quantity. Recently, synthetic biology approaches have begun to make their mark in improving existing BEVS reagents by de novo design of streamlined transfer plasmids and by engineering the baculovirus genome. Here we present OmniBac, comprising new custom designed reagents that further facilitate the integration of heterologous genes into the baculovirus genome for multiprotein expression. Based on comparative genome analysis and data mining, we herein present a blueprint to custom design and engineer the entire baculovirus genome for optimized production properties using a bottom-up synthetic biology approach. PMID:23328086

  10. Concurrent and Clonally Related Pediatric Follicular Lymphoma and Burkitt Lymphoma in a 5-Year-Old Boy.

    PubMed

    Shaver, Aaron C; Zimmerman, David; Liu, Mingya; Vnencak-Jones, Cindy; Kim, Annette S

    2016-02-01

    Pediatric follicular lymphoma shares morphologic similarities with the adult form of the disease but lacks other classic features of adult lymphoma, including t(14;18) translocation, BCL2 overexpression, and transformation to aggressive higher-grade lymphoma. Herein, we report a novel case in which a 5-year-old boy (ethnicity unknown) had follicular lymphoma, along with concurrent high-grade and clonally related disease that fulfilled all of the morphologic, immunophenotypic, and genetic criteria for Burkitt lymphoma, including a t(8;14) translocation involving the MYC gene. To our knowledge, this case is the first reported instance of transformation of follicular lymphoma of any sort into true Burkitt lymphoma and the first reported instance of acquisition of MYC abnormalities in pediatric follicular lymphoma.

  11. The light skin allele of SLC24A5 in South Asians and Europeans shares identity by descent.

    PubMed

    Basu Mallick, Chandana; Iliescu, Florin Mircea; Möls, Märt; Hill, Sarah; Tamang, Rakesh; Chaubey, Gyaneshwer; Goto, Rie; Ho, Simon Y W; Gallego Romero, Irene; Crivellaro, Federica; Hudjashov, Georgi; Rai, Niraj; Metspalu, Mait; Mascie-Taylor, C G Nicholas; Pitchappan, Ramasamy; Singh, Lalji; Mirazon-Lahr, Marta; Thangaraj, Kumarasamy; Villems, Richard; Kivisild, Toomas

    2013-11-01

    Skin pigmentation is one of the most variable phenotypic traits in humans. A non-synonymous substitution (rs1426654) in the third exon of SLC24A5 accounts for lighter skin in Europeans but not in East Asians. A previous genome-wide association study carried out in a heterogeneous sample of UK immigrants of South Asian descent suggested that this gene also contributes significantly to skin pigmentation variation among South Asians. In the present study, we have quantitatively assessed skin pigmentation for a largely homogeneous cohort of 1228 individuals from the Southern region of the Indian subcontinent. Our data confirm significant association of rs1426654 SNP with skin pigmentation, explaining about 27% of total phenotypic variation in the cohort studied. Our extensive survey of the polymorphism in 1573 individuals from 54 ethnic populations across the Indian subcontinent reveals wide presence of the derived-A allele, although the frequencies vary substantially among populations. We also show that the geospatial pattern of this allele is complex, but most importantly, reflects strong influence of language, geography and demographic history of the populations. Sequencing 11.74 kb of SLC24A5 in 95 individuals worldwide reveals that the rs1426654-A alleles in South Asian and West Eurasian populations are monophyletic and occur on the background of a common haplotype that is characterized by low genetic diversity. We date the coalescence of the light skin associated allele at 22-28 KYA. Both our sequence and genome-wide genotype data confirm that this gene has been a target for positive selection among Europeans. However, the latter also shows additional evidence of selection in populations of the Middle East, Central Asia, Pakistan and North India but not in South India. PMID:24244186

  12. Inhibition of A5 Neurons Facilitates the Occurrence of REM Sleep-Like Episodes in Urethane-Anesthetized Rats: A New Role for Noradrenergic A5 Neurons?

    PubMed

    Fenik, Victor B; Marchenko, Vitaliy; Davies, Richard O; Kubin, Leszek

    2012-01-01

    When rapid eye movement (REM) sleep occurs, noradrenergic cells become silent, with the abolition of activity in locus coeruleus (LC) neurons seen as a key event permissive for the occurrence of REM sleep. However, it is not known whether silencing of other than LC noradrenergic neurons contributes to the generation of REM sleep. In urethane-anesthetized rats, stereotyped REM sleep-like episodes can be repeatedly elicited by injections of the cholinergic agonist, carbachol, into a discrete region of the dorsomedial pons. We used this preparation to test whether inhibition of ventrolateral pontine noradrenergic A5 neurons only, or together with LC neurons, also can elicit REM sleep-like effects. To silence noradrenergic cells, we sequentially injected the α(2)-adrenergic agonist clonidine (20-40 nl, 0.75 mM) into both A5 regions and then the LC. In two rats, successful bilateral clonidine injections into the A5 region elicited the characteristic REM sleep-like episodes (hippocampal theta rhythm, suppression of hypoglossal nerve activity, reduced respiratory rate). In five rats, bilateral clonidine injections into the A5 region and then into one LC triggered REM sleep-like episodes, and in two rats injections into both A5 and then both LC were needed to elicit the effect. In contrast, in three rats, uni- or bilateral clonidine injections only into the LC had no effect, and clonidine injections placed in another six rats outside of the A5 and/or LC regions were without effect. The REM sleep-like episodes elicited by clonidine had similar magnitude of suppression of hypoglossal nerve activity (by 75%), similar pattern of hippocampal changes, and similar durations (2.5-5.3 min) to the episodes triggered in the same preparation by carbachol injections into the dorsomedial pontine reticular formation. Thus, silencing of A5 cells may importantly enable the occurrence of REM sleep-like episodes, at least under anesthesia. This is a new role for noradrenergic A5

  13. Inhibition of A5 Neurons Facilitates the Occurrence of REM Sleep-Like Episodes in Urethane-Anesthetized Rats: A New Role for Noradrenergic A5 Neurons?

    PubMed Central

    Fenik, Victor B.; Marchenko, Vitaliy; Davies, Richard O.; Kubin, Leszek

    2012-01-01

    When rapid eye movement (REM) sleep occurs, noradrenergic cells become silent, with the abolition of activity in locus coeruleus (LC) neurons seen as a key event permissive for the occurrence of REM sleep. However, it is not known whether silencing of other than LC noradrenergic neurons contributes to the generation of REM sleep. In urethane-anesthetized rats, stereotyped REM sleep-like episodes can be repeatedly elicited by injections of the cholinergic agonist, carbachol, into a discrete region of the dorsomedial pons. We used this preparation to test whether inhibition of ventrolateral pontine noradrenergic A5 neurons only, or together with LC neurons, also can elicit REM sleep-like effects. To silence noradrenergic cells, we sequentially injected the α2-adrenergic agonist clonidine (20–40 nl, 0.75 mM) into both A5 regions and then the LC. In two rats, successful bilateral clonidine injections into the A5 region elicited the characteristic REM sleep-like episodes (hippocampal theta rhythm, suppression of hypoglossal nerve activity, reduced respiratory rate). In five rats, bilateral clonidine injections into the A5 region and then into one LC triggered REM sleep-like episodes, and in two rats injections into both A5 and then both LC were needed to elicit the effect. In contrast, in three rats, uni- or bilateral clonidine injections only into the LC had no effect, and clonidine injections placed in another six rats outside of the A5 and/or LC regions were without effect. The REM sleep-like episodes elicited by clonidine had similar magnitude of suppression of hypoglossal nerve activity (by 75%), similar pattern of hippocampal changes, and similar durations (2.5–5.3 min) to the episodes triggered in the same preparation by carbachol injections into the dorsomedial pontine reticular formation. Thus, silencing of A5 cells may importantly enable the occurrence of REM sleep-like episodes, at least under anesthesia. This is a new role for noradrenergic A5

  14. 26 CFR 1.613A-5 - Election under section 613A(c)(4).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 7 2010-04-01 2010-04-01 true Election under section 613A(c)(4). 1.613A-5 Section 1.613A-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Natural Resources § 1.613A-5 Election under section 613A(c)(4). The election under section 613A(c)(4) is...

  15. Interaction between Darunavir and Etravirine Is Partly Mediated by CYP3A5 Polymorphism

    PubMed Central

    Belkhir, Leïla; Elens, Laure; Zech, Francis; Panin, Nadtha; Vincent, Anne; Yombi, Jean Cyr

    2016-01-01

    Objectives To assess the impact of the loss-of-function CYP3A5*3 allele (rs776746, 6986A>G SNP) on darunavir (DRV) plasma concentrations. Methods 135 HIV-1 infected patients treated with DRV-based therapy were included in the study and plasma samples were obtained immediately before drug intake in order to determine DRV trough concentrations using an ultra performance liquid chromatography method (UPLC) with diode-array detection (DAD). Noteworthy is the fact that in 16 (11.9%) patients, etravirine (ETR) was combined with DRV. CYP3A5 genotypes were determined using real time PCR method (TaqMan® genotyping assay). The patients were then classified into CYP3A5 expressors (CYP3A5*1 allele carriers) and non-expressors (CYP3A5*3 homozygous). Subsequently, the association between DRV plasma trough concentration ([DRV]plasma) and CYP3A5 genotype-based expression status was analyzed. Results 45% of the patients were classified as CYP3A5 expressors. In the whole cohort, mean [DRV]plasma was not different between CYP3A5 expressors and non-expressors (1894ng/ml [CI95%: 1566–2290] versus 1737ng/ml [CI95%: 1468–2057], p = 0.43). However, in the subgroup of the 16 patients receiving DRV combined with ETR, a significantly lower [DRV]plasma was observed for CYP3A5 expressors when compared to non-expressors (1385ng/ml [CI95%:886.3–2165] versus 3141ng/ml [CI95%:2042–4831], p = 0.007). Conclusions Interaction between DRV and ETR is partly mediated by CYP3A5 polymorphism with lower DRV plasma trough concentrations in CYP3A5 expressors suggesting a specific ETR-driven CYP3A5 activation only in CYP3A5 expressors. Consequently, these patients might be more at risk of infra-therapeutic [DRV]plasma. This potentially important observation is a good illustration of a genotype-based drug interaction, which could also have considerable consequences if translated to other CYP3A5-metabolized drugs. Further investigations are thus needed to confirm this association and to explore its

  16. Global pharmacogenomics: distribution of CYP3A5 polymorphisms and phenotypes in the Brazilian population.

    PubMed

    Suarez-Kurtz, Guilherme; Vargens, Daniela D; Santoro, Ana Beatriz; Hutz, Mara H; de Moraes, Maria Elisabete; Pena, Sérgio D J; Ribeiro-dos-Santos, Ândrea; Romano-Silva, Marco A; Struchiner, Claudio José

    2014-01-01

    The influence of self-reported "race/color", geographical origin and genetic ancestry on the distribution of three functional CYP3A5 polymorphisms, their imputed haplotypes and inferred phenotypes was examined in 909 healthy, adult Brazilians, self-identified as White, Brown or Black ("race/color" categories of the Brazilian census). The cohort was genotyped for CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343), CYP3A5 haplotypes were imputed and CYP3A5 metabolizer phenotypes were inferred according to the number of defective CYP3A5 alleles. Estimates of the individual proportions of Amerindian, African and European ancestry were available for the entire cohort. Multinomial log-linear regression models were applied to infer the statistical association between the distribution of CYP3A5 alleles, haplotypes and phenotypes (response variables), and self-reported Color, geographical region and ancestry (explanatory variables). We found that Color per se or in combination with geographical region associates significantly with the distribution of CYP3A5 variant alleles and CYP3A5 metabolizer phenotypes, whereas geographical region per se influences the frequency distribution of CYP3A5 variant alleles. The odds of having the default CYP3A5*3 allele and the poor metabolizer phenotype increases continuously with the increase of European ancestry and decrease of African ancestry. The opposite trend is observed in relation to CYP3A5*6, CYP3A5*7, the default CYP3A5*1 allele, and both the extensive and intermediate phenotypes. No significant effect of Amerindian ancestry on the distribution of CYP3A5 alleles or phenotypes was observed. In conclusion, this study strongly supports the notion that the intrinsic heterogeneity of the Brazilian population must be acknowledged in the design and interpretation of pharmacogenomic studies, and dealt with as a continuous variable, rather than proportioned in arbitrary categories that do not capture the diversity of the

  17. Global pharmacogenomics: distribution of CYP3A5 polymorphisms and phenotypes in the Brazilian population.

    PubMed

    Suarez-Kurtz, Guilherme; Vargens, Daniela D; Santoro, Ana Beatriz; Hutz, Mara H; de Moraes, Maria Elisabete; Pena, Sérgio D J; Ribeiro-dos-Santos, Ândrea; Romano-Silva, Marco A; Struchiner, Claudio José

    2014-01-01

    The influence of self-reported "race/color", geographical origin and genetic ancestry on the distribution of three functional CYP3A5 polymorphisms, their imputed haplotypes and inferred phenotypes was examined in 909 healthy, adult Brazilians, self-identified as White, Brown or Black ("race/color" categories of the Brazilian census). The cohort was genotyped for CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343), CYP3A5 haplotypes were imputed and CYP3A5 metabolizer phenotypes were inferred according to the number of defective CYP3A5 alleles. Estimates of the individual proportions of Amerindian, African and European ancestry were available for the entire cohort. Multinomial log-linear regression models were applied to infer the statistical association between the distribution of CYP3A5 alleles, haplotypes and phenotypes (response variables), and self-reported Color, geographical region and ancestry (explanatory variables). We found that Color per se or in combination with geographical region associates significantly with the distribution of CYP3A5 variant alleles and CYP3A5 metabolizer phenotypes, whereas geographical region per se influences the frequency distribution of CYP3A5 variant alleles. The odds of having the default CYP3A5*3 allele and the poor metabolizer phenotype increases continuously with the increase of European ancestry and decrease of African ancestry. The opposite trend is observed in relation to CYP3A5*6, CYP3A5*7, the default CYP3A5*1 allele, and both the extensive and intermediate phenotypes. No significant effect of Amerindian ancestry on the distribution of CYP3A5 alleles or phenotypes was observed. In conclusion, this study strongly supports the notion that the intrinsic heterogeneity of the Brazilian population must be acknowledged in the design and interpretation of pharmacogenomic studies, and dealt with as a continuous variable, rather than proportioned in arbitrary categories that do not capture the diversity of the

  18. Global Pharmacogenomics: Distribution of CYP3A5 Polymorphisms and Phenotypes in the Brazilian Population

    PubMed Central

    Suarez-Kurtz, Guilherme; Vargens, Daniela D.; Santoro, Ana Beatriz; Hutz, Mara H.; de Moraes, Maria Elisabete; Pena, Sérgio D. J.; Ribeiro-dos-Santos, Ândrea; Romano-Silva, Marco A.; Struchiner, Claudio José

    2014-01-01

    The influence of self-reported “race/color”, geographical origin and genetic ancestry on the distribution of three functional CYP3A5 polymorphisms, their imputed haplotypes and inferred phenotypes was examined in 909 healthy, adult Brazilians, self-identified as White, Brown or Black (“race/color” categories of the Brazilian census). The cohort was genotyped for CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343), CYP3A5 haplotypes were imputed and CYP3A5 metabolizer phenotypes were inferred according to the number of defective CYP3A5 alleles. Estimates of the individual proportions of Amerindian, African and European ancestry were available for the entire cohort. Multinomial log-linear regression models were applied to infer the statistical association between the distribution of CYP3A5 alleles, haplotypes and phenotypes (response variables), and self-reported Color, geographical region and ancestry (explanatory variables). We found that Color per se or in combination with geographical region associates significantly with the distribution of CYP3A5 variant alleles and CYP3A5 metabolizer phenotypes, whereas geographical region per se influences the frequency distribution of CYP3A5 variant alleles. The odds of having the default CYP3A5*3 allele and the poor metabolizer phenotype increases continuously with the increase of European ancestry and decrease of African ancestry. The opposite trend is observed in relation to CYP3A5*6, CYP3A5*7, the default CYP3A5*1 allele, and both the extensive and intermediate phenotypes. No significant effect of Amerindian ancestry on the distribution of CYP3A5 alleles or phenotypes was observed. In conclusion, this study strongly supports the notion that the intrinsic heterogeneity of the Brazilian population must be acknowledged in the design and interpretation of pharmacogenomic studies, and dealt with as a continuous variable, rather than proportioned in arbitrary categories that do not capture the diversity

  19. Pharmacokinetics of a Once-Daily Dose of Tacrolimus Early After Liver Transplantation: With Special Reference to CYP3A5 and ABCB1 Single Nucleotide Polymorphisms.

    PubMed

    Miyata, Yoichi; Akamatsu, Nobuhisa; Sugawara, Yasuhiko; Kaneko, Junichi; Yamamoto, Takehito; Suzuki, Hiroshi; Arita, Junichi; Sakamoto, Yoshihiro; Hasegawa, Kiyoshi; Tamura, Sumihito; Kokudo, Norihiro

    2016-01-01

    BACKGROUND The aim of the present study was to investigate the pharmacokinetics of the once-daily tacrolimus formulation (QD form) in relation to polymorphisms of the donor cytochrome P450 family 3 sub-family A polypeptide 5 (CYP3A5) gene and recipient adenosine triphosphate-binding cassette sub-family B member 1 (ABCB1) gene. MATERIAL AND METHODS A total of 80 consecutive living-donor liver transplant (LDLT) recipients were started on the QD form of tacrolimus (day 1), and 60 patients were completely followed for 7 days early after liver transplantation in order to evaluate the pharmacokinetics. RESULTS The concentration/dose (C/D) ratio in recipients with the donor CYP3A5 *1 allele was significantly lower throughout the observation period compared with those with the CYP3A5 genotype *3/*3 (p<0.001), while no effect of single-nucleotide polymorphisms (SNPs) of ABCB1 was observed. The administered doses required to achieve the target trough level were significantly higher on day 7 than on day 1 among all groups, regardless of the differences in the SNPs, especially among those with donor CYP3A5 *1 allele. The tacrolimus concentration was kept within the targeted level all through the study regardless of SNPs. CONCLUSIONS The donor CYP3A5 *1 allele correlated with the lower C/D ratio after administration of the QD form, and higher doses of QD-form tacrolimus and careful monitoring for the trough level should be considered, especially in recipients with the donor CYP3A5 *1 allele. PMID:27503662

  20. Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell

    SciTech Connect

    Xu, Ning; Zhang, Jianjun; Shen, Conghuan; Luo, Yi; Xia, Lei; Xue, Feng; Xia, Qiang

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer miR-199a-5p levels were significantly decreased after cisplatin treatment. Black-Right-Pointing-Pointer Cisplatin treatment induced autophagy activation. Black-Right-Pointing-Pointer Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell. -- Abstract: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Systemic chemotherapy plays an important role in the treatment of patients with advanced liver cancer. However, chemoresistance to cisplatin is a major limitation of cisplatin-based chemotherapy in the clinic, and the underlying mechanism of such resistance is not fully understood. In the study, we found that miR-199a-5p levels were significantly reduced in HCC patients treated with cisplatin-based chemotherapy. Cisplatin treatment also resulted in decreased miR-199a-5p levels in human HCC cell lines. Forced expression of miR-199a-5p promoted cisplatin-induced inhibition of cell proliferation. Cisplatin treatment activated autophagy in Huh7 and HepG2 cells, which increased cell proliferation. We further demonstrated that downregulated miR-199a-5p enhanced autophagy activation by targeting autophagy-associated gene 7 (ATG7). More important, autophagy inhibition abrogated miR-199a-5p downregulation-induced cell proliferation. These data demonstrated that miR-199a-5p/autophagy signaling represents a novel pathway regulating chemoresistance, thus offering a new target for chemotherapy of HCC.

  1. Organization of immunoglobulin genes.

    PubMed

    Tonegawa, S; Brack, C; Hozumi, N; Pirrotta, V

    1978-01-01

    The nucleotide-sequence determination of a cloned, embryonic Vlambda gene directly demonstrated that V genes are separate from a corresponding C gene in embryonic cells. Analysis by restriction enzymes of total cellular DNA from various sources strongly suggested that the two separate immunoglobulin genes become continuous during differentiation of B lymphocytes. There seems to be a strict correlation between the joining event and activation of the joined genes. Cloning of more immunoglobulin genes from embryo and plasma cells will not only provide direct demonstration of such a gene-joining event but also help in the elucidation of a possible relationship of the event to gene activation mechanisms.

  2. 17 CFR 240.17a-5 - Reports to be made by certain brokers and dealers.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... or carries customer accounts shall file Part I of Form X-17A-5 (§ 249.617 of this chapter) within 10... clears transactions or carries customer accounts shall file Part II of Form X-17A-5 (§ 249.617 of this... chapter). (iii) Every broker or dealer who does not carry nor clear transactions nor carry...

  3. 26 CFR 20.2056A-5 - Imposition of section 2056A estate tax.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 14 2013-04-01 2013-04-01 false Imposition of section 2056A estate tax. 20.2056A-5 Section 20.2056A-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) ESTATE AND GIFT TAXES ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Taxable...

  4. Membrane repair of human skeletal muscle cells requires Annexin-A5.

    PubMed

    Carmeille, Romain; Bouvet, Flora; Tan, Sisareuth; Croissant, Coralie; Gounou, Céline; Mamchaoui, Kamel; Mouly, Vincent; Brisson, Alain R; Bouter, Anthony

    2016-09-01

    Defect in membrane repair contributes to the development of limb girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy. In healthy skeletal muscle, unraveling membrane repair mechanisms requires to establish an exhaustive list of the components of the resealing machinery. Here we show that human myotubes rendered deficient for Annexin-A5 (AnxA5) suffer from a severe defect in membrane resealing. This defect is rescued by the addition of recombinant AnxA5 while an AnxA5 mutant, which is unable to form 2D protein arrays, has no effect. Using correlative light and electron microscopy, we show that AnxA5 binds to the edges of the torn membrane, as early as a few seconds after sarcolemma injury, where it probably self-assembles into 2D arrays. In addition, we observed that membrane resealing is associated with the presence of a cluster of lipid vesicles at the wounded site. AnxA5 is present at the surface of these vesicles and may thus participate in plugging the cell membrane disruption. Finally, we show that AnxA5 behaves similarly in myotubes from a muscle cell line established from a patient suffering from LGMD2B, a myopathy due to dysferlin mutations, which indicates that trafficking of AnxA5 during sarcolemma damage is independent of the presence of dysferlin. PMID:27286750

  5. 42 CFR 2a.5 - Contents of application; research projects in which drugs will be administered.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Contents of application; research projects in which drugs will be administered. 2a.5 Section 2a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH... (21 U.S.C. 872(d)) and 21 CFR 1316.22. If the request is in such form, and is supported by...

  6. Gene doping: gene delivery for olympic victory.

    PubMed

    Gould, David

    2013-08-01

    With one recently recommended gene therapy in Europe and a number of other gene therapy treatments now proving effective in clinical trials it is feasible that the same technologies will soon be adopted in the world of sport by unscrupulous athletes and their trainers in so called 'gene doping'. In this article an overview of the successful gene therapy clinical trials is provided and the potential targets for gene doping are highlighted. Depending on whether a doping gene product is secreted from the engineered cells or is retained locally to, or inside engineered cells will, to some extent, determine the likelihood of detection. It is clear that effective gene delivery technologies now exist and it is important that detection and prevention plans are in place. PMID:23082866

  7. Gene doping: gene delivery for olympic victory

    PubMed Central

    Gould, David

    2013-01-01

    With one recently recommended gene therapy in Europe and a number of other gene therapy treatments now proving effective in clinical trials it is feasible that the same technologies will soon be adopted in the world of sport by unscrupulous athletes and their trainers in so called ‘gene doping’. In this article an overview of the successful gene therapy clinical trials is provided and the potential targets for gene doping are highlighted. Depending on whether a doping gene product is secreted from the engineered cells or is retained locally to, or inside engineered cells will, to some extent, determine the likelihood of detection. It is clear that effective gene delivery technologies now exist and it is important that detection and prevention plans are in place. PMID:23082866

  8. Gene doping: gene delivery for olympic victory.

    PubMed

    Gould, David

    2013-08-01

    With one recently recommended gene therapy in Europe and a number of other gene therapy treatments now proving effective in clinical trials it is feasible that the same technologies will soon be adopted in the world of sport by unscrupulous athletes and their trainers in so called 'gene doping'. In this article an overview of the successful gene therapy clinical trials is provided and the potential targets for gene doping are highlighted. Depending on whether a doping gene product is secreted from the engineered cells or is retained locally to, or inside engineered cells will, to some extent, determine the likelihood of detection. It is clear that effective gene delivery technologies now exist and it is important that detection and prevention plans are in place.

  9. MicroRNA-33a-5p Modulates Japanese Encephalitis Virus Replication by Targeting Eukaryotic Translation Elongation Factor 1A1

    PubMed Central

    Chen, Zheng; Ye, Jing; Ashraf, Usama; Li, Yunchuan; Wei, Siqi; Wan, Shengfeng; Zohaib, Ali; Song, Yunfeng; Chen, Huanchun

    2016-01-01

    ABSTRACT Japanese encephalitis virus (JEV) is a typical mosquito-borne flavivirus responsible for acute encephalitis and meningitis in humans. However, the molecular mechanism for JEV pathogenesis is still unclear. MicroRNAs (miRNAs) are small noncoding RNAs that act as gene regulators. They are directly or indirectly involved in many cellular functions owing to their ability to target mRNAs for degradation or translational repression. However, how cellular miRNAs are regulated and their functions during JEV infection are largely unknown. In the present study, we found that JEV infection downregulated the expression of endogenous cellular miR-33a-5p. Notably, artificially transfecting with miR-33a-5p mimics led to a significant decrease in viral replication, suggesting that miR-33a-5p acts as a negative regulator of JEV replication. A dual-luciferase reporter assay identified eukaryotic translation elongation factor 1A1 (EEF1A1) as one of the miR-33a-5p target genes. Our study further demonstrated that EEF1A1 can interact with the JEV proteins NS3 and NS5 in replicase complex. Through this interaction, EEF1A1 can stabilize the components of viral replicase complex and thus facilitates viral replication during JEV infection. Taken together, these results suggest that miR-33a-5p is downregulated during JEV infection, which contributes to viral replication by increasing the intracellular level of EEF1A1, an interaction partner of JEV NS3 and NS5. This study provides a better understanding of the molecular mechanisms of JEV pathogenesis. IMPORTANCE MiRNAs are critical regulators of gene expression that utilize sequence complementarity to bind to and modulate the stability or translation efficiency of target mRNAs. Accumulating data suggest that miRNAs regulate a wide variety of molecular mechanisms in the host cells during viral infections. JEV, a neurotropic flavivirus, is one of the major causes of acute encephalitis in humans worldwide. The roles of cellular mi

  10. EphrinA5 suppresses colon cancer development by negatively regulating epidermal growth factor receptor stability.

    PubMed

    Wang, Tong-Hong; Chang, Junn-Liang; Ho, Jar-Yi; Wu, Hsiao-Chun; Chen, Tse-Ching

    2012-01-01

    Colon cancer is one of the most common human cancers worldwide. Owing to its aggressiveness and lethality, it is necessary to determine the mechanisms regulating the carcinogenesis of colon cancer. EphrinA5 has been reported to act as a putative tumor suppressor in glioma; however, little is known concerning the role of this protein in the context of colon cancer. To elucidate the biological significance of ephrinA5 in colon cancer, we examined ephrinA5 and epidermal growth factor receptor (EGFR) expression profiles in both colon cancer and normal tissues, using immunohistochemistry on a 96-spot tissue microarray. Gain-of-function and loss-of-function experiments were performed on the human colon cancer cell lines SW480 and WiDr to determine the biological effects of ephrinA5 in relation to cell proliferation, survival, and migration. It was found that ephrinA5 mRNA and protein levels were significantly reduced in colon cancer as compared with normal colon tissue specimens. EphrinA5 expression was also negatively associated with tumor differentiation and clinical stage. In colon cancer cell line models, ephrinA5 exerted an inhibitory effect on EGFR by promoting c-Cbl-mediated EGFR ubiquitination and degradation. EphrinA5 did not affect the transcriptional regulation of EGFR mRNA expression in colon cancer cells. Expression of ephrinA5 suppressed colon cancer cell proliferation, migration, and chemotherapeutic resistance. In conclusion, ephrinA5 inhibited colon cancer progression by promoting c-Cbl-mediated EGFR degradation. Our findings identify a novel mechanism that could be utilized to improve the therapeutic efficiency of EGFR-targeting strategies.

  11. The role of CYP2A5 in liver injury and fibrosis: chemical-specific difference.

    PubMed

    Hong, Feng; Si, Chuanping; Gao, Pengfei; Cederbaum, Arthur I; Xiong, Huabao; Lu, Yongke

    2016-01-01

    Liver injuries induced by carbon tetrachloride (CCL4) or thioacetamide (TAA) are dependent on cytochrome P450 2E1 (CYP2E1). CYP2A5 can be induced by TAA but not by CCL4. In this study, liver injury including fibrosis induced by CCL4 or TAA were investigated in wild-type (WT) mice and CYP2A5 knockout (cyp2a5 (-/-) ) mice as well as in CYP2E1 knockout (cyp2e1 (-/-) ) mice as a comparison. Acute and subchronic liver injuries including fibrosis were induced by CCL4 and TAA in WT mice but not in cyp2e1 (-/-) mice, confirming the indispensable role of CYP2E1 in CCL4 and TAA hepatotoxicity. WT mice and cyp2a5 (-/-) mice developed comparable acute liver injury induced by a single injection of CCL4 as well as subchronic liver injury including fibrosis induced by 1 month of repeated administration of CCL4, suggesting that CYP2A5 does not affect CCL4-induced liver injury and fibrosis. However, while 200 mg/kg TAA-induced acute liver injury was comparable in WT mice and cyp2a5 (-/-) mice, 75 and 100 mg/kg TAA-induced liver injury were more severe in cyp2a5 (-/-) mice than those found in WT mice. After multiple injections with 200 mg/kg TAA for 1 month, while subchronic liver injury as indicated by serum aminotransferases was comparable in WT mice and cyp2a5 (-/-) mice, liver fibrosis was more severe in cyp2a5 (-/-) mice than that found in WT mice. These results suggest that while both CCL4- and TAA-induced liver injuries and fibrosis are CYP2E1 dependent, under some conditions, CYP2A5 may protect against TAA-induced liver injury and fibrosis, but it does not affect CCL4 hepatotoxicity.

  12. A novel miR-371a-5p-mediated pathway, leading to BAG3 upregulation in cardiomyocytes in response to epinephrine, is lost in Takotsubo cardiomyopathy

    PubMed Central

    d'Avenia, M; Citro, R; De Marco, M; Veronese, A; Rosati, A; Visone, R; Leptidis, S; Philippen, L; Vitale, G; Cavallo, A; Silverio, A; Prota, C; Gravina, P; De Cola, A; Carletti, E; Coppola, G; Gallo, S; Provenza, G; Bossone, E; Piscione, F; Hahne, M; De Windt, L J; Turco, M C; De Laurenzi, V

    2015-01-01

    Molecular mechanisms protecting cardiomyocytes from stress-induced death, including tension stress, are essential for cardiac physiology and defects in these protective mechanisms can result in pathological alterations. Bcl2-associated athanogene 3 (BAG3) is expressed in cardiomyocytes and is a component of the chaperone-assisted autophagy pathway, essential for homeostasis of mechanically altered cells. BAG3 ablation in mice results in a lethal cardiomyopathy soon after birth and mutations of this gene have been associated with different cardiomyopathies including stress-induced Takotsubo cardiomyopathy (TTC). The pathogenic mechanism leading to TTC has not been defined, but it has been suggested that the heart can be damaged by excessive epinephrine (epi) spillover in the absence of a protective mechanism. The aim of this study was to provide more evidence for a role of BAG3 in the pathogenesis of TTC. Therefore, we sequenced BAG3 gene in 70 TTC patients and in 81 healthy donors with the absence of evaluable cardiovascular disease. Mutations and polymorphisms detected in the BAG3 gene included a frequent nucleotide change g2252c in the BAG3 3′-untranslated region (3′-UTR) of Takotsubo patients (P<0.05), resulting in loss of binding of microRNA-371a-5p (miR-371a-5p) as evidenced by dual-luciferase reporter assays and argonaute RNA-induced silencing complex catalytic component 2/pull-down assays. Moreover, we describe a novel signaling pathway in cardiomyocytes that leads to BAG3 upregulation on exposure to epi through an ERK-dependent upregulation of miR-371a-5p. In conclusion, the presence of a g2252c polymorphism in the BAG3 3′-UTR determines loss of miR-371a-5p binding and results in an altered response to epi, potentially representing a new molecular mechanism that contributes to TTC pathogenesis. PMID:26512958

  13. Targeted Delivery of MicroRNA125a-5p by Engineered Lipid Nanoparticles for the Treatment of HER2 Positive Metastatic Breast Cancer.

    PubMed

    Hayward, Stephen L; Francis, David M; Kholmatov, Parviz; Kidambi, Srivatsan

    2016-03-01

    MicroRNAs (miRNAs) are endogenous regulators of gene expression that play a pivotal role in biological processes spanning from global homeostasis to disease onset and progression. The ability to manipulate and induce cellular reequilibrium of deregulated miRNA expression profiles by inhibition of oncogenic miRNA or overexpression of tumor suppressor miRNA is a promising cancer strategy, but is currently hindered in application by the lack of nonviral delivery systems. Here we present a lipid nanoparticle (LNP) platform surface coated with Hyaluronic Acid (HA) for the delivery of mature tumor suppressor MicroRNA125a-5p to treat HER2 positive metastatic breast cancer. The delivery platform actively targets patient-derived metastatic breast cancer cells (21MT-1) isolated from the metastatic pleural effusion over normal breast tissue via an intrinsic HA-CD44 mediated endocytosis event, and has the ability to escape from the intracellular endolysosomal pathway for potent gene silencing. Knockdown of the HER2 proto-oncogene at the level of transcription and translation was achieved following HA-LNP mediated transfection with MicroRNA125a-5p. In addition, the PI3K/AKT and MAPK hyperactivated signaling pathways, cellular proliferation, and migration potential were also potently suppressed. Furthermore, the therapeutic efficacy of MicroRNA125a-5p by the HA-LNP platform was demonstrated to be significantly improved as compared to a commercial transfection reagent. This study highlights the therapeutic potential of MicroRNA125a-5p as a standalone treatment of HER2+ metastatic breast cancer via a translational nonviral delivery platform. These findings have major implications on future gene therapy regimens for breast cancer.

  14. Inducible bilirubin oxidase: A novel function for the mouse cytochrome P450 2A5

    SciTech Connect

    Abu-Bakar, A'edah; Arthur, Dionne Maioha; Aganovic, Simona; Ng, Jack C.; Lang, Matti A.

    2011-11-15

    We have previously shown that bilirubin (BR), a breakdown product of haem, is a strong inhibitor and a high affinity substrate of the mouse cytochrome P450 2A5 (CYP2A5). The antioxidant BR, which is cytotoxic at high concentrations, is potentially useful in cellular protection against oxygen radicals if its intracellular levels can be strictly controlled. The mechanisms that regulate cellular BR levels are still obscure. In this paper we provide preliminary evidence for a novel function of CYP2A5 as hepatic 'BR oxidase'. A high-performance liquid chromatography/electrospray ionisation mass spectrometry screening showed that recombinant yeast microsomes expressing the CYP2A5 oxidise BR to biliverdin, as the main metabolite, and to three other smaller products with m/z values of 301, 315 and 333. The metabolic profile is significantly different from that of chemical oxidation of BR. In chemical oxidation the smaller products were the main metabolites. This suggests that the enzymatic reaction is selective, towards biliverdin production. Bilirubin treatment of primary hepatocytes increased the CYP2A5 protein and activity levels with no effect on the corresponding mRNA. Co-treatment with cycloheximide (CHX), a protein synthesis inhibitor, resulted in increased half-life of the CYP2A5 compared to cells treated only with CHX. Collectively, the observations suggest that the CYP2A5 is potentially an inducible 'BR oxidase' where BR may accelerate its own metabolism through stabilization of the CYP2A5 protein. It is possible that this metabolic pathway is potentially part of the machinery controlling intracellular BR levels in transient oxidative stress situations, in which high amounts of BR are produced. -- Highlights: Black-Right-Pointing-Pointer CYP2A5 metabolizes bilirubin to biliverdin and dipyrroles. Black-Right-Pointing-Pointer Bilirubin increased the hepatic CYP2A5 protein and activity levels. Black-Right-Pointing-Pointer Bilirubin does not change the hepatic CYP2A5

  15. Role of major histocompatibility complex class I-related molecules A*A5·1 allele in ulcerative colitis in Chinese patients

    PubMed Central

    Lü, Min; Xia, Bing; Ge, Liuqing; Li, Yi; Zhao, Jie; Chen, Fan; Zhou, Feng; Zhang, Xiaolian; Tan, Jinquan

    2009-01-01

    The major histocompatibility complex (MHC) class I-related molecules A (MICA) is a stress-inducible cell surface antigen that is recognized by intestinal epithelial Vδ1 γδ T cells, natural killer (NK) cells and CD8+ T cells with NKG2D receptor participating in the immunological reaction in the intestinal mucosa. The present study aimed to investigate the functions of the MICA*A5.1 allele in the development of ulcerative colitis (UC) in the Chinese population. The microsatellite polymorphisms of MICA were genotyped in 124 unrelated Chinese patients with UC and 172 ethnically matched healthy controls using a semiautomatic fluorescently labelled polymerase chain reaction. MICA*A5.1-expressing Raji cells were generated by gene transfection. Cytotoxicity of NK cells to Raji cells expressing different MICA molecules was detected using the lactate dehydrogenase method. Soluble MICA in the culture supernatant was detected by enzyme-linked immunosorbent assay. The frequency of MICA*A5.1 was significantly higher in UC patients compared with the healthy controls (29·0% versus 17·4%, P= 0·001, corrected P= 0·005, OR = 1·936, 95% CI 1·310–2·863) and the frequency of a MICA*A5.1/A5.1 homozygous genotype was increased in UC patients (18·5% versus 7% in healthy controls, P= 0·0032, corrected P= 0·048, OR = 3·036, 95% CI 1·447–6·372). Raji cells with MICA*A5.1 expression produced more soluble MICA (t = 5·75, P < 0·01) than Raji cells with full-length MICA expression in culture supernatant. Raji cells with MICA*A5.1 expression were more resistant to killing by NK cells than Raji cells with full-length MICA expression. The MICA*A5.1 allele and MICA*A5.1/A5.1 genotype are significantly associated with Chinese UC patients in central China. MICA*A5.1 may play a role in the development of UC by producing more soluble MICA and resistance to NK cells. PMID:19016911

  16. MicroRNA-21a-5p Functions on the Regulation of Melanogenesis by Targeting Sox5 in Mouse Skin Melanocytes.

    PubMed

    Wang, Pengchao; Zhao, Yuanyuan; Fan, Ruiwen; Chen, Tianzhi; Dong, Changsheng

    2016-01-01

    MicroRNAs (miRNAs) play an important role in regulating almost all biological processes. miRNAs bind to the 3' untranslated region (UTR) of mRNAs by sequence matching. In a previous study, we demonstrated that miR-21 was differently expressed in alpaca skin with different hair color. However, the molecular and cellular mechanisms for miR-21 to regulate the coat color are not yet completely understood. In this study, we transfected miR-21a-5p into mouse melanocytes and demonstrated its function on melanogenesis of miR-21a-5p by targeting Sox5, which inhibits melanogenesis in mouse melanocytes. The results suggested that miR-21a-5p targeted Sox5 gene based on the binding site in 3' UTR of Sox5 and overexpression of miR-21a-5p significantly down-regulated Sox5 mRNA and protein expression. Meanwhile, mRNA and protein expression of microphthalmia transcription factor (MITF) and Tyrosinase (TYR) were up-regulated, which subsequently make the melanin production in melanocytes increased. The results suggest that miR-21a-5p regulates melanogenesis via MITF by targeting Sox5. PMID:27347933

  17. MicroRNA-21a-5p Functions on the Regulation of Melanogenesis by Targeting Sox5 in Mouse Skin Melanocytes

    PubMed Central

    Wang, Pengchao; Zhao, Yuanyuan; Fan, Ruiwen; Chen, Tianzhi; Dong, Changsheng

    2016-01-01

    MicroRNAs (miRNAs) play an important role in regulating almost all biological processes. miRNAs bind to the 3′ untranslated region (UTR) of mRNAs by sequence matching. In a previous study, we demonstrated that miR-21 was differently expressed in alpaca skin with different hair color. However, the molecular and cellular mechanisms for miR-21 to regulate the coat color are not yet completely understood. In this study, we transfected miR-21a-5p into mouse melanocytes and demonstrated its function on melanogenesis of miR-21a-5p by targeting Sox5, which inhibits melanogenesis in mouse melanocytes. The results suggested that miR-21a-5p targeted Sox5 gene based on the binding site in 3′ UTR of Sox5 and overexpression of miR-21a-5p significantly down-regulated Sox5 mRNA and protein expression. Meanwhile, mRNA and protein expression of microphthalmia transcription factor (MITF) and Tyrosinase (TYR) were up-regulated, which subsequently make the melanin production in melanocytes increased. The results suggest that miR-21a-5p regulates melanogenesis via MITF by targeting Sox5. PMID:27347933

  18. Autism and Genes

    ERIC Educational Resources Information Center

    National Institutes of Health, 2005

    2005-01-01

    This document defines and discusses autism and how genes play a role in the condition. Answers to the following questions are covered: (1) What are genes? (2) What is autism? (3) What causes autism? (4) Why study genes to learn about autism? (5) How do researchers look for the genes involved in autism? (screen the whole genome; conduct cytogenetic…

  19. Compare Gene Profiles

    2014-05-31

    Compare Gene Profiles (CGP) performs pairwise gene content comparisons among a relatively large set of related bacterial genomes. CGP performs pairwise BLAST among gene calls from a set of input genome and associated annotation files, and combines the results to generate lists of common genes, unique genes, homologs, and genes from each genome that differ substantially in length from corresponding genes in the other genomes. CGP is implemented in Python and runs in a Linuxmore » environment in serial or parallel mode.« less

  20. neXtA5: accelerating annotation of articles via automated approaches in neXtProt

    PubMed Central

    Mottin, Luc; Gobeill, Julien; Pasche, Emilie; Michel, Pierre-André; Cusin, Isabelle; Gaudet, Pascale; Ruch, Patrick

    2016-01-01

    The rapid increase in the number of published articles poses a challenge for curated databases to remain up-to-date. To help the scientific community and database curators deal with this issue, we have developed an application, neXtA5, which prioritizes the literature for specific curation requirements. Our system, neXtA5, is a curation service composed of three main elements. The first component is a named-entity recognition module, which annotates MEDLINE over some predefined axes. This report focuses on three axes: Diseases, the Molecular Function and Biological Process sub-ontologies of the Gene Ontology (GO). The automatic annotations are then stored in a local database, BioMed, for each annotation axis. Additional entities such as species and chemical compounds are also identified. The second component is an existing search engine, which retrieves the most relevant MEDLINE records for any given query. The third component uses the content of BioMed to generate an axis-specific ranking, which takes into account the density of named-entities as stored in the Biomed database. The two ranked lists are ultimately merged using a linear combination, which has been specifically tuned to support the annotation of each axis. The fine-tuning of the coefficients is formally reported for each axis-driven search. Compared with PubMed, which is the system used by most curators, the improvement is the following: +231% for Diseases, +236% for Molecular Functions and +3153% for Biological Process when measuring the precision of the top-returned PMID (P0 or mean reciprocal rank). The current search methods significantly improve the search effectiveness of curators for three important curation axes. Further experiments are being performed to extend the curation types, in particular protein–protein interactions, which require specific relationship extraction capabilities. In parallel, user-friendly interfaces powered with a set of JSON web services are currently being

  1. neXtA5: accelerating annotation of articles via automated approaches in neXtProt.

    PubMed

    Mottin, Luc; Gobeill, Julien; Pasche, Emilie; Michel, Pierre-André; Cusin, Isabelle; Gaudet, Pascale; Ruch, Patrick

    2016-01-01

    The rapid increase in the number of published articles poses a challenge for curated databases to remain up-to-date. To help the scientific community and database curators deal with this issue, we have developed an application, neXtA5, which prioritizes the literature for specific curation requirements. Our system, neXtA5, is a curation service composed of three main elements. The first component is a named-entity recognition module, which annotates MEDLINE over some predefined axes. This report focuses on three axes: Diseases, the Molecular Function and Biological Process sub-ontologies of the Gene Ontology (GO). The automatic annotations are then stored in a local database, BioMed, for each annotation axis. Additional entities such as species and chemical compounds are also identified. The second component is an existing search engine, which retrieves the most relevant MEDLINE records for any given query. The third component uses the content of BioMed to generate an axis-specific ranking, which takes into account the density of named-entities as stored in the Biomed database. The two ranked lists are ultimately merged using a linear combination, which has been specifically tuned to support the annotation of each axis. The fine-tuning of the coefficients is formally reported for each axis-driven search. Compared with PubMed, which is the system used by most curators, the improvement is the following: +231% for Diseases, +236% for Molecular Functions and +3153% for Biological Process when measuring the precision of the top-returned PMID (P0 or mean reciprocal rank). The current search methods significantly improve the search effectiveness of curators for three important curation axes. Further experiments are being performed to extend the curation types, in particular protein-protein interactions, which require specific relationship extraction capabilities. In parallel, user-friendly interfaces powered with a set of JSON web services are currently being

  2. miR-146a-5p inhibits TNF-α-induced adipogenesis via targeting insulin receptor in primary porcine adipocytes[S

    PubMed Central

    Wu, Di; Xi, Qian-Yun; Cheng, Xiao; Dong, Tao; Zhu, Xiao-Tong; Shu, Gang; Wang, Li-Na; Jiang, Qing-Yan; Zhang, Yong-Liang

    2016-01-01

    TNF-α is a multifunctional cytokine participating in immune disorders, inflammation, and tumor development with regulatory effects on energy metabolism. Our work focused on the function of TNF-α in adipogenesis of primary porcine adipocytes. TNF-α could suppress the insulin receptor (IR) at the mRNA and protein levels. Microarray analysis of TNF-α-treated porcine adipocytes was used to screen out 29 differentially expressed microRNAs (miRNAs), 13 of which were remarkably upregulated and 16 were intensely downregulated. These 29 differentially expressed miRNAs were predicted to mainly participate in the insulin signaling pathway, adipocytokine signaling pathway, and type 2 diabetes mellitus pathway by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. miR-146a-5p, reportedly involved in immunity and cancer relevant processes, was one of the most highly differentially expressed miRNAs after TNF-α treatment. Red Oil O staining and TG assay revealed that miR-146a-5p suppressed adipogenesis. A dual-luciferase reporter and siRNA assay verified that miR-146a-5p targeted IR and could inhibit its protein expression. miR-146a-5p was also validated to be involved in the insulin signaling pathway by reducing tyrosine phosphorylation of insulin receptor substrate-1. Our study provides the first evidence of miR-146a-5p targeting IR, which facilitates future studies related to obesity and diabetes using pig models. PMID:27324794

  3. miR-146a-5p inhibits TNF-α-induced adipogenesis via targeting insulin receptor in primary porcine adipocytes.

    PubMed

    Wu, Di; Xi, Qian-Yun; Cheng, Xiao; Dong, Tao; Zhu, Xiao-Tong; Shu, Gang; Wang, Li-Na; Jiang, Qing-Yan; Zhang, Yong-Liang

    2016-08-01

    TNF-α is a multifunctional cytokine participating in immune disorders, inflammation, and tumor development with regulatory effects on energy metabolism. Our work focused on the function of TNF-α in adipogenesis of primary porcine adipocytes. TNF-α could suppress the insulin receptor (IR) at the mRNA and protein levels. Microarray analysis of TNF-α-treated porcine adipocytes was used to screen out 29 differentially expressed microRNAs (miRNAs), 13 of which were remarkably upregulated and 16 were intensely downregulated. These 29 differentially expressed miRNAs were predicted to mainly participate in the insulin signaling pathway, adipocytokine signaling pathway, and type 2 diabetes mellitus pathway by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. miR-146a-5p, reportedly involved in immunity and cancer relevant processes, was one of the most highly differentially expressed miRNAs after TNF-α treatment. Red Oil O staining and TG assay revealed that miR-146a-5p suppressed adipogenesis. A dual-luciferase reporter and siRNA assay verified that miR-146a-5p targeted IR and could inhibit its protein expression. miR-146a-5p was also validated to be involved in the insulin signaling pathway by reducing tyrosine phosphorylation of insulin receptor substrate-1. Our study provides the first evidence of miR-146a-5p targeting IR, which facilitates future studies related to obesity and diabetes using pig models. PMID:27324794

  4. Microrna-199a-5p Functions as a Tumor Suppressor via Suppressing Connective Tissue Growth Factor (CTGF) in Follicular Thyroid Carcinoma

    PubMed Central

    Sun, Dawei; Han, Shen; Liu, Chao; Zhou, Rui; Sun, Weihai; Zhang, Zhijun; Qu, Jianjun

    2016-01-01

    Background The objective of this study was to explore the role of miR-199a-5p in the development of thyroid cancer, including its anti-proliferation effect and downstream signaling pathway. Material/Methods We conducted qRT-PCR analysis to detect the expressions of several microRNAs in 42 follicular thyroid carcinoma patients and 42 controls. We identified CTGF as target of miR-491, and viability and cell cycle status were determined in FTC-133 cells transfected with CTGF siRNA, miR-199a mimics, or inhibitors. Results We identified an underexpression of miR-199a-5p in follicular thyroid carcinoma tissue samples compared with controls. Then we confirmed CTGF as a target of miR-199a-5p thyroid cells by using informatics analysis and luciferase reporter assay. Additionally, we found that mRNA and protein expression levels of CTGF were both clearly higher in malignant tissues than in benign tissues. miR-199a-5p mimics and CTGF siRNA similarly downregulated the expression of CTGF, and reduced the viability of FTC-133 cells by arresting the cell cycle in G0 phase. Transfection of miR-199a-5p inhibitors increased the expression of CTGF and promoted the viability of the cells by increasing the fraction of cells in G2/M and S phases. Conclusions Our study proves that the CTGF gene is a target of miR-199a-5p, demonstrating the negatively related association between CTGF and miR-199a. These findings suggest that miR-199a-5p might be a novel therapeutic target in the treatment of follicular thyroid carcinoma. PMID:27062921

  5. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing

    PubMed Central

    Birdwell, Kelly A.; Decker, Brian; Barbarino, Julia M.; Peterson, Josh F.; Stein, C. Michael; Sadee, Wolfgang; Wang, Danxin; Vinks, Alexander A.; He, Yijing; Swen, Jesse J.; Leeder, J. Steven; van Schaik, RHN; Thummel, Kenneth E.; Klein, Teri E.; Caudle, Kelly E.; MacPhee, Iain A.M.

    2015-01-01

    Tacrolimus is the mainstay immunosuppressant drug used after solid organ and hematopoietic stem cell transplantation. Individuals who express CYP3A5 (extensive and intermediate metabolizers) generally have decreased dose-adjusted trough concentrations of tacrolimus as compared to those who are CYP3A5 non-expressers (poor metabolizers), possibly delaying achievement of target blood concentrations. We summarize evidence from the published literature supporting this association and provide dosing recommendations for tacrolimus based on CYP3A5 genotype when known (updates at www.pharmgkb.org). PMID:25801146

  6. Long non-coding RNA XIST exerts oncogenic functions in human nasopharyngeal carcinoma by targeting miR-34a-5p.

    PubMed

    Song, Peng; Ye, Lin-Feng; Zhang, Cen; Peng, Tao; Zhou, Xu-Hong

    2016-10-30

    Long non-coding RNA (lncRNA) X inactivate-specific transcript (XIST) has been verified as an oncogenic gene in several human malignant tumors, and its dysregulation was closed associated with tumor initiation, development and progression. Nevertheless, whether the aberrant expression of XIST in human nasopharyngeal carcinoma (NPC) is corrected with malignancy, metastasis or prognosis has not been elaborated. Here, we discovered that XIST was up-regulated in NPC tissues and higher expression of XIST contributed to a markedly poorer survival time. In addition, multivariate analysis demonstrated XIST was an independent risk factor for prognosis. XIST over-expression enhanced, while XIST silencing hampered the cell growth in NPC. Additionally, mechanistic analysis revealed that XIST up-regulated the expression of miR-34a-5p targeted gene E2F3 through acting as a competitive 'sponge' of miR-34a-5p. Taking all into account, we concluded that XIST functioned as an oncogene in NPC through up-regulating E2F3 in part through 'spongeing' miR-34a-5p. PMID:27461945

  7. Mutations in SLC13A5 Cause Autosomal-Recessive Epileptic Encephalopathy with Seizure Onset in the First Days of Life

    PubMed Central

    Thevenon, Julien; Milh, Mathieu; Feillet, François; St-Onge, Judith; Duffourd, Yannis; Jugé, Clara; Roubertie, Agathe; Héron, Delphine; Mignot, Cyril; Raffo, Emmanuel; Isidor, Bertrand; Wahlen, Sandra; Sanlaville, Damien; Villeneuve, Nathalie; Darmency-Stamboul, Véronique; Toutain, Annick; Lefebvre, Mathilde; Chouchane, Mondher; Huet, Frédéric; Lafon, Arnaud; de Saint Martin, Anne; Lesca, Gaetan; El Chehadeh, Salima; Thauvin-Robinet, Christel; Masurel-Paulet, Alice; Odent, Sylvie; Villard, Laurent; Philippe, Christophe; Faivre, Laurence; Rivière, Jean-Baptiste

    2014-01-01

    Epileptic encephalopathy (EE) refers to a clinically and genetically heterogeneous group of severe disorders characterized by seizures, abnormal interictal electro-encephalogram, psychomotor delay, and/or cognitive deterioration. We ascertained two multiplex families (including one consanguineous family) consistent with an autosomal-recessive inheritance pattern of EE. All seven affected individuals developed subclinical seizures as early as the first day of life, severe epileptic disease, and profound developmental delay with no facial dysmorphism. Given the similarity in clinical presentation in the two families, we hypothesized that the observed phenotype was due to mutations in the same gene, and we performed exome sequencing in three affected individuals. Analysis of rare variants in genes consistent with an autosomal-recessive mode of inheritance led to identification of mutations in SLC13A5, which encodes the cytoplasmic sodium-dependent citrate carrier, notably expressed in neurons. Disease association was confirmed by cosegregation analysis in additional family members. Screening of 68 additional unrelated individuals with early-onset epileptic encephalopathy for SLC13A5 mutations led to identification of one additional subject with compound heterozygous mutations of SLC13A5 and a similar clinical presentation as the index subjects. Mutations affected key residues for sodium binding, which is critical for citrate transport. These findings underline the value of careful clinical characterization for genetic investigations in highly heterogeneous conditions such as EE and further highlight the role of citrate metabolism in epilepsy. PMID:24995870

  8. Mutations in SLC13A5 cause autosomal-recessive epileptic encephalopathy with seizure onset in the first days of life.

    PubMed

    Thevenon, Julien; Milh, Mathieu; Feillet, François; St-Onge, Judith; Duffourd, Yannis; Jugé, Clara; Roubertie, Agathe; Héron, Delphine; Mignot, Cyril; Raffo, Emmanuel; Isidor, Bertrand; Wahlen, Sandra; Sanlaville, Damien; Villeneuve, Nathalie; Darmency-Stamboul, Véronique; Toutain, Annick; Lefebvre, Mathilde; Chouchane, Mondher; Huet, Frédéric; Lafon, Arnaud; de Saint Martin, Anne; Lesca, Gaetan; El Chehadeh, Salima; Thauvin-Robinet, Christel; Masurel-Paulet, Alice; Odent, Sylvie; Villard, Laurent; Philippe, Christophe; Faivre, Laurence; Rivière, Jean-Baptiste

    2014-07-01

    Epileptic encephalopathy (EE) refers to a clinically and genetically heterogeneous group of severe disorders characterized by seizures, abnormal interictal electro-encephalogram, psychomotor delay, and/or cognitive deterioration. We ascertained two multiplex families (including one consanguineous family) consistent with an autosomal-recessive inheritance pattern of EE. All seven affected individuals developed subclinical seizures as early as the first day of life, severe epileptic disease, and profound developmental delay with no facial dysmorphism. Given the similarity in clinical presentation in the two families, we hypothesized that the observed phenotype was due to mutations in the same gene, and we performed exome sequencing in three affected individuals. Analysis of rare variants in genes consistent with an autosomal-recessive mode of inheritance led to identification of mutations in SLC13A5, which encodes the cytoplasmic sodium-dependent citrate carrier, notably expressed in neurons. Disease association was confirmed by cosegregation analysis in additional family members. Screening of 68 additional unrelated individuals with early-onset epileptic encephalopathy for SLC13A5 mutations led to identification of one additional subject with compound heterozygous mutations of SLC13A5 and a similar clinical presentation as the index subjects. Mutations affected key residues for sodium binding, which is critical for citrate transport. These findings underline the value of careful clinical characterization for genetic investigations in highly heterogeneous conditions such as EE and further highlight the role of citrate metabolism in epilepsy.

  9. 10. NAVFAC Drawing 6101591 (814A5) (1978), 'Various Repairs to Building ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    10. NAVFAC Drawing 6101591 (814-A-5) (1978), 'Various Repairs to Building 814, Sections and Miscellaneous Details' - Mare Island Naval Shipyard, Chemical Cleaning Facility, North of Fourteenth Street, between California & Railroad Avenue, Vallejo, Solano County, CA

  10. Isolation of Copper from a 5-Cent Coin: An Example of Electrorefining

    ERIC Educational Resources Information Center

    Sogo, Steven G.

    2004-01-01

    Copper is isolated from a 5-cent coin with the help of electrolysis. This experiment is useful for conceptual understanding of the significance of reduction potentials in situation of competition for electrons.

  11. 26 CFR 1.401(a)(5)-1 - Special rules relating to nondiscrimination requirements.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... section 401(a)(5) by section 1111(b) of the Tax Reform Act of 1986 (TRA '86) apply, a plan must be... account pre-existing guidance and the amendments made by TRA '86 to related provisions of the...

  12. 26 CFR 1.401(a)(5)-1 - Special rules relating to nondiscrimination requirements.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... section 401(a)(5) by section 1111(b) of the Tax Reform Act of 1986 (TRA '86) apply, a plan must be... account pre-existing guidance and the amendments made by TRA '86 to related provisions of the...

  13. 26 CFR 1.401(a)(5)-1 - Special rules relating to nondiscrimination requirements.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... section 401(a)(5) by section 1111(b) of the Tax Reform Act of 1986 (TRA '86) apply, a plan must be... account pre-existing guidance and the amendments made by TRA '86 to related provisions of the...

  14. 26 CFR 1.401(a)(5)-1 - Special rules relating to nondiscrimination requirements.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... section 401(a)(5) by section 1111(b) of the Tax Reform Act of 1986 (TRA '86) apply, a plan must be... account pre-existing guidance and the amendments made by TRA '86 to related provisions of the...

  15. Receptor Tyrosine Kinase EphA5 Is a Functional Molecular Target in Human Lung Cancer*

    PubMed Central

    Staquicini, Fernanda I.; Qian, Ming D.; Salameh, Ahmad; Dobroff, Andrey S.; Edwards, Julianna K.; Cimino, Daniel F.; Moeller, Benjamin J.; Kelly, Patrick; Nunez, Maria I.; Tang, Ximing; Liu, Diane D.; Lee, J. Jack; Hong, Waun Ki; Ferrara, Fortunato; Bradbury, Andrew R. M.; Lobb, Roy R.; Edelman, Martin J.; Sidman, Richard L.; Wistuba, Ignacio I.; Arap, Wadih; Pasqualini, Renata

    2015-01-01

    Lung cancer is often refractory to radiotherapy, but molecular mechanisms of tumor resistance remain poorly defined. Here we show that the receptor tyrosine kinase EphA5 is specifically overexpressed in lung cancer and is involved in regulating cellular responses to genotoxic insult. In the absence of EphA5, lung cancer cells displayed a defective G1/S cell cycle checkpoint, were unable to resolve DNA damage, and became radiosensitive. Upon irradiation, EphA5 was transported into the nucleus where it interacted with activated ATM (ataxia-telangiectasia mutated) at sites of DNA repair. Finally, we demonstrate that a new monoclonal antibody against human EphA5 sensitized lung cancer cells and human lung cancer xenografts to radiotherapy and significantly prolonged survival, thus suggesting the likelihood of translational applications. PMID:25623065

  16. Receptor tyrosine kinase EphA5 is a functional molecular target in human lung cancer

    SciTech Connect

    Staquicini, Fernanda I.; Qian, Ming D.; Salameh, Ahmad; Dobroff, Andrey S.; Edwards, Julianna K.; Cimino, Daniel F.; Moeller, Benjamin J.; Kelly, Patrick; Nunez, Maria I.; Tang, Ximing; Liu, Diane D.; Lee, J. Jack; Hong, Waun Ki; Ferrara, Fortunato; Bradbury, Andrew R. M.; Lobb, Roy R.; Edelman, Martin J.; Sidman, Richard L.; Wistuba, Ignacio I.; Arap, Wadih; Pasqualini, Renata

    2015-03-20

    Lung cancer is often refractory to radiotherapy, but molecular mechanisms of tumor resistance remain poorly defined. Here we show that the receptor tyrosine kinase EphA5 is specifically overexpressed in lung cancer and is involved in regulating cellular responses to genotoxic insult. In the absence of EphA5, lung cancer cells displayed a defective G1/S cell cycle checkpoint, were unable to resolve DNA damage, and became radiosensitive. Upon irradiation, EphA5 was transported into the nucleus where it interacted with activated ATM (ataxia-telangiectasia mutated) at sites of DNA repair. In conclusion, we demonstrate that a new monoclonal antibody against human EphA5 sensitized lung cancer cells and human lung cancer xenografts to radiotherapy and significantly prolonged survival, thus suggesting the likelihood of translational applications.

  17. Receptor tyrosine kinase EphA5 is a functional molecular target in human lung cancer

    DOE PAGES

    Staquicini, Fernanda I.; Qian, Ming D.; Salameh, Ahmad; Dobroff, Andrey S.; Edwards, Julianna K.; Cimino, Daniel F.; Moeller, Benjamin J.; Kelly, Patrick; Nunez, Maria I.; Tang, Ximing; et al

    2015-03-20

    Lung cancer is often refractory to radiotherapy, but molecular mechanisms of tumor resistance remain poorly defined. Here we show that the receptor tyrosine kinase EphA5 is specifically overexpressed in lung cancer and is involved in regulating cellular responses to genotoxic insult. In the absence of EphA5, lung cancer cells displayed a defective G1/S cell cycle checkpoint, were unable to resolve DNA damage, and became radiosensitive. Upon irradiation, EphA5 was transported into the nucleus where it interacted with activated ATM (ataxia-telangiectasia mutated) at sites of DNA repair. In conclusion, we demonstrate that a new monoclonal antibody against human EphA5 sensitized lungmore » cancer cells and human lung cancer xenografts to radiotherapy and significantly prolonged survival, thus suggesting the likelihood of translational applications.« less

  18. [Local injection of bleomycin A 5 in children with hemangiomas. Analysis of 210 cases].

    PubMed

    Zheng, Q T

    1991-05-01

    210 children with hemangiomas were treated by local injection of Bleomycin A5. Bleomycin A5 was effective in all patients with strawberry and mixed hemangiomas, 91.2% of patients with cavernous hemangiomas, 44.4% of patients with port-wine stain. There was no response in pampiniform hemangioma. The therapeutic mechanism, indications and complications of the new method for treatment of hemangioma are discussed. PMID:1717207

  19. 26 CFR 1.613A-5 - Election under section 613A(c)(4).

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 7 2011-04-01 2009-04-01 true Election under section 613A(c)(4). 1.613A-5... TAX (CONTINUED) INCOME TAXES (CONTINUED) Natural Resources § 1.613A-5 Election under section 613A(c)(4). The election under section 613A(c)(4) is an annual election which the taxpayer may make by...

  20. 26 CFR 48.4161(a)-5 - Tax-free sales.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 16 2013-04-01 2013-04-01 false Tax-free sales. 48.4161(a)-5 Section 48.4161(a... EXCISE TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Sporting Goods § 48.4161(a)-5 Tax-free sales. For provisions relating to the tax-free sales of articles referred to in section 4161(a) see: (a) Section...

  1. 26 CFR 48.4161(a)-5 - Tax-free sales.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 16 2012-04-01 2012-04-01 false Tax-free sales. 48.4161(a)-5 Section 48.4161(a... EXCISE TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Sporting Goods § 48.4161(a)-5 Tax-free sales. For provisions relating to the tax-free sales of articles referred to in section 4161(a) see: (a) Section...

  2. 26 CFR 48.4161(a)-5 - Tax-free sales.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 16 2011-04-01 2011-04-01 false Tax-free sales. 48.4161(a)-5 Section 48.4161(a... EXCISE TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Sporting Goods § 48.4161(a)-5 Tax-free sales. For provisions relating to the tax-free sales of articles referred to in section 4161(a) see: (a) Section...

  3. 26 CFR 48.4161(a)-5 - Tax-free sales.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 16 2010-04-01 2010-04-01 true Tax-free sales. 48.4161(a)-5 Section 48.4161(a... EXCISE TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Sporting Goods § 48.4161(a)-5 Tax-free sales. For provisions relating to the tax-free sales of articles referred to in section 4161(a) see: (a) Section...

  4. Post-Heparin LPL Activity Measurement Using VLDL As a Substrate: A New Robust Method for Routine Assessment of Plasma Triglyceride Lipolysis Defects

    PubMed Central

    Di Filippo, Mathilde; Marçais, Christophe; Charrière, Sybil; Marmontel, Oriane; Broyer, Martine; Delay, Mireille; Merlin, Micheline; Nollace, Axel; Valéro, René; Lagarde, Michel; Pruneta-Deloche, Valérie; Moulin, Philippe; Sassolas, Agnès

    2014-01-01

    Background Determination of lipoprotein lipase (LPL) activity is important for hyperchylomicronemia diagnosis, but remains both unreliable and cumbersome with current methods. Consequently by using human VLDL as substrate we developed a new LPL assay which does not require sonication, radioactive or fluorescent particles. Methods Post-heparin plasma was added to the VLDL substrate prepared by ultracentrifugation of heat inactivated normolipidemic human serums, diluted in buffer, pH 8.15. Following incubation at 37°c, the NEFA (non esterified fatty acids) produced were assayed hourly for 4 hours. LPL activity was expressed as µmol/l/min after subtraction of hepatic lipase (HL) activity, obtained following LPL inhibition with NaCl 1.5 mmol/l. Molecular analysis of LPL, GPIHBP1, APOA5, APOC2, APOE genes was available for 62 patients. Results Our method was reproducible (coefficient of variation (CV): intra-assay 5.6%, inter-assay 7.1%), and tightly correlated with the conventional radiolabelled triolein emulsion method (n = 26, r = 0.88). Normal values were established at 34.8±12.8 µmol/l/min (mean±SD) from 20 control subjects. LPL activities obtained from 71 patients with documented history of major hypertriglyceridemia showed a trimodal distribution. Among the 11 patients with a very low LPL activity (<10 µmol/l/min), 5 were homozygous or compound heterozygous for LPL or GPIHBP1 deleterious mutations, 3 were compound heterozygous for APOA5 deleterious mutations and the p.S19W APOA5 susceptibility variant, and 2 were free of any mutations in the usual candidate genes. No homozygous gene alteration in LPL, GPIHBP1 and APOC2 genes was found in any of the patients with LPL activity >10 µmol/l/min. Conclusion This new reproducible method is a valuable tool for routine diagnosis and reliably identifies LPL activity defects. PMID:24788417

  5. A p53-dependent tumor suppressor network is induced by selective miR-125a-5p inhibition in multiple myeloma cells.

    PubMed

    Leotta, Marzia; Biamonte, Lavinia; Raimondi, Lavinia; Ronchetti, Domenica; Di Martino, Maria Teresa; Botta, Cirino; Leone, Emanuela; Pitari, Maria Rita; Neri, Antonino; Giordano, Antonio; Tagliaferri, Pierosandro; Tassone, Pierfrancesco; Amodio, Nicola

    2014-12-01

    The analysis of deregulated microRNAs (miRNAs) is emerging as a novel approach to disclose the regulation of tumor suppressor or tumor promoting pathways in tumor cells. Targeting aberrantly expressed miRNAs is therefore a promising strategy for cancer treatment. By miRNA profiling of primary plasma cells from multiple myeloma (MM) patients, we previously reported increased miR-125a-5p levels associated to specific molecular subgroups. On these premises, we aimed at investigating the biological effects triggered by miR-125a-5p modulation in MM cells. Expression of p53 pathway-related genes was down-regulated in MM cells transfected with miR-125a-5p mimics. Luciferase reporter assays confirmed specific p53 targeting at 3'UTR level by miR-125a-5p mimics. Interestingly, bone marrow stromal cells (BMSCs) affected the miR-125a-5p/p53 axis, since adhesion of MM cells to BMSCs strongly up-regulated miR-125a-5p levels, while reduced p53 expression. Moreover, ectopic miR-125a-5p reduced, while miR-125-5p inhibitors promoted, the expression of tumor suppressor miR-192 and miR-194, transcriptionally regulated by p53. Lentiviral-mediated stable inhibition of miR-125a-5p expression in wild-type p53 MM cells dampened cell growth, increased apoptosis and reduced cell migration. Importantly, inhibition of in vitro MM cell proliferation and migration was also achieved by synthetic miR-125a-5p inhibitors and was potentiated by the co-expression of miR-192 or miR-194. Taken together, our data indicate that miR-125a-5p antagonism results in the activation of p53 pathway in MM cells, underlying the crucial role of this miRNA in the biopathology of MM and providing the molecular rationale for the combinatory use of miR-125a inhibitors and miR-192 or miR-194 mimics for MM treatment. PMID:24819167

  6. Ephrin-A5 regulates inter-male aggression in mice.

    PubMed

    Sheleg, Michal; Yochum, Carrie L; Richardson, Jason R; Wagner, George C; Zhou, Renping

    2015-06-01

    The Eph family of receptor tyrosine kinases play key roles in both the patterning of the developing nervous system and neural plasticity in the mature brain. To determine functions of ephrin-A5, a GPI-linked ligand to the Eph receptors, in animal behavior regulations, we examined effects of its inactivation on male mouse aggression. When tested in the resident-intruder paradigm for offensive aggression, ephrin-A5-mutant animals (ephrin-A5(-/-)) exhibited severe reduction in conspecific aggression compared to wild-type controls. On the contrary, defensive aggression in the form of target biting was higher in ephrin-A5(-/-) mice, indicating that the mutant mice are capable of attacking behavior. In addition, given the critical role of olfaction in aggressive behavior, we examined the ability of the ephrin-A5(-/-) mice to smell and found no differences between the mutant and control animals. Testosterone levels in the mutant mice were also found to be within the normal range. Taken together, our data reveal a new role of ephrin-A5 in the regulation of aggressive behavior in mice.

  7. [Genes associated to cancer].

    PubMed

    Peralta-Rodríguez, Raúl; Valdivia, Alejandra; Mendoza, Mónica; Rodríguez, Jade; Marrero, Daniel; Paniagua, Lucero; Romero, Pablo; Taniguchi, Keiko; Salcedo, Mauricio

    2015-01-01

    In 2010, in a cancer genes census, 291 genes were enumerated. These represent near to the 1 % of the total genes, for which there is enough biological evidence that they belong to a new genes classification, known as the cancer genes. These have been defined as the causal genes for sporadic or familiar cancer, when they mutate. The mutation types for these genes includes amplifications, point mutations, deletions, genomic rearranges, amongst others, which lead to a protein over-expression, muting, production of chimeric proteins or a de novo expression. In conjunction these genomic alterations or those of the genetic expression, when they affect specific genes which contribute to the development of cancer, are denominated as cancer genes. It is possible that the list of these alterations will grow longer due to new strategies being developed, for example, the genomic analysis.

  8. Gene doping in sports.

    PubMed

    Unal, Mehmet; Ozer Unal, Durisehvar

    2004-01-01

    Gene or cell doping is defined by the World Anti-Doping Agency (WADA) as "the non-therapeutic use of genes, genetic elements and/or cells that have the capacity to enhance athletic performance". New research in genetics and genomics will be used not only to diagnose and treat disease, but also to attempt to enhance human performance. In recent years, gene therapy has shown progress and positive results that have highlighted the potential misuse of this technology and the debate of 'gene doping'. Gene therapies developed for the treatment of diseases such as anaemia (the gene for erythropoietin), muscular dystrophy (the gene for insulin-like growth factor-1) and peripheral vascular diseases (the gene for vascular endothelial growth factor) are potential doping methods. With progress in gene technology, many other genes with this potential will be discovered. For this reason, it is important to develop timely legal regulations and to research the field of gene doping in order to develop methods of detection. To protect the health of athletes and to ensure equal competitive conditions, the International Olympic Committee, WADA and International Sports Federations have accepted performance-enhancing substances and methods as being doping, and have forbidden them. Nevertheless, the desire to win causes athletes to misuse these drugs and methods. This paper reviews the current status of gene doping and candidate performance enhancement genes, and also the use of gene therapy in sports medicine and ethics of genetic enhancement.

  9. Human Gene Therapy: Genes without Frontiers?

    ERIC Educational Resources Information Center

    Simon, Eric J.

    2002-01-01

    Describes the latest advancements and setbacks in human gene therapy to provide reference material for biology teachers to use in their science classes. Focuses on basic concepts such as recombinant DNA technology, and provides examples of human gene therapy such as severe combined immunodeficiency syndrome, familial hypercholesterolemia, and…

  10. Improved innate immune responses by Frondanol A5, a sea cucumber extract, prevent intestinal tumorigenesis.

    PubMed

    Janakiram, Naveena B; Mohammed, Altaf; Bryant, Taylor; Lightfoot, Stan; Collin, Peter D; Steele, Vernon E; Rao, Chinthalapally V

    2015-04-01

    Sea cucumbers are a source of antibacterial, anti-inflammatory, and anticancer compounds. We show that sea cucumber extract Frondanol A5 is capable of enhancing innate immune responses and inhibiting intestinal tumors in APC(Min/+) mice. APC(Min/+) mice were fed semi-purified diets containing 0, 250, or 500 ppm FrondanolA5 for 14 weeks before we assessed intestinal tumor inhibition. Dietary Frondanol A5 suppressed small intestinal polyp sizes and formation up to 30% (P < 0.02) in males and up to 50% (P < 0.01) in females. Importantly, 250 and 500 ppm Frondanol A5 diet suppressed colon tumor multiplicities by 65% (P < 0.007) and 75% (P < 0.0001), compared with untreated male APC(Min/+) mice. In female APC(Min/+) mice, both dose levels of Frondanol A5 suppressed colon tumor multiplicities up to 80% (P < 0.0001). Isolated peritoneal macrophages from treated mice showed increased phagocytosis efficiency (control 24% vs. treated 50%; P < 0.01) and an increase in GILT mRNA expression, indicating increased innate immune responses by these cells in treated animals. Similarly, we observed an increase in GILT expression in treated tumors, compared with untreated tumors. Furthermore, an increase in G-CSF cytokine, a decrease in inflammatory cytokines and marker 5-LOX, its regulator FLAP, proliferation (PCNA), and angiogenesis (VEGF) markers were observed in treatment groups. These data suggest that Frondanol A5 decreased inflammatory angiogenic molecules and increased GILT expression and macrophage phagocytosis. These decreases may have improved the innate immune systems of the treated mice, thus aiding in inhibition of intestinal tumor formation. These results suggest that Frondanol A5 exhibits significant chemopreventive potential against intestinal tumorigenesis. PMID:25657017

  11. Changes in attack behavior and activity in EphA5 knockout mice.

    PubMed

    Mamiya, Ping Chao; Hennesy, Zach; Zhou, Renping; Wagner, George C

    2008-04-18

    During development, Eph tyrosine kinase receptors and their ephrin ligands function as axon guidance molecules while, in adults, these molecules appear to be involved in the regulation of neural plasticity and emotion. The absence of EphA5 receptor mediated forward signaling may cause alterations in connectivity of neural networks and boundary formation during development, including central monoaminergic systems. In the present studies, we demonstrated altered aggressive responses by animals lacking functional EphA5 receptors. These behavioral changes were accompanied by altered concentrations of serotonin (5-HT) and the metabolite, 5-HIAA, in the hypothalamus. The changes of serotonin activity in hypothalamus also result in increase of body weight in EphA5 knockout mice. Furthermore, EphA5 knockout mice exhibited a significant decrease in activity levels following exposure to naïve intruders in their home cages. We conclude that the EphA5 receptor may be involved in mediation of aggressive behavior regulated, in part, by hypothalamic serotonin. PMID:18353288

  12. Cleft Lip/Palate, Short Stature, and Developmental Delay in a Boy with a 5.6-Mb Interstitial Deletion Involving 10p15.3p14

    PubMed Central

    Gamba, Bruno F.; Rosenberg, Carla; Costa, Silvia; Richieri-Costa, Antonio; Ribeiro-Bicudo, Lucilene A.

    2015-01-01

    The chromosome interval 10p15.3p14 harbors about a dozen genes. This region has been implicated in a few well-known human phenotypes, namely HDR syndrome (hypoparathyroidism, sensorineural deafness, and renal dysplasia) and DGS2 (DiGeorge syndrome 2), but a number of variable phenotypes have also been reported. Cleft lip/palate seems to be a very unusual finding within the clinical spectrum of patients with this deletion. Here, we report a male child born with short stature, cleft lip/palate, and feeding problems who was found to have a 5.6-Mb deletion at 10p15.3p14. PMID:25852446

  13. Cooperative binding of Annexin A5 to phosphatidylserine on apoptotic cell membranes

    NASA Astrophysics Data System (ADS)

    Janko, Christina; Jeremic, Ivica; Biermann, Mona; Chaurio, Ricardo; Schorn, Christine; Muñoz, Luis E.; Herrmann, Martin

    2013-12-01

    Healthy cells exhibit an asymmetric plasma membrane with phosphatidylserine (PS) located on the cytoplasmic leaflet of the plasma membrane bilayer. Annexin A5-FITC, a PS binding protein, is commonly used to evaluate apoptosis in flow cytometry. PS exposed by apoptotic cells serves as a major ‘eat-me’ signal for phagocytes. Although exposition of PS has been observed after alternative stimuli, no clearance of viable, PS exposing cells has been detected. Thus, besides PS exposure, membranes of viable and apoptotic cells might exhibit specific characteristics. Here, we show that Annexin A5 binds in a cooperative manner to different types of dead cells. Shrunken apoptotic cells thereby showed the highest Hill coefficient values. Contrarily, parafomaldehyde fixation of apoptotic cells completely abrogates the cooperativity effect seen with dead and dying cells. We tend to speculate that the cooperative binding of Annexin A5 to the membranes of apoptotic cells reflects higher fluidity of the exposed membranes facilitating PS clustering.

  14. Myocardial gene therapy

    NASA Astrophysics Data System (ADS)

    Isner, Jeffrey M.

    2002-01-01

    Gene therapy is proving likely to be a viable alternative to conventional therapies in coronary artery disease and heart failure. Phase 1 clinical trials indicate high levels of safety and clinical benefits with gene therapy using angiogenic growth factors in myocardial ischaemia. Although gene therapy for heart failure is still at the pre-clinical stage, experimental data indicate that therapeutic angiogenesis using short-term gene expression may elicit functional improvement in affected individuals.

  15. Evolution of Gene Expression after Gene Amplification

    PubMed Central

    Garcia, Nelson; Zhang, Wei; Wu, Yongrui; Messing, Joachim

    2015-01-01

    We took a rather unique approach to investigate the conservation of gene expression of prolamin storage protein genes across two different subfamilies of the Poaceae. We took advantage of oat plants carrying single maize chromosomes in different cultivars, called oat–maize addition (OMA) lines, which permitted us to determine whether regulation of gene expression was conserved between the two species. We found that γ-zeins are expressed in OMA7.06, which carries maize chromosome 7 even in the absence of the trans-acting maize prolamin-box-binding factor (PBF), which regulates their expression. This is likely because oat PBF can substitute for the function of maize PBF as shown in our transient expression data, using a γ-zein promoter fused to green fluorescent protein (GFP). Despite this conservation, the younger, recently amplified prolamin genes in maize, absent in oat, are not expressed in the corresponding OMAs. However, maize can express the oldest prolamin gene, the wheat high-molecular weight glutenin Dx5 gene, even when maize Pbf is knocked down (through PbfRNAi), and/or another maize transcription factor, Opaque-2 (O2) is knocked out (in maize o2 mutant). Therefore, older genes are conserved in their regulation, whereas younger ones diverged during evolution and eventually acquired a new repertoire of suitable transcriptional activators. PMID:25912045

  16. Ephrin-A5 acts as a repulsive cue for migrating cortical interneurons.

    PubMed

    Zimmer, Geraldine; Garcez, Patricia; Rudolph, Judith; Niehage, Ronny; Weth, Franco; Lent, Roberto; Bolz, Jürgen

    2008-07-01

    Cortical interneurons are born in the germinative zones of the ganglionic eminences in the subpallium, and migrate tangentially in spatially and temporally well-defined corridors into the neocortex. Because ephrin-A5 is expressed in the ventricular zone (VZ) of the ganglionic eminences at these developmental stages, we examined the possible effects of this molecule on interneuron migration. Double-immunocytochemistry of dissociated neurons from the medial ganglionic eminences (MGE) revealed that calbindin-positive cells express the EphA4-receptor. In situ, EphA4 is strongly expressed in the subventricular zone of the ganglionic eminences. Using different in vitro assays, we found that ephrin-A5 acts as a repellent cue for MGE neurons. We then examined interneuron migration in slice overlay experiments, where MGE-derived explants from enhanced green fluorescent protein-expressing transgenic mice were homotopically grafted into host slices from wild-type littermate embryos. In these in vitro preparations, interneurons recapitulated in vivo cell migration in several respects. However, interneurons in brain slices also migrated in the VZ of the ganglionic eminences, a region that is strictly avoided in vivo. In situ hybridizations revealed that ephrin-A5 became downregulated in the VZ in vitro. When recombinant ephrin-A5-Fc was added to the slices, it preferentially bound to the VZ, and migrating MGE neurons avoided the VZ as in vivo. The restoration of the normal migration pathway in slices required ephrin-A5 clustering and signalling of Src family kinases. Together, these experiments suggest that ephrin-A5 acts as an inhibitory flank that contributes to define the pathway of migrating interneurons. PMID:18662335

  17. Reading and Generalist Genes

    ERIC Educational Resources Information Center

    Haworth, Claire M. A.; Meaburn, Emma L.; Harlaar, Nicole; Plomin, Robert

    2007-01-01

    Twin-study research suggests that many (but not all) of the same genes contribute to genetic influence on diverse learning abilities and disabilities, a hypothesis called "generalist genes". This generalist genes hypothesis was tested using a set of 10 DNA markers (single nucleotide polymorphisms [SNPs]) found to be associated with early reading…

  18. CEST MRI reporter genes.

    PubMed

    Liu, Guanshu; Bulte, Jeff W M; Gilad, Assaf A

    2011-01-01

    In recent years, several reporter genes have been developed that can serve as a beacon for non-invasive magnetic resonance imaging (MRI). Here, we provide a brief summary of recent advances in MRI reporter gene technology, as well as detailed "hands-on" protocols for cloning, expression, and imaging of reporter genes based on chemical exchange saturation transfer (CEST).

  19. Cytochrome P450 3A4 and CYP3A5-Catalyzed Bioactivation of Lapatinib.

    PubMed

    Towles, Joanna K; Clark, Rebecca N; Wahlin, Michelle D; Uttamsingh, Vinita; Rettie, Allan E; Jackson, Klarissa D

    2016-10-01

    Metabolic activation of the dual-tyrosine kinase inhibitor lapatinib by cytochromes CYP3A4 and CYP3A5 has been implicated in lapatinib-induced idiosyncratic hepatotoxicity; however, the relative enzyme contributions have not been established. The objective of this study was to examine the roles of CYP3A4 and CYP3A5 in lapatinib bioactivation leading to a reactive, potentially toxic quinoneimine. Reaction phenotyping experiments were performed using individual human recombinant P450 enzymes and P450-selective chemical inhibitors. Lapatinib metabolites and quinoneimine-glutathione (GSH) adducts were analyzed using liquid chromatography-tandem mass spectrometry. A screen of cDNA-expressed P450s confirmed that CYP3A4 and CYP3A5 are the primary enzymes responsible for quinoneimine-GSH adduct formation using lapatinib or O-dealkylated lapatinib as the substrate. The mean kinetic parameters (Km and kcat) of lapatinib O-dealkylation revealed that CYP3A4 was 5.2-fold more efficient than CYP3A5 at lapatinib O-dealkylation (CYP3A4 kcat/Km = 6.8 μM(-1) min(-1) versus CYP3A5 kcat/Km = 1.3 μM(-1) min(-1)). Kinetic analysis of GSH adduct formation indicated that CYP3A4 was also 4-fold more efficient at quinoneimine-GSH adduct formation as measured by kcat (maximum relative GSH adduct levels)/Km (CYP3A4 = 0.0082 vs. CYP3A5 = 0.0021). In human liver microsomal (HLM) incubations, CYP3A4-selective inhibitors SR-9186 and CYP3cide reduced formation of GSH adducts by 78% and 72%, respectively, compared with >90% inhibition by the pan-CYP3A inhibitor ketoconazole. The 16%-22% difference between CYP3A- and CYP3A4-selective inhibition indicates the involvement of remaining CYP3A5 activity in generating reactive metabolites from lapatinib in pooled HLMs. Collectively, these findings support the conclusion that both CYP3A4 and CYP3A5 are quantitatively important contributors to lapatinib bioactivation. PMID:27450182

  20. Compartmentalized PDE4A5 Signaling Impairs Hippocampal Synaptic Plasticity and Long-Term Memory

    PubMed Central

    Park, Alan J.; Tolentino, Rosa E.; Bruinenberg, Vibeke M.; Tudor, Jennifer C.; Lee, Yool; Hansen, Rolf T.; Guercio, Leonardo A.; Linton, Edward; Neves-Zaph, Susana R.; Meerlo, Peter; Baillie, George S.; Houslay, Miles D.

    2016-01-01

    Alterations in cAMP signaling are thought to contribute to neurocognitive and neuropsychiatric disorders. Members of the cAMP-specific phosphodiesterase 4 (PDE4) family, which contains >25 different isoforms, play a key role in determining spatial cAMP degradation so as to orchestrate compartmentalized cAMP signaling in cells. Each isoform binds to a different set of protein complexes through its unique N-terminal domain, thereby leading to targeted degradation of cAMP in specific intracellular compartments. However, the functional role of specific compartmentalized PDE4 isoforms has not been examined in vivo. Here, we show that increasing protein levels of the PDE4A5 isoform in mouse hippocampal excitatory neurons impairs a long-lasting form of hippocampal synaptic plasticity and attenuates hippocampus-dependent long-term memories without affecting anxiety. In contrast, viral expression of a truncated version of PDE4A5, which lacks the unique N-terminal targeting domain, does not affect long-term memory. Further, overexpression of the PDE4A1 isoform, which targets a different subset of signalosomes, leaves memory undisturbed. Fluorescence resonance energy transfer sensor-based cAMP measurements reveal that the full-length PDE4A5, in contrast to the truncated form, hampers forskolin-mediated increases in neuronal cAMP levels. Our study indicates that the unique N-terminal localization domain of PDE4A5 is essential for the targeting of specific cAMP-dependent signaling underlying synaptic plasticity and memory. The development of compounds to disrupt the compartmentalization of individual PDE4 isoforms by targeting their unique N-terminal domains may provide a fruitful approach to prevent cognitive deficits in neuropsychiatric and neurocognitive disorders that are associated with alterations in cAMP signaling. SIGNIFICANCE STATEMENT Neurons exhibit localized signaling processes that enable biochemical cascades to be activated selectively in specific subcellular

  1. DNA Physical Mapping via the Controlled Translocation of Single Molecules through a 5-10nm Silicon Nitride Nanopore

    NASA Astrophysics Data System (ADS)

    Stein, Derek; Reisner, Walter; Jiang, Zhijun; Hagerty, Nick; Wood, Charles; Chan, Jason

    2009-03-01

    The ability to map the binding position of sequence-specific markers, including transcription-factors, protein-nucleic acids (PNAs) or deactivated restriction enzymes, along a single DNA molecule in a nanofluidic device would be of key importance for the life-sciences. Such markers could give an indication of the active genes at particular stage in a cell's transcriptional cycle, pinpoint the location of mutations or even provide a DNA barcode that could aid in genomics applications. We have developed a setup consisting of a 5-10 nm nanopore in a 20nm thick silicon nitride film coupled to an optical tweezer setup. The translocation of DNA across the nanopore can be detected via blockades in the electrical current through the pore. By anchoring one end of the translocating DNA to an optically trapped microsphere, we hope to stretch out the molecule in the nanopore and control the translocation speed, enabling us to slowly scan across the genome and detect changes in the baseline current due to the presence of bound markers.

  2. Gene hunting in autoinflammation

    PubMed Central

    2013-01-01

    Steady progress in our understanding of the genetic basis of autoinflammatory diseases has been made over the past 16 years. Since the discovery of the familial Mediterranean fever gene MEFV (also known as marenostrin) in 1997, 18 other genes responsible for monogenic autoinflammatory diseases have been identified to date. The discovery of these genes was made through the utilisation of many genetic mapping techniques, including next generation sequencing platforms. This review article clearly describes the gene hunting approaches, methods of data analysis and the technological platforms used, which has relevance to all those working within the field of gene discovery for Mendelian disorders. PMID:24070009

  3. Human disease genes.

    PubMed

    Jimenez-Sanchez, G; Childs, B; Valle, D

    2001-02-15

    The complete human genome sequence will facilitate the identification of all genes that contribute to disease. We propose that the functional classification of disease genes and their products will reveal general principles of human disease. We have determined functional categories for nearly 1,000 documented disease genes, and found striking correlations between the function of the gene product and features of disease, such as age of onset and mode of inheritance. As knowledge of disease genes grows, including those contributing to complex traits, more sophisticated analyses will be possible; their results will yield a deeper understanding of disease and an enhanced integration of medicine with biology.

  4. Journey from Jumping Genes to Gene Therapy.

    PubMed

    Whartenby, Katharine A

    2015-01-01

    Gene therapy for cancer is a still evolving approach that resulted from a long history of studies into genetic modification of organisms. The fascination with manipulating gene products has spanned hundreds if not thousands of years, beginning with observations of the hereditary nature of traits in plants and culminating to date in the alteration of genetic makeup in humans via modern technology. From early discoveries noting the potential for natural mobility of genetic material to the culmination of clinical trials in a variety of disease, gene transfer has had an eventful and sometimes tumultuous course. Within the present review is a brief history of the biology of gene transfer, how it came to be applied to genetic diseases, and its early applications to cancer therapies. Some of the different types of methods used to modify cells, the theories behind the approaches, and some of the limitations encountered along the way are reviewed. PMID:27279244

  5. 26 CFR 1.50A-5 - Electing small business corporations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 1 2010-04-01 2010-04-01 true Electing small business corporations. 1.50A-5... business corporations. (a) In general—(1) Termination of employment by a corporation. If an electing small business corporation (as defined in section 1371(b)) or a former electing small business...

  6. Delayed refractory hyperventilation following endoscopic third ventriculostomy in a 5-year-old boy.

    PubMed

    Merola, J; Liang, E; Hoskins, J; Balakrishnan, V; Gan, P

    2016-09-01

    We present the case of a 5-year-old boy who developed a delayed onset intractable hyperventilation following endoscopic third ventriculostomy. The proposed aetiology of this exceptionally rare phenomenon is discussed. To our knowledge, previous cases have only been reported in the adult population.

  7. 26 CFR 1.401(a)(5)-1 - Special rules relating to nondiscrimination requirements.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... administrator must give clear written notice to each employee of the employee's right to supply actual... requirements under the remaining provisions of section 401(a)(5). (b) Salaried or clerical employees. A plan... contributions or benefits provided under the plan are limited to salaried or clerical employees. (c)...

  8. 45 CFR 12a.5 - Real property reported excess to GSA.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... determine interest in the property in accordance with current regulations. (See 41 CFR 101-47.203-5, 101-47... protect and maintain any property which is reported excess to GSA as provided in 41 CFR 101-47.402. ... in § 12a.5(e). In lieu of the above, GSA may submit a new checklist to HUD and follow the...

  9. 45 CFR 12a.5 - Real property reported excess to GSA.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... determine interest in the property in accordance with current regulations. (See 41 CFR 101-47.203-5, 101-47... protect and maintain any property which is reported excess to GSA as provided in 41 CFR 101-47.402. ... in § 12a.5(e). In lieu of the above, GSA may submit a new checklist to HUD and follow the...

  10. The Dynamics of an Online Knowledge Building Community: A 5-Year Longitudinal Study

    ERIC Educational Resources Information Center

    Myllari, Jarkko; Ahlberg, Mauri; Dillon, Patrick

    2010-01-01

    This paper reports a 5-year design experiment on cumulative knowledge building as part of an international project. Through a longitudinal study and analysis of cumulative research data, we sought to answer the question, "what happened and why in knowledge building?" Research data constitute messages which participants have written into a shared…

  11. 26 CFR 301.6104(a)-5 - Withholding of certain information from public inspection.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 18 2010-04-01 2010-04-01 false Withholding of certain information from public... TREASURY (CONTINUED) PROCEDURE AND ADMINISTRATION PROCEDURE AND ADMINISTRATION Information and Returns Returns and Records § 301.6104(a)-5 Withholding of certain information from public inspection. (a)...

  12. 26 CFR 1.50A-5 - Electing small business corporations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 1 2011-04-01 2009-04-01 true Electing small business corporations. 1.50A-5... business corporations. (a) In general—(1) Termination of employment by a corporation. If an electing small business corporation (as defined in section 1371(b)) or a former electing small business...

  13. 26 CFR 1.142(a)(5)-1 - Exempt facility bonds: Sewage facilities.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 2 2013-04-01 2013-04-01 false Exempt facility bonds: Sewage facilities. 1.142... Bonds § 1.142(a)(5)-1 Exempt facility bonds: Sewage facilities. (a) In general. Under section 103(a), a private activity bond is a tax-exempt bond only if it is a qualified bond. A qualified bond includes...

  14. 26 CFR 1.142(a)(5)-1 - Exempt facility bonds: Sewage facilities.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 2 2012-04-01 2012-04-01 false Exempt facility bonds: Sewage facilities. 1.142... Bonds § 1.142(a)(5)-1 Exempt facility bonds: Sewage facilities. (a) In general. Under section 103(a), a private activity bond is a tax-exempt bond only if it is a qualified bond. A qualified bond includes...

  15. 26 CFR 1.142(a)(5)-1 - Exempt facility bonds: Sewage facilities.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 2 2014-04-01 2014-04-01 false Exempt facility bonds: Sewage facilities. 1.142... Bonds § 1.142(a)(5)-1 Exempt facility bonds: Sewage facilities. (a) In general. Under section 103(a), a private activity bond is a tax-exempt bond only if it is a qualified bond. A qualified bond includes...

  16. 26 CFR 1.142(a)(5)-1 - Exempt facility bonds: Sewage facilities.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 2 2011-04-01 2011-04-01 false Exempt facility bonds: Sewage facilities. 1.142... Bonds § 1.142(a)(5)-1 Exempt facility bonds: Sewage facilities. (a) In general. Under section 103(a), a private activity bond is a tax-exempt bond only if it is a qualified bond. A qualified bond includes...

  17. A 5E Nature of Science Introduction: Preparing Students to Learn about Evolution

    ERIC Educational Resources Information Center

    Bilica, Kimberly

    2012-01-01

    Teachers often struggle with controversy when teaching biological evolution in American schools. Research indicates that curriculum with a nature of science (NOS) focus quells controversy (McComas 2004; Scharmann 2005; Staver 2003). This article presents a 5E NOS series that is a first step in a NOS curriculum that situates student understanding…

  18. An Uncontrolled Examination of a 5-Day Intensive Treatment for Pediatric OCD

    ERIC Educational Resources Information Center

    Whiteside, Stephen P.; Jacobsen, Amy Brown

    2010-01-01

    This study examined the feasibility of a 5-day intensive treatment for pediatric obsessive-compulsive disorder (OCD). Fifteen children with OCD received a week-long treatment based on exposure and response prevention (ERP). The intervention also emphasized teaching children and parents how to conduct ERP independently at home. All families…

  19. 42 CFR 51a.5 - What criteria will DHHS use to decide which projects to fund?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... SERVICES GRANTS PROJECT GRANTS FOR MATERNAL AND CHILD HEALTH § 51a.5 What criteria will DHHS use to decide...) The extent to which the project will contribute to the advancement of maternal and child health and/or... mortality rate (relative to the latest average infant mortality rate in the United States or in the State...

  20. Introducing Engineering in Elementary Education: A 5-Year Study of Teachers and Students

    ERIC Educational Resources Information Center

    Diefes-Dux, Heidi A.

    2015-01-01

    Engineering, when integrated into K-12 education, may offer a number of potential student learning and future success benefits. In a 5-year study, four cohorts of elementary teachers of grades 2 to 4 in a single US school district were provided with teacher professional development with engineering education. Teachers were prepared to teach…

  1. 26 CFR 48.4061(a)-5 - Sale of automobile truck bodies and chassis.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 16 2013-04-01 2013-04-01 false Sale of automobile truck bodies and chassis. 48..., Tread Rubber, and Taxable Fuel Automotive and Related Items § 48.4061(a)-5 Sale of automobile truck bodies and chassis. (a) Sale of completed vehicle. An automobile truck (as defined by §...

  2. 26 CFR 48.4061(a)-5 - Sale of automobile truck bodies and chassis.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 16 2012-04-01 2012-04-01 false Sale of automobile truck bodies and chassis. 48..., Tread Rubber, and Taxable Fuel Automotive and Related Items § 48.4061(a)-5 Sale of automobile truck bodies and chassis. (a) Sale of completed vehicle. An automobile truck (as defined by §...

  3. 29 CFR 2520.104a-5 - Annual reporting filing requirements.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 2520.104a-5 Labor Regulations Relating to Labor (Continued) EMPLOYEE BENEFITS SECURITY ADMINISTRATION... employee benefit plan required to file an annual report pursuant to section 104(a)(1) of the Act shall file... the close of any plan year which begins after December 31, 1975, unless extended. See “When to...

  4. 42 CFR 51a.5 - What criteria will DHHS use to decide which projects to fund?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... SERVICES GRANTS PROJECT GRANTS FOR MATERNAL AND CHILD HEALTH § 51a.5 What criteria will DHHS use to decide... Children 2000: National Health Promotion and Disease Prevention Objectives Related to Mothers, Infants, Children, Adolescents, and Youth is a special compendium of health status goals and national...

  5. 42 CFR 51a.5 - What criteria will DHHS use to decide which projects to fund?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... SERVICES GRANTS PROJECT GRANTS FOR MATERNAL AND CHILD HEALTH § 51a.5 What criteria will DHHS use to decide... Children 2000: National Health Promotion and Disease Prevention Objectives Related to Mothers, Infants, Children, Adolescents, and Youth is a special compendium of health status goals and national...

  6. 42 CFR 51a.5 - What criteria will DHHS use to decide which projects to fund?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... SERVICES GRANTS PROJECT GRANTS FOR MATERNAL AND CHILD HEALTH § 51a.5 What criteria will DHHS use to decide... Children 2000: National Health Promotion and Disease Prevention Objectives Related to Mothers, Infants, Children, Adolescents, and Youth is a special compendium of health status goals and national...

  7. Accumulation of annexin A5 at the nuclear envelope is a biomarker of cellular aging.

    PubMed

    Klement, Karolin; Melle, Christian; Murzik, Ulrike; Diekmann, Stephan; Norgauer, Johannes; Hemmerich, Peter

    2012-07-01

    Cellular senescence is a permanent cell cycle arrest induced by short telomeres or oncogenic stress in vitro and in vivo. Because no single of the established biomarkers can reliably identify senescent cells, the application of new ones may aid the diagnosis of aged cells. Here we show that annexin A5 accumulates at the nuclear envelope during replicative and drug-induced cellular senescence in primary human fibroblasts. This new cellular aging phenotype that we have termed SA-ANX5 (senescence-associated accumulation at the nuclear envelope of annexin A5) is as efficient and quantitative as the well-established senescence-associated β-galactosidase activity assay and p21 immunoreactivity. SA-ANX5 is also observed in aged human skin where is exclusively detected in DNA damage foci-positive/Ki-67-negative cells. We also observed that depletion of annexin A5 by siRNA in human fibroblasts accelerates premature senescence through the p38MAP kinase pathway. These observations establish SA-ANX5 as a new biomarker for cellular aging and implicate a functional role for annexin A5 in cellular senescence.

  8. 26 CFR 1.382-3 - Definitions and rules relating to a 5-percent shareholder.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 4 2014-04-01 2014-04-01 false Definitions and rules relating to a 5-percent..., 1990, but with respect to any group of persons that pursuant to a formal or informal understanding among themselves makes a coordinated acquisition of stock before November 20, 1990, only if the...

  9. 26 CFR 1.382-3 - Definitions and rules relating to a 5-percent shareholder.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... shareholder. 1.382-3 Section 1.382-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... relating to a 5-percent shareholder. (a) Definitions—(1) Entity—(i) In general. An entity is any... old shareholders of L (a total of 60 percent of L stock), with each member purchasing 30 shares....

  10. Regulated Gene Therapy.

    PubMed

    Breger, Ludivine; Wettergren, Erika Elgstrand; Quintino, Luis; Lundberg, Cecilia

    2016-01-01

    Gene therapy represents a promising approach for the treatment of monogenic and multifactorial neurological disorders. It can be used to replace a missing gene and mutated gene or downregulate a causal gene. Despite the versatility of gene therapy, one of the main limitations lies in the irreversibility of the process: once delivered to target cells, the gene of interest is constitutively expressed and cannot be removed. Therefore, efficient, safe and long-term gene modification requires a system allowing fine control of transgene expression.Different systems have been developed over the past decades to regulate transgene expression after in vivo delivery, either at transcriptional or post-translational levels. The purpose of this chapter is to give an overview on current regulatory system used in the context of gene therapy for neurological disorders. Systems using external regulation of transgenes using antibiotics are commonly used to control either gene expression using tetracycline-controlled transcription or protein levels using destabilizing domain technology. Alternatively, specific promoters of genes that are regulated by disease mechanisms, increasing expression as the disease progresses or decreasing expression as disease regresses, are also examined. Overall, this chapter discusses advantages and drawbacks of current molecular methods for regulated gene therapy in the central nervous system.

  11. Gene conversion in human rearranged immunoglobulin genes.

    PubMed

    Darlow, John M; Stott, David I

    2006-07-01

    Over the past 20 years, many DNA sequences have been published suggesting that all or part of the V(H) segment of a rearranged immunoglobulin gene may be replaced in vivo. Two different mechanisms appear to be operating. One of these is very similar to primary V(D)J recombination, involving the RAG proteins acting upon recombination signal sequences, and this has recently been proven to occur. Other sequences, many of which show partial V(H) replacements with no addition of untemplated nucleotides at the V(H)-V(H) joint, have been proposed to occur by an unusual RAG-mediated recombination with the formation of hybrid (coding-to-signal) joints. These appear to occur in cells already undergoing somatic hypermutation in which, some authors are convinced, RAG genes are silenced. We recently proposed that the latter type of V(H) replacement might occur by homologous recombination initiated by the activity of AID (activation-induced cytidine deaminase), which is essential for somatic hypermutation and gene conversion. The latter has been observed in other species, but not in human Ig genes, so far. In this paper, we present a new analysis of sequences published as examples of the second type of rearrangement. This not only shows that AID recognition motifs occur in recombination regions but also that some sequences show replacement of central sections by a sequence from another gene, similar to gene conversion in the immunoglobulin genes of other species. These observations support the proposal that this type of rearrangement is likely to be AID-mediated rather than RAG-mediated and is consistent with gene conversion.

  12. MicroRNA MiR-199a-5p regulates smooth muscle cell proliferation and morphology by targeting WNT2 signaling pathway.

    PubMed

    Hashemi Gheinani, Ali; Burkhard, Fiona C; Rehrauer, Hubert; Aquino Fournier, Catharine; Monastyrskaya, Katia

    2015-03-13

    MicroRNA miR-199a-5p impairs tight junction formation, leading to increased urothelial permeability in bladder pain syndrome. Now, using transcriptome analysis in urothelial TEU-2 cells, we implicate it in the regulation of cell cycle, cytoskeleton remodeling, TGF, and WNT signaling pathways. MiR-199a-5p is highly expressed in the smooth muscle layer of the bladder, and we altered its levels in bladder smooth muscle cells (SMCs) to validate the pathway analysis. Inhibition of miR-199a-5p with antimiR increased SMC proliferation, reduced cell size, and up-regulated miR-199a-5p targets, including WNT2. Overexpression of WNT2 protein or treating SMCs with recombinant WNT2 closely mimicked the miR-199a-5p inhibition, whereas down-regulation of WNT2 in antimiR-expressing SMCs with shRNA restored cell phenotype and proliferation rates. Overexpression of miR-199a-5p in the bladder SMCs significantly increased cell size and up-regulated SM22, SM α-actin, and SM myosin heavy chain mRNA and protein levels. These changes as well as increased expression of ACTG2, TGFB1I1, and CDKN1A were mediated by up-regulation of the smooth muscle-specific transcriptional activator myocardin at mRNA and protein levels. Myocardin-related transcription factor A downstream targets Id3 and MYL9 were also induced. Up-regulation of myocardin was accompanied by down-regulation of WNT-dependent inhibitory Krüppel-like transcription factor 4 in miR-199a-5p-overexpressing cells. In contrast, Krüppel-like transcription factor 4 was induced in antimiR-expressing cells following the activation of WNT2 signaling, leading to repression of myocardin-dependent genes. MiR-199a-5p plays a critical role in the WNT2-mediated regulation of proliferative and differentiation processes in the smooth muscle and may behave as a key modulator of smooth muscle hypertrophy, which is relevant for organ remodeling.

  13. Retrieval with gene queries

    PubMed Central

    Sehgal, Aditya K; Srinivasan, Padmini

    2006-01-01

    Background Accuracy of document retrieval from MEDLINE for gene queries is crucially important for many applications in bioinformatics. We explore five information retrieval-based methods to rank documents retrieved by PubMed gene queries for the human genome. The aim is to rank relevant documents higher in the retrieved list. We address the special challenges faced due to ambiguity in gene nomenclature: gene terms that refer to multiple genes, gene terms that are also English words, and gene terms that have other biological meanings. Results Our two baseline ranking strategies are quite similar in performance. Two of our three LocusLink-based strategies offer significant improvements. These methods work very well even when there is ambiguity in the gene terms. Our best ranking strategy offers significant improvements on three different kinds of ambiguities over our two baseline strategies (improvements range from 15.9% to 17.7% and 11.7% to 13.3% depending on the baseline). For most genes the best ranking query is one that is built from the LocusLink (now Entrez Gene) summary and product information along with the gene names and aliases. For others, the gene names and aliases suffice. We also present an approach that successfully predicts, for a given gene, which of these two ranking queries is more appropriate. Conclusion We explore the effect of different post-retrieval strategies on the ranking of documents returned by PubMed for human gene queries. We have successfully applied some of these strategies to improve the ranking of relevant documents in the retrieved sets. This holds true even when various kinds of ambiguity are encountered. We feel that it would be very useful to apply strategies like ours on PubMed search results as these are not ordered by relevance in any way. This is especially so for queries that retrieve a large number of documents. PMID:16630348

  14. Oncogenes, genes, and growth factors

    SciTech Connect

    Guroff, G.

    1989-01-01

    This book contains 12 chapters. Some of the chapter titles are: The Epidermal Growth Factor Receptor Gene; Structure and Expression of the Nerve Growth Factor Gene; The Erythropoietin Gene; The Interleukin-2 Gene; The Transferrin Gene; and The Transferrin Receptor Gene.

  15. Do Housekeeping Genes Exist?

    PubMed Central

    Sun, Bingyun

    2015-01-01

    The searching of human housekeeping (HK) genes has been a long quest since the emergence of transcriptomics, and is instrumental for us to understand the structure of genome and the fundamentals of biological processes. The resolved genes are frequently used in evolution studies and as normalization standards in quantitative gene-expression analysis. Within the past 20 years, more than a dozen HK-gene studies have been conducted, yet none of them sampled human tissues completely. We believe an integration of these results will help remove false positive genes owing to the inadequate sampling. Surprisingly, we only find one common gene across 15 examined HK-gene datasets comprising 187 different tissue and cell types. Our subsequent analyses suggest that it might not be appropriate to rigidly define HK genes as expressed in all tissue types that have diverse developmental, physiological, and pathological states. It might be beneficial to use more robustly identified HK functions for filtering criteria, in which the representing genes can be a subset of genome. These genes are not necessarily the same, and perhaps need not to be the same, everywhere in our body. PMID:25970694

  16. Do housekeeping genes exist?

    PubMed

    Zhang, Yijuan; Li, Ding; Sun, Bingyun

    2015-01-01

    The searching of human housekeeping (HK) genes has been a long quest since the emergence of transcriptomics, and is instrumental for us to understand the structure of genome and the fundamentals of biological processes. The resolved genes are frequently used in evolution studies and as normalization standards in quantitative gene-expression analysis. Within the past 20 years, more than a dozen HK-gene studies have been conducted, yet none of them sampled human tissues completely. We believe an integration of these results will help remove false positive genes owing to the inadequate sampling. Surprisingly, we only find one common gene across 15 examined HK-gene datasets comprising 187 different tissue and cell types. Our subsequent analyses suggest that it might not be appropriate to rigidly define HK genes as expressed in all tissue types that have diverse developmental, physiological, and pathological states. It might be beneficial to use more robustly identified HK functions for filtering criteria, in which the representing genes can be a subset of genome. These genes are not necessarily the same, and perhaps need not to be the same, everywhere in our body. PMID:25970694

  17. Towards Consensus Gene Ages.

    PubMed

    Liebeskind, Benjamin J; McWhite, Claire D; Marcotte, Edward M

    2016-01-01

    Correctly estimating the age of a gene or gene family is important for a variety of fields, including molecular evolution, comparative genomics, and phylogenetics, and increasingly for systems biology and disease genetics. However, most studies use only a point estimate of a gene's age, neglecting the substantial uncertainty involved in this estimation. Here, we characterize this uncertainty by investigating the effect of algorithm choice on gene-age inference and calculate consensus gene ages with attendant error distributions for a variety of model eukaryotes. We use 13 orthology inference algorithms to create gene-age datasets and then characterize the error around each age-call on a per-gene and per-algorithm basis. Systematic error was found to be a large factor in estimating gene age, suggesting that simple consensus algorithms are not enough to give a reliable point estimate. We also found that different sources of error can affect downstream analyses, such as gene ontology enrichment. Our consensus gene-age datasets, with associated error terms, are made fully available at so that researchers can propagate this uncertainty through their analyses (geneages.org). PMID:27259914

  18. Human HOX gene disorders.

    PubMed

    Quinonez, Shane C; Innis, Jeffrey W

    2014-01-01

    The Hox genes are an evolutionarily conserved family of genes, which encode a class of important transcription factors that function in numerous developmental processes. Following their initial discovery, a substantial amount of information has been gained regarding the roles Hox genes play in various physiologic and pathologic processes. These processes range from a central role in anterior-posterior patterning of the developing embryo to roles in oncogenesis that are yet to be fully elucidated. In vertebrates there are a total of 39 Hox genes divided into 4 separate clusters. Of these, mutations in 10 Hox genes have been found to cause human disorders with significant variation in their inheritance patterns, penetrance, expressivity and mechanism of pathogenesis. This review aims to describe the various phenotypes caused by germline mutation in these 10 Hox genes that cause a human phenotype, with specific emphasis paid to the genotypic and phenotypic differences between allelic disorders. As clinical whole exome and genome sequencing is increasingly utilized in the future, we predict that additional Hox gene mutations will likely be identified to cause distinct human phenotypes. As the known human phenotypes closely resemble gene-specific murine models, we also review the homozygous loss-of-function mouse phenotypes for the 29 Hox genes without a known human disease. This review will aid clinicians in identifying and caring for patients affected with a known Hox gene disorder and help recognize the potential for novel mutations in patients with phenotypes informed by mouse knockout studies.

  19. Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures

    PubMed Central

    Stödberg, Tommy; McTague, Amy; Ruiz, Arnaud J.; Hirata, Hiromi; Zhen, Juan; Long, Philip; Farabella, Irene; Meyer, Esther; Kawahara, Atsuo; Vassallo, Grace; Stivaros, Stavros M.; Bjursell, Magnus K.; Stranneheim, Henrik; Tigerschiöld, Stephanie; Persson, Bengt; Bangash, Iftikhar; Das, Krishna; Hughes, Deborah; Lesko, Nicole; Lundeberg, Joakim; Scott, Rod C.; Poduri, Annapurna; Scheffer, Ingrid E.; Smith, Holly; Gissen, Paul; Schorge, Stephanie; Reith, Maarten E. A.; Topf, Maya; Kullmann, Dimitri M.; Harvey, Robert J.; Wedell, Anna; Kurian, Manju A.

    2015-01-01

    The potassium-chloride co-transporter KCC2, encoded by SLC12A5, plays a fundamental role in fast synaptic inhibition by maintaining a hyperpolarizing gradient for chloride ions. KCC2 dysfunction has been implicated in human epilepsy, but to date, no monogenic KCC2-related epilepsy disorders have been described. Here we show recessive loss-of-function SLC12A5 mutations in patients with a severe infantile-onset pharmacoresistant epilepsy syndrome, epilepsy of infancy with migrating focal seizures (EIMFS). Decreased KCC2 surface expression, reduced protein glycosylation and impaired chloride extrusion contribute to loss of KCC2 activity, thereby impairing normal synaptic inhibition and promoting neuronal excitability in this early-onset epileptic encephalopathy. PMID:26333769

  20. Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures.

    PubMed

    Stödberg, Tommy; McTague, Amy; Ruiz, Arnaud J; Hirata, Hiromi; Zhen, Juan; Long, Philip; Farabella, Irene; Meyer, Esther; Kawahara, Atsuo; Vassallo, Grace; Stivaros, Stavros M; Bjursell, Magnus K; Stranneheim, Henrik; Tigerschiöld, Stephanie; Persson, Bengt; Bangash, Iftikhar; Das, Krishna; Hughes, Deborah; Lesko, Nicole; Lundeberg, Joakim; Scott, Rod C; Poduri, Annapurna; Scheffer, Ingrid E; Smith, Holly; Gissen, Paul; Schorge, Stephanie; Reith, Maarten E A; Topf, Maya; Kullmann, Dimitri M; Harvey, Robert J; Wedell, Anna; Kurian, Manju A

    2015-01-01

    The potassium-chloride co-transporter KCC2, encoded by SLC12A5, plays a fundamental role in fast synaptic inhibition by maintaining a hyperpolarizing gradient for chloride ions. KCC2 dysfunction has been implicated in human epilepsy, but to date, no monogenic KCC2-related epilepsy disorders have been described. Here we show recessive loss-of-function SLC12A5 mutations in patients with a severe infantile-onset pharmacoresistant epilepsy syndrome, epilepsy of infancy with migrating focal seizures (EIMFS). Decreased KCC2 surface expression, reduced protein glycosylation and impaired chloride extrusion contribute to loss of KCC2 activity, thereby impairing normal synaptic inhibition and promoting neuronal excitability in this early-onset epileptic encephalopathy. PMID:26333769

  1. Synovial Sarcoma in the Foot of a 5-Year-Old ChildA Case Report.

    PubMed

    Lepow, Gary M; Grimmer, Daniel L; Lemar, Onya V; Bridges, Evan A

    2016-07-01

    The purpose of this case report is to present a rare finding of synovial sarcoma in a 5-year-old child. Most soft-tissue masses of the foot are too often presumed to be small and benign; therefore, compared with soft-tissue sarcomas, they are difficult to clinically differentiate and treat. A 5-year-old girl presented with a painful lesion that was diagnosed as synovial sarcoma after an excisional biopsy was performed. This was an unexpected finding of synovial sarcoma involving the tibialis posterior tendon of her right foot. The patient presented with an 8-month history of tenderness and an antalgic gait. We would like to encourage that all soft-tissue tumors of the foot be preoperatively evaluated with the aid of diagnostic imaging so that a well-planned biopsy assessment can be performed, with adequate margins excised.

  2. Synovial Sarcoma in the Foot of a 5-Year-Old ChildA Case Report.

    PubMed

    Lepow, Gary M; Grimmer, Daniel L; Lemar, Onya V; Bridges, Evan A

    2016-07-01

    The purpose of this case report is to present a rare finding of synovial sarcoma in a 5-year-old child. Most soft-tissue masses of the foot are too often presumed to be small and benign; therefore, compared with soft-tissue sarcomas, they are difficult to clinically differentiate and treat. A 5-year-old girl presented with a painful lesion that was diagnosed as synovial sarcoma after an excisional biopsy was performed. This was an unexpected finding of synovial sarcoma involving the tibialis posterior tendon of her right foot. The patient presented with an 8-month history of tenderness and an antalgic gait. We would like to encourage that all soft-tissue tumors of the foot be preoperatively evaluated with the aid of diagnostic imaging so that a well-planned biopsy assessment can be performed, with adequate margins excised. PMID:27489968

  3. Pyopneumothorax with Stocker type III congenital cystic adenomatoid malformation in a 5-month-old infant

    PubMed Central

    Chilkar, Sujeet M; Leelakumar, Venkat; Ranjani, Chakravarthy P; Musthyala, Bharati; Narayana, Kotte VS

    2016-01-01

    Congenital cystic adenomatoid malformation (CCAM) is a rare, developmental, hamartomatous abnormality of the lung characterized by a cessation of normal bronchiolar maturation, resulting in cystic overgrowth of the terminal bronchioles. We report one such case of CCAM in a 5-month-old female infant who was in perfect health until she suffered from spontaneous pyopneumothorax with type III CCAM of the lung and recovered after lobectomy. PMID:27051113

  4. Bilateral total parenteral nutrition pleural effusions in a 5-week-old male infant

    PubMed Central

    Flannigan, Christopher; Bourke, Thomas; Keown, Karen; Terris, Mark

    2012-01-01

    A 5-week-old male infant was admitted to the paediatric intensive care unit with small bowel obstruction secondary to an inguinal hernia. His postoperative course was complicated by suspected migration of his left internal jugular central venous catheter into branches of the inferior thyroid artery and mediastinum. This resulted in bilateral pleural effusions which were biochemically and visually similar to the total parenteral nutrition he was receiving. After drainage of the pleural effusions he made an uneventful recovery. PMID:22761198

  5. Calcifying cystic odontogenic tumor in a 5-year-old boy: a case report.

    PubMed

    Desai, Rajiv S; Sabnis, Rajesh; Bhuta, Bansari A; Yadav, Archana

    2015-03-01

    The calcifying cystic odontogenic tumor (CCOT), formerly known as calcifying odontogenic cyst, is a rare developmental neoplasm/cyst of odontogenic epithelial origin with considerable histopathologic diversity and variable clinical behaviour. The occurrence of CCOT in the first decade of life is very uncommon. We report an interestingly rare variant of CCOT with ameloblastomatous proliferation affecting the mandibular left posterior region associated with an impacted permanent tooth in a 5-year-old boy.

  6. Notch signaling genes

    PubMed Central

    Terragni, Jolyon; Zhang, Guoqiang; Sun, Zhiyi; Pradhan, Sriharsa; Song, Lingyun; Crawford, Gregory E; Lacey, Michelle; Ehrlich, Melanie

    2014-01-01

    Notch intercellular signaling is critical for diverse developmental pathways and for homeostasis in various types of stem cells and progenitor cells. Because Notch gene products need to be precisely regulated spatially and temporally, epigenetics is likely to help control expression of Notch signaling genes. Reduced representation bisulfite sequencing (RRBS) indicated significant hypomethylation in myoblasts, myotubes, and skeletal muscle vs. many nonmuscle samples at intragenic or intergenic regions of the following Notch receptor or ligand genes: NOTCH1, NOTCH2, JAG2, and DLL1. An enzymatic assay of sites in or near these genes revealed unusually high enrichment of 5-hydroxymethylcytosine (up to 81%) in skeletal muscle, heart, and cerebellum. Epigenetics studies and gene expression profiles suggest that hypomethylation and/or hydroxymethylation help control expression of these genes in heart, brain, myoblasts, myotubes, and within skeletal muscle myofibers. Such regulation could promote cell renewal, cell maintenance, homeostasis, and a poised state for repair of tissue damage. PMID:24670287

  7. Gene therapy for radioprotection.

    PubMed

    Everett, W H; Curiel, D T

    2015-03-01

    Radiation therapy is a critical component of cancer treatment with over half of patients receiving radiation during their treatment. Despite advances in image-guided therapy and dose fractionation, patients receiving radiation therapy are still at risk for side effects due to off-target radiation damage of normal tissues. To reduce normal tissue damage, researchers have sought radioprotectors, which are agents capable of protecting tissue against radiation by preventing radiation damage from occurring or by decreasing cell death in the presence of radiation damage. Although much early research focused on small-molecule radioprotectors, there has been a growing interest in gene therapy for radioprotection. The amenability of gene therapy vectors to targeting, as well as the flexibility of gene therapy to accomplish ablation or augmentation of biologically relevant genes, makes gene therapy an excellent strategy for radioprotection. Future improvements to vector targeting and delivery should greatly enhance radioprotection through gene therapy.

  8. The Absence of CYP3A5*3 Is a Protective Factor to Anticonvulsants Hypersensitivity Reactions: A Case-Control Study in Brazilian Subjects.

    PubMed

    Tanno, Luciana Kase; Kerr, Daniel Shikanai; dos Santos, Bernardo; Talib, Leda Leme; Yamaguti, Célia; Rodrigues, Helcio; Gattaz, Wagner Farid; Kalil, Jorge

    2015-01-01

    Although aromatic anticonvulsants are usually well tolerated, they can cause cutaneous adverse drug reactions in up to 10% of patients. The clinical manifestations of the antiepileptics-induced hypersensitivity reactions (AHR) vary from mild skin rashes to severe cutaneous drug adverse reactions which are related to high mortality and significant morbidity. Genetic polymorphisms in cytochrome P450 genes are associated with altered enzymatic activity and may contribute to the risk of AHR. Here we present a case-control study in which we genotyped SNPs of CYP2C19, 2C9 and 3A5 of 55 individuals with varying severities of AHR, 83 tolerant, and 366 healthy control subjects from São Paulo, Brazil. Clinical characterization was based on standardized scoring systems and drug patch test. All in vivo investigation followed the ENDA (European Network of Drug Allergy) recommendations. Genotype was determined by real time PCR using peripheral blood DNA as a template. Of all 504 subjects, 65% were females, 45% self-identified as Afro-American, 38% as Caucasian and 17% as having non-African mixed ascendancy. Amongst 55 subjects with AHR, 44 had severe cutaneous drug adverse reactions. Of the 46 drug patch tests performed, 29 (63%) were positive. We found a strong association between the absence of CYP3A5*3 and tolerant subjects when compared to AHR (p = 0.0002, OR = 5.28 [CI95% 2.09-14.84]). None of our groups presented positive association with CYP2C19 and 2C9 polymorphisms, however, both SNPs contributed to separation of cases and tolerants in a Classification and Regression Tree. Our findings indicate that drug metabolism genes can contribute in the tolerability of antiepileptics. CYP3A5*3 is the most prevalent CYP3A5 allele associated with reduced enzymatic function. The current study provides evidence that normal CYP3A5 activity might be a protective factor to aromatic antiepileptics-induced hypersensitivity reactions in Brazilian subjects. PMID:26291084

  9. Peptide synthetase gene in Trichoderma virens.

    PubMed

    Wilhite, S E; Lumsden, R D; Straney, D C

    2001-11-01

    Trichoderma virens (synonym, Gliocladium virens), a deuteromycete fungus, suppresses soilborne plant diseases caused by a number of fungi and is used as a biocontrol agent. Several traits that may contribute to the antagonistic interactions of T. virens with disease-causing fungi involve the production of peptide metabolites (e.g., the antibiotic gliotoxin and siderophores used for iron acquisition). We cloned a 5,056-bp partial cDNA encoding a putative peptide synthetase (Psy1) from T. virens using conserved motifs found within the adenylate domain of peptide synthetases. Sequence similarities with conserved motifs of the adenylation domain, acyl transfer, and two condensation domains support identification of the Psy1 gene as a gene that encodes a peptide synthetase. Disruption of the native Psy1 gene through gene replacement was used to identify the function of this gene. Psy1 disruptants produced normal amounts of gliotoxin but grew poorly under low-iron conditions, suggesting that Psy1 plays a role in siderophore production. Psy1 disruptants cannot produce the major T. virens siderophore dimerum acid, a dipetide of acylated N(delta)-hydroxyornithine. Biocontrol activity against damping-off diseases caused by Pythium ultimum and Rhizoctonia solani was not reduced by the Psy1 disruption, suggesting that iron competition through dimerum acid production does not contribute significantly to disease suppression activity under the conditions used.

  10. Peptide Synthetase Gene in Trichoderma virens

    PubMed Central

    Wilhite, S. E.; Lumsden, R. D.; Straney, D. C.

    2001-01-01

    Trichoderma virens (synonym, Gliocladium virens), a deuteromycete fungus, suppresses soilborne plant diseases caused by a number of fungi and is used as a biocontrol agent. Several traits that may contribute to the antagonistic interactions of T. virens with disease-causing fungi involve the production of peptide metabolites (e.g., the antibiotic gliotoxin and siderophores used for iron acquisition). We cloned a 5,056-bp partial cDNA encoding a putative peptide synthetase (Psy1) from T. virens using conserved motifs found within the adenylate domain of peptide synthetases. Sequence similarities with conserved motifs of the adenylation domain, acyl transfer, and two condensation domains support identification of the Psy1 gene as a gene that encodes a peptide synthetase. Disruption of the native Psy1 gene through gene replacement was used to identify the function of this gene. Psy1 disruptants produced normal amounts of gliotoxin but grew poorly under low-iron conditions, suggesting that Psy1 plays a role in siderophore production. Psy1 disruptants cannot produce the major T. virens siderophore dimerum acid, a dipetide of acylated Nδ-hydroxyornithine. Biocontrol activity against damping-off diseases caused by Pythium ultimum and Rhizoctonia solani was not reduced by the Psy1 disruption, suggesting that iron competition through dimerum acid production does not contribute significantly to disease suppression activity under the conditions used. PMID:11679326

  11. NPY modulates miR-30a-5p and BDNF in opposite direction in an in vitro model of Alzheimer disease: a possible role in neuroprotection?

    PubMed

    Croce, Nicoletta; Gelfo, Francesca; Ciotti, Maria Teresa; Federici, Giorgio; Caltagirone, Carlo; Bernardini, Sergio; Angelucci, Francesco

    2013-04-01

    Using in vitro models of Alzheimer's disease (AD), we found that the toxic effects of amyloid beta 25-35 (Aβ(25-35)) on the neurotrophin brain-derived neurotrophic factor (BDNF) were counteracted by pre-incubation with neuropeptide Y (NPY), a neuropeptide expressed within the central nervous system. Nonetheless, the mechanism of action of NPY on BDNF neuronal production in the presence of Aβ is not known. BDNF expression might be directly regulated by microRNA (miRs), small non-coding DNA fragments that regulate the expression of target genes. Thus, there is the possibility that miRs alterations are present in AD-affected neurons and that NPY influences miR expression. To test this hypothesis, we exposed NPY-pretreated primary rat cortical neurons to Aβ(25-35) and measured miR-30a-5p (a member of the miR-30a family involved in BDNF tuning expression) and BDNF mRNA and protein expression after 24 and 48 h. Our results demonstrated that pre-treatment with NPY decreased miR-30a-5p expression and increased BDNF mRNA and protein expression at 24 and 48 h of incubation with Aβ. Therefore, this study demonstrates that NPY modulates BDNF and its regulating microRNA miR-30a-5p in opposite direction with a mechanism that possibly contributes to the neuroprotective effect of NPY in rat cortical neurons exposed to Aβ.

  12. Towards Consensus Gene Ages

    PubMed Central

    Liebeskind, Benjamin J.; McWhite, Claire D.; Marcotte, Edward M.

    2016-01-01

    Correctly estimating the age of a gene or gene family is important for a variety of fields, including molecular evolution, comparative genomics, and phylogenetics, and increasingly for systems biology and disease genetics. However, most studies use only a point estimate of a gene’s age, neglecting the substantial uncertainty involved in this estimation. Here, we characterize this uncertainty by investigating the effect of algorithm choice on gene-age inference and calculate consensus gene ages with attendant error distributions for a variety of model eukaryotes. We use 13 orthology inference algorithms to create gene-age datasets and then characterize the error around each age-call on a per-gene and per-algorithm basis. Systematic error was found to be a large factor in estimating gene age, suggesting that simple consensus algorithms are not enough to give a reliable point estimate. We also found that different sources of error can affect downstream analyses, such as gene ontology enrichment. Our consensus gene-age datasets, with associated error terms, are made fully available at so that researchers can propagate this uncertainty through their analyses (geneages.org). PMID:27259914

  13. Supervised clustering of genes

    PubMed Central

    Dettling, Marcel; Bühlmann, Peter

    2002-01-01

    Background We focus on microarray data where experiments monitor gene expression in different tissues and where each experiment is equipped with an additional response variable such as a cancer type. Although the number of measured genes is in the thousands, it is assumed that only a few marker components of gene subsets determine the type of a tissue. Here we present a new method for finding such groups of genes by directly incorporating the response variables into the grouping process, yielding a supervised clustering algorithm for genes. Results An empirical study on eight publicly available microarray datasets shows that our algorithm identifies gene clusters with excellent predictive potential, often superior to classification with state-of-the-art methods based on single genes. Permutation tests and bootstrapping provide evidence that the output is reasonably stable and more than a noise artifact. Conclusions In contrast to other methods such as hierarchical clustering, our algorithm identifies several gene clusters whose expression levels clearly distinguish the different tissue types. The identification of such gene clusters is potentially useful for medical diagnostics and may at the same time reveal insights into functional genomics. PMID:12537558

  14. Annexin A5 Promoter Haplotype M2 Is Not a Risk Factor for Recurrent Pregnancy Loss in Northern Europe

    PubMed Central

    Rull, Kristiina; Christiansen, Ole B.; Nielsen, Henriette S.; Laan, Maris

    2015-01-01

    Introduction Annexin A5 is an essential component of placental integrity that may potentially mediate susceptibility to phenotypes of compromised pregnancy. A promoter haplotype termed M2 of the coding gene ANXA5 has been implicated in various pregnancy complications such as preeclampsia and recurrent pregnancy loss (RPL), however with inconclusive results. Study subjects and methods A retrospective case-control study combining resequencing and restriction fragment length polymorphism (RFLP) analysis was undertaken in 313 women with unexplained RPL and 214 fertile women from Estonia and Denmark to estimate the RPL disease risk of the M2 haplotype in Northern Europe. Comparative prevalence of the studied ANXA5 genetic variants in human populations was estimated based on the 1000 Genomes Project (n = 675, whole-genome sequencing data) and the KORA S3 500K dataset of South German samples (n = 1644, genome-wide genotyping data). Results Minor allele frequency of common polymorphisms in ANXA5 promoter was up to two-fold lower among Estonian RPL subjects than fertile controls. The M2 haplotype was not associated with RPL and a trend for decreased prevalence was observed among RPL patients compared to controls both in Estonia (8.1% vs 15.2%, respectively) and Denmark (9.7% vs 12.6%). The high M2 prevalence in fertile controls was consistent with estimations for European and East Asian populations (9.6%-16.0%). Conclusions This study cautions to consider the M2 haplotype as a deterministic factor in early pregnancy success because: i) no RPL disease risk was associated with the haplotype in two clinically well-characterized RPL case-control study samples, ii) high prevalence of the haplotype among fertile controls and world-wide populations is inconsistent with the previously proposed severe impact on early pregnancy success, iii) weak impact of M2 haplotype on the production of ANXA5 protein has been established by others. PMID:26135579

  15. Soil bacterial community structure remains stable over a 5-year chronosequence of insect-induced tree mortality.

    PubMed

    Ferrenberg, Scott; Knelman, Joseph E; Jones, Jennifer M; Beals, Stower C; Bowman, William D; Nemergut, Diana R

    2014-01-01

    Extensive tree mortality from insect epidemics has raised concern over possible effects on soil biogeochemical processes. Yet despite the importance of microbes in nutrient cycling, how soil bacterial communities respond to insect-induced tree mortality is largely unknown. We examined soil bacterial community structure (via 16S rRNA gene pyrosequencing) and community assembly processes (via null deviation analysis) along a 5-year chronosequence (substituting space for time) of bark beetle-induced tree mortality in the southern Rocky Mountains, USA. We also measured microbial biomass and soil chemistry, and used in situ experiments to assess inorganic nitrogen mineralization rates. We found that bacterial community structure and assembly-which was strongly influenced by stochastic processes-were largely unaffected by tree mortality despite increased soil ammonium ([Formula: see text]) pools and reductions in soil nitrate ([Formula: see text]) pools and net nitrogen mineralization rates after tree mortality. Linear models suggested that microbial biomass and bacterial phylogenetic diversity are significantly correlated with nitrogen mineralization rates of this forested ecosystem. However, given the overall resistance of the bacterial community to disturbance from tree mortality, soil nitrogen processes likely remained relatively stable following tree mortality when considered at larger spatial and longer temporal scales-a supposition supported by the majority of available studies regarding biogeochemical effects of bark beetle infestations in this region. Our results suggest that soil bacterial community resistance to disturbance helps to explain the relatively weak effects of insect-induced tree mortality on soil N and C pools reported across the Rocky Mountains, USA. PMID:25566204

  16. Soil bacterial community structure remains stable over a 5-year chronosequence of insect-induced tree mortality

    PubMed Central

    Ferrenberg, Scott; Knelman, Joseph E.; Jones, Jennifer M.; Beals, Stower C.; Bowman, William D.; Nemergut, Diana R.

    2014-01-01

    Extensive tree mortality from insect epidemics has raised concern over possible effects on soil biogeochemical processes. Yet despite the importance of microbes in nutrient cycling, how soil bacterial communities respond to insect-induced tree mortality is largely unknown. We examined soil bacterial community structure (via 16S rRNA gene pyrosequencing) and community assembly processes (via null deviation analysis) along a 5-year chronosequence (substituting space for time) of bark beetle-induced tree mortality in the southern Rocky Mountains, USA. We also measured microbial biomass and soil chemistry, and used in situ experiments to assess inorganic nitrogen mineralization rates. We found that bacterial community structure and assembly—which was strongly influenced by stochastic processes—were largely unaffected by tree mortality despite increased soil ammonium (NH4+) pools and reductions in soil nitrate (NO3−) pools and net nitrogen mineralization rates after tree mortality. Linear models suggested that microbial biomass and bacterial phylogenetic diversity are significantly correlated with nitrogen mineralization rates of this forested ecosystem. However, given the overall resistance of the bacterial community to disturbance from tree mortality, soil nitrogen processes likely remained relatively stable following tree mortality when considered at larger spatial and longer temporal scales—a supposition supported by the majority of available studies regarding biogeochemical effects of bark beetle infestations in this region. Our results suggest that soil bacterial community resistance to disturbance helps to explain the relatively weak effects of insect-induced tree mortality on soil N and C pools reported across the Rocky Mountains, USA. PMID:25566204

  17. Meta-analysis of lipid-traits in Hispanics identifies novel loci, population-specific effects, and tissue-specific enrichment of eQTLs

    PubMed Central

    Below, Jennifer E.; Parra, Esteban J.; Gamazon, Eric R.; Torres, Jason; Krithika, S.; Candille, Sophie; Lu, Yingchang; Manichakul, Ani; Peralta-Romero, Jesus; Duan, Qing; Li, Yun; Morris, Andrew P.; Gottesman, Omri; Bottinger, Erwin; Wang, Xin-Qun; Taylor, Kent D.; Ida Chen, Y.-D.; Rotter, Jerome I.; Rich, Stephen S.; Loos, Ruth J. F.; Tang, Hua; Cox, Nancy J.; Cruz, Miguel; Hanis, Craig L.; Valladares-Salgado, Adan

    2016-01-01

    We performed genome-wide meta-analysis of lipid traits on three samples of Mexican and Mexican American ancestry comprising 4,383 individuals, and followed up significant and highly suggestive associations in three additional Hispanic samples comprising 7,876 individuals. Genome-wide significant signals were observed in or near CELSR2, ZNF259/APOA5, KANK2/DOCK6 and NCAN/MAU2 for total cholesterol, LPL, ABCA1, ZNF259/APOA5, LIPC and CETP for HDL cholesterol, CELSR2, APOB and NCAN/MAU2 for LDL cholesterol, and GCKR, TRIB1, ZNF259/APOA5 and NCAN/MAU2 for triglycerides. Linkage disequilibrium and conditional analyses indicate that signals observed at ABCA1 and LIPC for HDL cholesterol and NCAN/MAU2 for triglycerides are independent of previously reported lead SNP associations. Analyses of lead SNPs from the European Global Lipids Genetics Consortium (GLGC) dataset in our Hispanic samples show remarkable concordance of direction of effects as well as strong correlation in effect sizes. A meta-analysis of the European GLGC and our Hispanic datasets identified five novel regions reaching genome-wide significance: two for total cholesterol (FN1 and SAMM50), two for HDL cholesterol (LOC100996634 and COPB1) and one for LDL cholesterol (LINC00324/CTC1/PFAS). The top meta-analysis signals were found to be enriched for SNPs associated with gene expression in a tissue-specific fashion, suggesting an enrichment of tissue-specific function in lipid-associated loci. PMID:26780889

  18. Meta-analysis of lipid-traits in Hispanics identifies novel loci, population-specific effects, and tissue-specific enrichment of eQTLs.

    PubMed

    Below, Jennifer E; Parra, Esteban J; Gamazon, Eric R; Torres, Jason; Krithika, S; Candille, Sophie; Lu, Yingchang; Manichakul, Ani; Peralta-Romero, Jesus; Duan, Qing; Li, Yun; Morris, Andrew P; Gottesman, Omri; Bottinger, Erwin; Wang, Xin-Qun; Taylor, Kent D; Ida Chen, Y-D; Rotter, Jerome I; Rich, Stephen S; Loos, Ruth J F; Tang, Hua; Cox, Nancy J; Cruz, Miguel; Hanis, Craig L; Valladares-Salgado, Adan

    2016-01-01

    We performed genome-wide meta-analysis of lipid traits on three samples of Mexican and Mexican American ancestry comprising 4,383 individuals, and followed up significant and highly suggestive associations in three additional Hispanic samples comprising 7,876 individuals. Genome-wide significant signals were observed in or near CELSR2, ZNF259/APOA5, KANK2/DOCK6 and NCAN/MAU2 for total cholesterol, LPL, ABCA1, ZNF259/APOA5, LIPC and CETP for HDL cholesterol, CELSR2, APOB and NCAN/MAU2 for LDL cholesterol, and GCKR, TRIB1, ZNF259/APOA5 and NCAN/MAU2 for triglycerides. Linkage disequilibrium and conditional analyses indicate that signals observed at ABCA1 and LIPC for HDL cholesterol and NCAN/MAU2 for triglycerides are independent of previously reported lead SNP associations. Analyses of lead SNPs from the European Global Lipids Genetics Consortium (GLGC) dataset in our Hispanic samples show remarkable concordance of direction of effects as well as strong correlation in effect sizes. A meta-analysis of the European GLGC and our Hispanic datasets identified five novel regions reaching genome-wide significance: two for total cholesterol (FN1 and SAMM50), two for HDL cholesterol (LOC100996634 and COPB1) and one for LDL cholesterol (LINC00324/CTC1/PFAS). The top meta-analysis signals were found to be enriched for SNPs associated with gene expression in a tissue-specific fashion, suggesting an enrichment of tissue-specific function in lipid-associated loci. PMID:26780889

  19. Arabidopsis gene expression patterns are altered during spaceflight

    NASA Astrophysics Data System (ADS)

    Paul, Anna-Lisa; Popp, Michael P.; Gurley, William B.; Guy, Charles; Norwood, Kelly L.; Ferl, Robert J.

    The exposure of Arabidopsis thaliana (Arabidopsis) plants to spaceflight environments results in differential gene expression. A 5-day mission on orbiter Columbia in 1999 (STS-93) carried transgenic Arabidopsis plants engineered with a transgene composed of the alcohol dehydrogenase (Adh) gene promoter linked to the β-Glucuronidase (GUS) reporter gene. The plants were used to evaluate the effects of spaceflight on gene expression patterns initially by using the Adh/GUS transgene to address specifically the possibility that spaceflight induces a hypoxic stress response (Paul, A.L., Daugherty, C.J., Bihn, E.A., Chapman, D.K., Norwood, K.L., Ferl, R.J., 2001. Transgene expression patterns indicate that spaceflight affects stress signal perception and transduction in arabidopsis, Plant Physiol. 126, 613-621). As a follow-on to the reporter gene analysis, we report here the evaluation of genome-wide patterns of native gene expression within Arabidopsis shoots utilizing the Agilent DNA array of 21,000 Arabidopsis genes. As a control for the veracity of the array analyses, a selection of genes was further characterized with quantitative Real-Time RT PCR (ABI - Taqman®). Comparison of the patterns of expression for arrays probed with RNA isolated from plants exposed to spaceflight compared to RNA isolated from ground control plants revealed 182 genes that were differentially expressed in response to the spaceflight mission by more than 4-fold, and of those only 50 genes were expressed at levels chosen to support a conservative change call. None of the genes that are hallmarks of hypoxic stress were induced to this level. However, genes related to heat shock were dramatically induced - but in a pattern and under growth conditions that are not easily explained by elevated temperatures. These gene expression data are discussed in light of current models for plant responses to the spaceflight environment and with regard to potential future spaceflight experiment

  20. Conceptual design considerations of a 5-cell dual-axis SRF cavity for ERLs.

    SciTech Connect

    Wang, C.-X.; Accelerator Systems Division

    2007-01-01

    Recently a dual-axis energy recovery linac has been proposed for ERL applications, in which accelerating and decelerating beams can go through separate axes but still recover energy in novel dual-axis cavities. Here we discuss a conceptual design of a 5-cell dual-axis cavity evolved from side-by-side jointed TESLA-type cavities. Instead of an engineering design, we aim to explore the feasibility of such a new cavity, giving particular attention to its nonstandard features that might cause concern to the beam. This is a preliminary work-in-progress report.

  1. Giant parietal lobe infantile gliosarcoma in a 5-year-old child

    PubMed Central

    Savant, Hemant V.; Balasubramaniam, Srikant; Mahajan, Vijay

    2015-01-01

    The relative frequency of pediatric gliosarcoma (GSM) is 1.9% among glioblastomas and 0.5% among pediatric central nervous system tumors. A 5-year-old female child came to us with history of fever and loss of appetite since 2 weeks and right sided weakness since 4 days. Magnetic resonance imaging showed a large heterogeneously enhancing space occupying lesion in the left parieto-occipital region. A parieto-occipital craniotomy with radical excision of tumor was performed. The patient was given adjuvant therapy following surgery and survived until 9 months following surgery. The etiopathogenesis, treatment modalities and prognosis of GSM is discussed. PMID:26167224

  2. Infantile fibrosarcoma of ethmoid sinus, misdiagnosed as an adenoid in a 5-year-old child.

    PubMed

    Geramizadeh, Bita; Khademi, Bijan; Karimi, Mehran; Shekarkhar, Golsa

    2015-01-01

    Infantile fibrosarcoma of head and neck is rare and the presence of this tumor in ethmoid sinus is even more uncommon. To the best of our knowledge, <5 cases have been reported in the last 20 years in the English literature, so far, only one of which has been infantile type in a 15 months old girl. In this case report, we will explain our experience with a rare case of infantile fibrosarcoma originating from ethmoid sinus in a 5-year-old boy who presented with dyspnea and epistaxis. After biopsy, it was diagnosed as fibrosarcoma of sinus origin. PMID:26604519

  3. Carbon Dioxide Adsorption on a 5A Zeolite Designed for CO2 Removal in Spacecraft Cabins

    NASA Technical Reports Server (NTRS)

    Mulloth, Lila M.; Finn, John E.

    1998-01-01

    Carbon dioxide adsorption data were obtained for a 5A zeolite manufactured by AlliedSignal Inc. (Des Plaines, Illinois). The material is planned for use in the Carbon Dioxide Removal Assembly (CDRA) for U.S. elements of the International Space Station. The family of adsorption isotherms covers a temperature range of O to 250 C, and a pressure range of 0.001 to 800 torr. Coefficients of the Toth equation are fit to the data. Isosteric heats of adsorption are derived from the equilibrium loading data.

  4. Stacked optical antennas for plasmon propagation in a 5 nm-confined cavity.

    PubMed

    Saeed, A; Panaro, S; Zaccaria, R Proietti; Raja, W; Liberale, C; Dipalo, M; Messina, G C; Wang, H; De Angelis, F; Toma, A

    2015-06-09

    The sub-wavelength concentration and propagation of electromagnetic energy are two complementary aspects of plasmonics that are not necessarily co-present in a single nanosystem. Here we exploit the strong nanofocusing properties of stacked optical antennas in order to highly concentrate the electromagnetic energy into a 5 nm metal-insulator-metal (MIM) cavity and convert free radiation into guided modes. The proposed nano-architecture combines the concentration properties of optical nanoantennas with the propagation capability of MIM systems, paving the way to highly miniaturized on-chip plasmonic waveguiding.

  5. Giant pericardial cyst in a 5-year-old child: A rare anomaly

    PubMed Central

    Kumar, Sanjay; Jain, Promil; Sen, Rajeev; Rattan, KN; Agarwal, Ruchi; Garg, Shilpa

    2011-01-01

    Pericardial cysts are uncommon congenital abnormalities that occur in the middle mediastinum. Most of these are found incidentally on chest x-rays. The occurrence of pericardial cyst in children is quite rare. It needs to be differentiated from other cystic mediastinal masses. A rare case of pericardial cyst in a 5 year old male child is reported. The child presented with chest pain, cough and fever. The preoperative diagnosis of pericardial cyst was suggestive on echocardiography and CT scan. It was confirmed on histopathology after successful surgical excision. The rarity of this benign mediastinal lesion in children prompted us to report this case. PMID:21677811

  6. The design and evaluation of a 5.8 ghz laptop-based radar system

    NASA Astrophysics Data System (ADS)

    Teng, Kevin Chi-Ming

    This project involves design and analysis of a 5.8 GHz laptop-based radar system. The radar system measures Doppler, ranging and forming Synthetic Aperture Radar (SAR) images utilizing Matlab software provided from MIT Open Courseware and performs data acquisition and signal processing. The main purpose of this work is to bring new perspective to the existing radar project by increasing the ISM band frequency from 2.4 GHz to 5.8 GHz and to carry out a series of experiments on the implementation of the radar kit. Demonstrating the radar at higher operating frequency is capable of providing accurate data results in Doppler, ranging and SAR images.

  7. A single axis electrostatic beam deflection system for a 5-cm diameter ion thruster

    NASA Technical Reports Server (NTRS)

    Lathem, W. C.

    1972-01-01

    A single-axis electrostatic beam deflection system has been tested on a 5-cm diameter mercury ion thruster at a thrust level of about 0.43 mlb (25 mA beam current at 1400 volts). The accelerator voltage was 500 volts. Beam deflection capability of plus or minus 10 deg was demonstrated. A life test of 1367 hours was run at the above conditions. Results of the test indicated that the system could possibly perform for upwards of 10,000 hours.

  8. [A case of endocardial elastosis in a 5-week old infant].

    PubMed

    Zinka, E; Czarnecki, L

    1992-09-01

    A case is presented of fulminant endocardial elastosis in a 5-week-old infant. The baby died after four days from the appearance of the first pathological symptoms with evidence of extreme circulatory insufficiency. Of main importance for intravital diagnosis was echocardiographic examination. The autopsy confirmed the diagnosis. The myocardium was hypertrophic without evidence of inflammation. The typical changes for this disease were found in parietal endocardium of both ventricles, both atria, as well as both atrioventricular valves, and aortic valve. PMID:1295263

  9. Early Eruption of Maxillary Pre Molar with Turner's Hypoplasia in a 5-Year-Old Boy.

    PubMed

    Rai, Nitya; Mathur, Shivani; Sandhu, Meera; Sachdev, Vinod

    2016-08-01

    Early eruption of permanent maxillary premolar appears to be a unique finding, at such an early chronological age. Untimely eruption of permanent maxillary premolar is discussed in a 5-year-old male patient. On intra oral examination grossly carious primary maxillary first molar (tooth number 54,64) were reported. The erupting teeth presented with a hypomineralized cusp tip. Extraction following space maintainer in 64 region was given. Pediatric dentist should consider these kinds of rarities in eruption pattern while examining a pediatric patient. PMID:27656581

  10. Giant parietal lobe infantile gliosarcoma in a 5-year-old child.

    PubMed

    Savant, Hemant V; Balasubramaniam, Srikant; Mahajan, Vijay

    2015-01-01

    The relative frequency of pediatric gliosarcoma (GSM) is 1.9% among glioblastomas and 0.5% among pediatric central nervous system tumors. A 5-year-old female child came to us with history of fever and loss of appetite since 2 weeks and right sided weakness since 4 days. Magnetic resonance imaging showed a large heterogeneously enhancing space occupying lesion in the left parieto-occipital region. A parieto-occipital craniotomy with radical excision of tumor was performed. The patient was given adjuvant therapy following surgery and survived until 9 months following surgery. The etiopathogenesis, treatment modalities and prognosis of GSM is discussed.

  11. Early Eruption of Maxillary Pre Molar with Turner's Hypoplasia in a 5-Year-Old Boy.

    PubMed

    Rai, Nitya; Mathur, Shivani; Sandhu, Meera; Sachdev, Vinod

    2016-08-01

    Early eruption of permanent maxillary premolar appears to be a unique finding, at such an early chronological age. Untimely eruption of permanent maxillary premolar is discussed in a 5-year-old male patient. On intra oral examination grossly carious primary maxillary first molar (tooth number 54,64) were reported. The erupting teeth presented with a hypomineralized cusp tip. Extraction following space maintainer in 64 region was given. Pediatric dentist should consider these kinds of rarities in eruption pattern while examining a pediatric patient.

  12. Hypervitaminosis D causing nephrogenic diabetes insipidus in a 5-month-old infant.

    PubMed

    Ahmad, Ihab A; Al-Agha, Abdulmoein E

    2013-02-01

    Vitamin D intoxication in infancy leads to acute hypercalcemia and subsequent hypercalcuria with nephrocalcinosis. Strategies used for patients with vitamin D intoxication are unsatisfactory and associated with prolonged periods of hypercalcemia. We present a 5-month-old infant who had failure to thrive, refusal to feed, delayed motor development, truncal hypotonia, and dehydration. She had high plasma sodium and osmolality with low urine osmolality, and did not respond to intravenous desmopressin administration. She was diagnosed as nephrogenic diabetes insipidus due to hypercalcemia caused by hypervitaminosis D, and was treated with hydrochlorothiazide 2 mg/kg twice daily, and hydration.

  13. Microelectro-optical devices in a 5-level polysilicon surface micromachining technology

    SciTech Connect

    Smith, J.H.; Rodgers, M.S.; Sniegowski, J.J.; Miller, S.L.; Hetherington, D.; McWhorter, P.J.; Warren, M.E.

    1998-08-01

    The authors recently reported on the development of a 5-level polysilicon surface micromachine fabrication process consisting of four levels of mechanical poly plus an electrical interconnect layer and its application to complex mechanical systems. This paper describes the application of this technology to create micro-optical systems-on-a-chip. These are demonstration systems, which show that five levels of polysilicon provide greater performance, reliability, and significantly increased functionality. This new technology makes it possible to realize levels of system complexity that have so far only existed on paper, while simultaneously adding to the robustness of many of the individual subassemblies.

  14. Integron associated mobile genes

    PubMed Central

    Labbate, Maurizio; Boucher, Yan; Luu, Ivan; Chowdhury, Piklu Roy; Stokes, H.W.

    2012-01-01

    Lateral gene transfer (LGT) impacts on the evolution of prokaryotes in both the short and long-term. The short-term impacts of mobilized genes are a concern to humans since LGT explains the global rise of multi drug resistant pathogens seen in the past 70 years. However, LGT has been a feature of prokaryotes from the earliest days of their existence and the concept of a bifurcating tree of life is not entirely applicable to prokaryotes since most genes in extant prokaryotic genomes have probably been acquired from other lineages. Successful transfer and maintenance of a gene in a new host is understandable if it acts independently of cell networks and confers an advantage. Antibiotic resistance provides an example of this whereby a gene can be advantageous in virtually any cell across broad species backgrounds. In a longer evolutionary context however laterally transferred genes can be assimilated into even essential cell networks. How this happens is not well understood and we discuss recent work that identifies a mobile gene, unique to a cell lineage, which is detrimental to the cell when lost. We also present some additional data and believe our emerging model will be helpful in understanding how mobile genes integrate into cell networks. PMID:22754748

  15. Your Genes, Your Choices

    MedlinePlus

    Table of Contents Your Genes, Your Choices describes the Human Genome Project, the science behind it, and the ethical, legal, and social issues that are ... Nothing could be further from the truth. Your Genes, Your Choices points out how the progress of ...

  16. What Is a Gene?

    MedlinePlus

    ... a new kind of medicine — so new that scientists are still doing experiments to see if it works. It uses the technology of genetic engineering to treat a disease caused by a gene that has changed in some way. One method being tested is replacing sick genes with healthy ...

  17. Engineered gene circuits

    NASA Astrophysics Data System (ADS)

    Hasty, Jeff; McMillen, David; Collins, J. J.

    2002-11-01

    A central focus of postgenomic research will be to understand how cellular phenomena arise from the connectivity of genes and proteins. This connectivity generates molecular network diagrams that resemble complex electrical circuits, and a systematic understanding will require the development of a mathematical framework for describing the circuitry. From an engineering perspective, the natural path towards such a framework is the construction and analysis of the underlying submodules that constitute the network. Recent experimental advances in both sequencing and genetic engineering have made this approach feasible through the design and implementation of synthetic gene networks amenable to mathematical modelling and quantitative analysis. These developments have signalled the emergence of a gene circuit discipline, which provides a framework for predicting and evaluating the dynamics of cellular processes. Synthetic gene networks will also lead to new logical forms of cellular control, which could have important applications in functional genomics, nanotechnology, and gene and cell therapy.

  18. A gene expression screen.

    PubMed Central

    Wang, Z; Brown, D D

    1991-01-01

    A gene expression screen identifies mRNAs that differ in abundance between two mRNA mixtures by a subtractive hybridization method. The two mRNA populations are converted to double-stranded cDNAs, fragmented, and ligated to linkers for polymerase chain reaction (PCR) amplification. The multiple cDNA fragments isolated from any given gene can be treated as alleles in a genetic screen. Probability analysis of the frequency with which multiple alleles are found provides an estimation of the total number of up- and down-regulated genes. We have applied this method to genes that are differentially expressed in amphibian tadpole tail tissue in the first 24 hr after thyroid hormone treatment, which ultimately induces tail resorption. We estimate that there are about 30 up-regulated genes; 16 have been isolated. Images PMID:1722336

  19. Autophagy genes in immunity

    PubMed Central

    Virgin, Herbert W; Levine, Beth

    2009-01-01

    In its classical form, autophagy is a pathway by which cytoplasmic constituents, including intracellular pathogens, are sequestered in a double-membrane–bound autophagosome and delivered to the lysosome for degradation. This pathway has been linked to diverse aspects of innate and adaptive immunity, including pathogen resistance, production of type I interferon, antigen presentation, tolerance and lymphocyte development, as well as the negative regulation of cytokine signaling and inflammation. Most of these links have emerged from studies in which genes encoding molecules involved in autophagy are inactivated in immune effector cells. However, it is not yet known whether all of the critical functions of such genes in immunity represent ‘classical autophagy’ or possible as-yet-undefined autophagolysosome-independent functions of these genes. This review summarizes phenotypes that result from the inactivation of autophagy genes in the immune system and discusses the pleiotropic functions of autophagy genes in immunity. PMID:19381141

  20. Genes, genome and Gestalt.

    PubMed

    Grisolia, Cesar Koppe

    2005-01-01

    According to Gestalt thinking, biological systems cannot be viewed as the sum of their elements, but as processes of the whole. To understand organisms we must start from the whole, observing how the various parts are related. In genetics, we must observe the genome over and above the sum of its genes. Either loss or addition of one gene in a genome can change the function of the organism. Genomes are organized in networks of genes, which need to be well integrated. In the case of genetically modified organisms (GMOs), for example, soybeans, rats, Anopheles mosquitoes, and pigs, the insertion of an exogenous gene into a receptive organism generally causes disturbance in the networks, resulting in the breakdown of gene interactions. In these cases, genetic modification increased the genetic load of the GMO and consequently decreased its adaptability (fitness). Therefore, it is hard to claim that the production of such organisms with an increased genetic load does not have ethical implications.

  1. Aging process on spectrally determined spontaneous baroreflex sensitivity: a 5-year prospective study.

    PubMed

    Fauvel, Jean-Pierre; Cerutti, Catherine; Mpio, Ignace; Ducher, Michel

    2007-09-01

    The interindividual age-related decrease in baroreflex sensitivity (BRS) was reported in many cross-sectional studies. However, the long-term intraindividual decrease in BRS has never been confirmed by longitudinal studies. Data obtained from a 5-year prospective study designed to assess the 5-year stress effects on blood pressure (BP) provided the opportunity to assess longitudinal aging process on spectrally determined BRS (S-BRS) using the cross spectral analysis. This analysis was carried out in 205 men aged between 18 and 50 years who had 2 valid beat to beat BP recordings (Finapress) at a mean 5-year interval. At inclusion and at end of follow-up, S-BRS was significantly correlated with age (r=-0.50, P<0.001, r=-0.33, P<0.001 respectively). Interestingly, the slopes and the intercepts were not significantly different at a 5-year interval. This result is in favor of the good reproducibility of S-BRS. The attenuation with age of S-BRS was calculated at 3.6% a year. This decrease was slightly higher than the one obtained with the baseline data (2.3% per year). This longitudinal study provided, for the first time, an estimate of the slope of the age-related physiological S-BRS decrease in a mid-aged healthy male population. Our findings reinforce the interest of evaluating spontaneous BRS reported to predict hypertension and cardiovascular events in various populations.

  2. Regulation of the activity of the Bacillus licheniformis A5 glutamine synthetase.

    PubMed

    Donohue, T J; Bernlohr, R W

    1981-10-01

    The regulation of glutamine synthetase activity by positive and negative effectors of enzyme activity singularly and in combinations was studied by using a homogeneous enzyme preparation from Bacillus licheniformis A5. Phosphorylribosyl pyrophosphate at concentrations greater than 2mM stimulated glutamine synthetase activity by approximately 70%. The concentration of phosphorylribosyl pyrophosphate required for half-maximal stimulation of enzyme activity was 0.4 mM. Results obtained from studies of fractional inhibition of glutamine synthetase activity were consistent with the presence of one allosteric site for glutamine binding (apparent I0.5, 2.2mM) per active enzyme unit at a glutamate concentration of 50 mM. At a glutamate concentration of 30 mM or less, the data were consistent with the enzyme containing two binding sites for glutamine (one of which was an allosteric site with an apparent I0.5 of 0.4 mM). Bases on an analysis of the response of glutamine synthetase activity to positive and negative effectors in vitro and to the intracellular concentration of these effectors in vivo, the primary modulators of glutamine synthetase activity in B. licheniformis A5 appear to be glutamine and alanine (apparent I0.5, 5.2mM). PMID:6169702

  3. Conceptual design of a 5-m terahertz telescope at Dome A

    NASA Astrophysics Data System (ADS)

    Yang, Dehua; Wang, Hai; Zhang, Yong; Chen, Yi; Zhou, Guohua; Cheng, Jingquan; Li, Guoping

    2012-09-01

    A 5-meter terahertz telescope is proposed by the Chinese Center for Antarctic Astronomy (CCAA) for the East Antarctica site of the Dome A plateau. The Dome A 5-m terahertz telescope (DATE 5) will be operated at sub-millimeter waveband taking the unique advantage of the transparent atmospheric windows between 200 and 350 μm wavelengths at Dome A. A preliminary design has been conducted according to the given technical requirements and the special environmental conditions at Dome A. A symmetric R-C Cassegrain optical system is designed for the telescope, with a primary f-ratio of 0.4 and a wide field of view of 10 arcmin. The magnification of the sub-reflector is 9.4, leading to the final focal ratio of 3.76 and the focus 0.2 m below the vertex of the primary reflector. To ensure surface accuracy of the reflectors precise as small as 10 um RMS, we consider using Carbon Fiber Reinforced Plastics (CFRP) to build the backup structure (BUS) of the primary reflector and the sub-reflector itself. An alt-azimuthal mounting is adopted and a tall base structure beneath the telescope is set up to lift the telescope above the low atmosphere turbulent layer. All the mechanics, as well as control electronics, are strictly designed to fit the lower temperature operation in the Dome A environment. This paper is to generally present the mentioned systematic optical, structural and electronic design of the DATE 5 telescope.

  4. Antiphospholipid antibody syndrome: the flow cytometric annexin A5 competition assay as a diagnostic tool.

    PubMed

    Tomer, A; Bar-Lev, S; Fleisher, S; Shenkman, B; Friger, M; Abu-Shakra, M

    2007-10-01

    The mechanism underlying hypercoagulability in antiphospholipid antibody syndrome (APS) is uncertain. Here, we present a flow-cytometric assay (FCA) based on the hypothesis that anti-platelet-anionic-phospholipid autoantibodies (aPL) interfere with the activity of the natural anticoagulant protein annexin A5, thereby accelerating platelet procoagulant activity. This study assessed the clinical utility of the feasible FCA, which demonstrates the competition of the patient's aPL with the binding of annexin A5 to the platelet-anionic-phospholipids, in the diagnosis of APS. Sixty-two (94%) of 66 APS patients, 20 (51%) of 39 patients with systemic lupus erythematosus and two (4%) of 49 healthy individuals were positive by FCA. Compared with the anticardiolipin (aCL) assay, the relative sensitivity was 82% and the specificity 73.3%. However, 19 (25%) aCL-negative patients were positive by FCA; 12 were positive for lupus-anticoagulant (LA). Compared with LA assay, the relative sensitivity was 85% and the specificity 72.2%. However, 21 (26%) LA-negative patients were FCA-positive, 12 were positive for aCL. The FCA was particularly sensitive for APS patients with arterial (97.0%) and gestational vascular complications (100%) with overall sensitivity of 95% and specificity of 97%. Our findings suggest that the FCA is practical, sensitive and specific for the detection of clinically relevant aPL in the diagnosis of APS.

  5. Characterization of the fan1 locus in soybean line A5 and development of molecular assays for high-throughput genotyping of FAD3 genes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Soybean is one of the most important oil crops in the world, and reduced linolenic acid content of soybean oil will provide increased stability of the oil to consumers and food manufacturers and limit the amount of trans-fat to be used in the processed foods. The linolenic content in soybean seeds i...

  6. 4. AERIAL VIEW OF GENE WASH RESERVOIR AND GENE CAMP ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    4. AERIAL VIEW OF GENE WASH RESERVOIR AND GENE CAMP LOOKING SOUTHWEST. DAM AND SPILLWAY VISIBLE IN BOTTOM OF PHOTO. - Gene Wash Reservoir & Dam, 2 miles west of Parker Dam, Parker Dam, San Bernardino County, CA

  7. The evolution of small gene clusters: evidence for an independent origin of the maltase gene cluster in Drosophila virilis and Drosophila melanogaster.

    PubMed

    Vieira, C P; Vieira, J; Hartl, D L

    1997-10-01

    We analyzed a 5,770-bp genomic region of Drosophila virilis that contains a cluster of two maltase genes showing sequence similarity with genes in a cluster of three maltase genes previously identified in Drosophila melanogaster. The D. virilis maltase genes are designated Mav1 and Mav2. In addition to being different in gene number, the cluster of genes in D. virilis differs dramatically in intron-exon structure from the maltase genes in D. melanogaster, the transcriptional orientation of the genes in the cluster also differs between the species. Our findings support a model in which the maltase gene cluster in D. virilis and D. melanogaster evolved independently. Furthermore, while in D. melanogaster the maltase gene cluster lies only 10 kb distant from the larval cuticle gene cluster, the maltase and larval cuticle gene clusters in D. virilis are located very far apart and on a different chromosome than that expected from the known chromosome arm homologies between D. virilis and D. melanogaster. A region of the genome containing the maltase and larval cuticle gene clusters appears to have been relocated between nonhomologous chromosomes.

  8. Duplicate genes increase gene expression diversity within and between species.

    PubMed

    Gu, Zhenglong; Rifkin, Scott A; White, Kevin P; Li, Wen-Hsiung

    2004-06-01

    Using microarray gene expression data from several Drosophila species and strains, we show that duplicated genes, compared with single-copy genes, significantly increase gene expression diversity during development. We show further that duplicate genes tend to cause expression divergences between Drosophila species (or strains) to evolve faster than do single-copy genes. This conclusion is also supported by data from different yeast strains.

  9. [Is gene technology immoral?].

    PubMed

    Halter, H

    1994-10-01

    Since it came into being in the USA in the early 1970s, gene technology has always been fundamentally controversial, especially in the German-speaking countries. The optimistic--or critical--supporters of gene technology are convinced that, in view of gene technology's not otherwise attainable advantages for human and animal health, for food production and other important aims, it would be ethically unacceptable to restrict to the minimum or even ban it. On the other hand, the radical critics are convinced that gene technology, in view of its anthropologically false starting-point, the questionable interests behind it, and above all its unforeseeable, serious negative implications for mankind and environment, is unacceptable on ethical grounds. Critical reflexion on these polarized arguments must start from the question why precisely gene technology is so controversial, and what are the criteria for ethical assessment. These reflexions presuppose that the prior judgement of gene technology as a technology in the ideological field is rooted in life attitudes, history and nature in general, and this is true not only of gene technology's opponents but also its supporters. It is thus a question of one ideology vs. another. Chief importance here attaches to the mankind-nature relationship and the need to take seriously the fundamental ambivalence of all (!) human action with unforeseeable consequences. The conclusion is that neither to demonize nor to glorify gene technology, as a matter of principle, does justice to its wide and varied positive or negative potential. The ethical assessment of gene technology must be differentiated according to the aims and possible implications.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7939540

  10. Clock genes and cancer.

    PubMed

    Wood, Patricia A; Yang, Xiaoming; Hrushesky, William J M

    2009-12-01

    Period genes ( Per2, Per1) are essential circadian clock genes. They also function as negative growth regulators. Per2 mutant mice show de novo and radiation-induced epithelial hyperplasia, tumors, and an abnormal DNA damage response. Human tumors show Period gene mutations or decreased expression. Other murine clock gene mutations are not associated with a tumor prone phenotype. Shift work and nocturnal light exposure are associated with circadian clock disruption and with increased cancer risk. The mechanisms responsible for the connection between the circadian clock and cancer are not well defined. We propose that circadian disruption per se is not uniformly tumor promoting and the mechanisms for tumor promotion by specific circadian clock disturbances will differ dependent upon the genes and pathways involved. We propose that Period clock gene mutations promote tumorigenesis by unique molecular pathways. Per2 and Per1 modulate beta-catenin and cell proliferation in colon and non-colon cancer cells. Per2 mutation increases intestinal beta-catenin levels and colon polyp formation. Per2 mutation also increases Apc(Min/+)-mediated intestinal and colonic polyp formation. Intestinal tumorigenesis per se may also alter clock function as a result of increased beta-catenin destabilizing PER2 protein. Levels and circadian rhythm of PER2 in Apc(Min/+) mouse intestine are markedly decreased, and selective abnormalities in intestinal clock gene and clock-controlled gene expression are seen. We propose that tumor promotion by loss of PERIOD clock proteins is unique to these clock genes as a result of altered beta-catenin signaling and DNA damage response. PERIOD proteins may offer new targets for cancer prevention and control.

  11. Annexin A5 Increases Survival in Murine Sepsis Model by Inhibiting HMGB1-Mediated Proinflammation and Coagulation

    PubMed Central

    Park, Jung Hwa; Jang, Jong-Hwa; Choi, Eun Jung; Kim, Young Seob; Lee, Eun Ji; Jung, In Duk; Han, Hee Dong; Wu, T-C; Hung, Chien-Fu; Kang, Tae Heung; Park, Yeong-Min

    2016-01-01

    The identification of HMGB1 as a late mediator in sepsis has highlighted HMGB1 as a promising therapeutic target for sepsis treatment. Recent studies have revealed that annexin A5, a 35 kDa Ca2+-dependent phospholipid binding protein, exerts antiinflammatory effect by inhibiting LPS binding to TLR4/MD2 complex. Annexin A5 administration has been shown to protect against endotoxin lethality even when the treatment was given after the early cytokine response, which prompted our group to suspect that annexin A5 may inhibit the binding of HMGB1, as well as endotoxin, to TLR4. Here we suggest annexin A5 as a new inhibitor of HMGB1-mediated proinflammatory cytokine production and coagulation in sepsis. We first confirmed the inhibitory role of annexin A5 in LPS-induced production of proinflammatory cytokines both in vitro and in vivo. We observed that annexin A5 protects against tissue damage and organ dysfunction during endotoxemia in vivo. We then assessed the inhibiting role of annexin A5 in HMGB1/TLR4 interaction, and showed that annexin A5 treatment reduces HMGB1-mediated cytokines IL6 and TNFα both in vitro and in vivo. Finally, we confirmed that anticoagulant property of annexin A5 persists in various septic conditions including elevated HMGB1. Overall, we suggest annexin A5 as an alternative therapeutic approach for controlling HMGB1-mediated proinflammation and coagulation in patients with sepsis. PMID:27447360

  12. Dexamethasone Regulates EphA5, a Potential Inhibitory Factor with Osteogenic Capability of Human Bone Marrow Stromal Cells

    PubMed Central

    Yamada, Tsuyoshi; Yoshii, Toshitaka; Yasuda, Hiroaki; Okawa, Atsushi; Sotome, Shinichi

    2016-01-01

    We previously demonstrated the importance of quality management procedures for the handling of human bone marrow stromal cells (hBMSCs) and provided evidence for the existence of osteogenic inhibitor molecules in BMSCs. One candidate inhibitor is the ephrin type-A receptor 5 (EphA5), which is expressed in hBMSCs and upregulated during long-term culture. In this study, forced expression of EphA5 diminished the expression of osteoblast phenotypic markers. Downregulation of endogenous EphA5 by dexamethasone treatment promoted osteoblast marker expression. EphA5 could be involved in the normal growth regulation of BMSCs and could be a potential marker for replicative senescence. Although Eph forward signaling stimulated by ephrin-B-Fc promoted the expression of ALP mRNA in BMSCs, exogenous addition of EphA5-Fc did not affect the ALP level. The mechanism underlying the silencing of EphA5 in early cultures remains unclear. EphA5 promoter was barely methylated in hBMSCs while histone deacetylation could partially suppress EphA5 expression in early-passage cultures. In repeatedly passaged cultures, the upregulation of EphA5 independent of methylation could competitively inhibit osteogenic signal transduction pathways such as EphB forward signaling. Elucidation of the potential inhibitory function of EphA5 in hBMSCs may provide an alternative approach for lineage differentiation in cell therapy strategies and regenerative medicine. PMID:27057165

  13. Genes in sweeping competition.

    PubMed

    Nurminsky, D I

    2001-01-01

    Analysis of DNA variation is a powerful tool for detecting adaptation at the genomic level. The contribution of adaptive evolution is evident from examples of rapidly evolving genes, which represent the likely targets for strong selection. More subtle adaptation is also an integral component of routine maintenance of gene performance, continuously applied to every gene. Adaptive changes in the population are accomplished through selective sweeps, i.e. complete or partial fixation of beneficial alleles. The evidence is accumulating that selective sweeps are quite frequent events which, together with associated genetic hitchhiking, represent dominant forces that influence molecular evolution by shaping the variability pattern in the genome.

  14. Haemophagocytic lymphohistiocytosis: a cause of unresponsive malaria in a 5-year-old girl.

    PubMed

    Bhagat, Manish; Kanhere, Sujata; Kadakia, Purvi; Phadke, Varsha; George, Riya; Chaudhari, Kushagra

    2015-01-01

    A 5-year-old immunocompetent girl presented with fever, jaundice, hepatosplenomegaly and pancytopenia. The peripheral blood smear demonstrated mixed malaria infection (Plasmodium vivax and Plasmodium falciparum). Fever was persistent despite antimalarials in the absence of any coexisting bacterial or viral infection. Laboratory findings included cytopaenia, hyperbilirubinaemia, hyperferritinaemia, hypertriglyceridaemia, hyponatraemia, deranged partial thromboplastin time, decreasing ESR and megaloblastic changes on bone marrow aspiration. A final diagnosis of haemophagocytic lymphohistiocytosis (HLH) with megaloblastic anaemia associated with severe mixed malaria was made. There was a dramatic response to corticosteroid treatment with improvement in her clinical condition. This report endorses the use of corticosteroids in malaria-associated HLH whenever there is no clinical improvement with antimalarials alone. PMID:26744159

  15. Haemophagocytic lymphohistiocytosis: a cause of unresponsive malaria in a 5-year-old girl.

    PubMed

    Bhagat, Manish; Kanhere, Sujata; Kadakia Affiliation When The Manuscript Was Written Department Of Paediatrics K J Somaiya Medical College And Hospital Mumbai India, Purvi; Phadke, Varsha; George, Riya; Chaudhari, Kushagra

    2014-11-19

    A 5-year-old immunocompetent girl presented with fever, jaundice, hepatosplenomegaly and pancytopenia. The peripheral blood smear demonstrated mixed malaria infection (Plasmodium vivax and Plasmodium falciparum). Fever was persistent despite antimalarials in the absence of any coexisting bacterial or viral infection. Laboratory findings included cytopaenia, hyperbilirubinaemia, hyperferritinaemia, hypertriglyceridaemia, hyponatraemia, deranged partial thromboplastin time, decreasing ESR and megaloblastic changes on bone marrow aspiration. A final diagnosis of haemophagocytic lymphohistiocytosis (HLH) with megaloblastic anaemia associated with severe mixed malaria was made. There was a dramatic response to corticosteroid treatment with improvement in her clinical condition. This report endorses the use of corticosteroids in malaria-associated HLH whenever there is no clinical improvement with antimalarials alone. PMID:25410687

  16. Isolation and characterization of a bacteriophage for bacillus licheniformis A5

    SciTech Connect

    Schreier, H.J.; Vonada, E.K.; Yasbin, R.E.; Bernlohr, R.W.

    1982-01-01

    The isolation of a virulent bacteriophage for Bacillus licheniformis A5 is reported. This bacteriophage, designated NLP-1, has an icosahedral head 100 nm in diameter and a contractible tail with a maximum length of 130 nm. Its DNA has a density of 1.741 g/cm/sup 3/ and a T/sub m/ of 78.4/sup 0/C. Base composition analysis showed that thymine is absent and is replaced by hydroxymethyluracil. NLP-1 appears to belong to the Bacillus group of bacteriophages that includes SP01 and SP82. It will infect B. cereus T and B. brevis 8185, but will not infect B. subtilis W23 or 168.

  17. Effects of Burning Alternative Fuel in a 5-Cup Combustor Sector

    NASA Technical Reports Server (NTRS)

    Tacina, K. M.; Chang, C. T.; Lee, C.-M.; He, Z.; Herbon, J.

    2015-01-01

    A goal of NASA's Environmentally Responsible Aviation (ERA) program is to develop a combustor that will reduce the NOx emissions and that can burn both standard and alternative fuels. To meet this goal, NASA partnered with General Electric Aviation to develop a 5-cup combustor sector; this sector was tested in NASA Glenn's Advanced Subsonic Combustion Rig (ASCR). To verify that the combustor sector was fuel-flexible, it was tested with a 50-50 blend of JP-8 and a biofuel made from the camelina sativa plant. Results from this test were compared to results from tests where the fuel was neat JP-8. Testing was done at three combustor inlet conditions: cruise, 30% power, and 7% power. When compared to burning JP-8, burning the 50-50 blend did not significantly affect emissions of NOx, CO, or total hydrocarbons. Furthermore, it did not significantly affect the magnitude and frequency of the dynamic pressure fluctuations.

  18. Atlantoaxial rotatory subluxation as a cause of torticollis in a 5-year-old girl.

    PubMed

    Bagouri, Elmunzar; Deshmukh, Sandeep; Lakshmanan, Palaniappan

    2014-05-15

    Many patients present to the emergency department complaining of a sore or stiff neck and lateral flexion of the neck with contralateral rotation. Under the pressure of the breaching time and busy shifts some of the patients are discharged to the care of their general practitioners without adequate investigations. While most of the cases are due to benign causes, torticollis can be due to many congenital and acquired pathologies, some of which may need further investigation and urgent management. Atlantoaxial subluxation (AAS), tumours of the base of the skull and infections are among these causes. Delayed diagnosis may lead to worsening neurology and complicate the management. We report a case of a 5-year-old girl who presented to our fracture clinic with a fractured clavicle and torticollis; her subsequent investigations confirmed the diagnosis of AAS. Our patient responded to non-operative treatment and improved with no neurological complications.

  19. Phased Acoustic Array Measurements of a 5.75 Percent Hybrid Wing Body Aircraft

    NASA Technical Reports Server (NTRS)

    Burnside, Nathan J.; Horne, William C.; Elmer, Kevin R.; Cheng, Rui; Brusniak, Leon

    2016-01-01

    Detailed acoustic measurements of the noise from the leading-edge Krueger flap of a 5.75 percent Hybrid Wing Body (HWB) aircraft model were recently acquired with a traversing phased microphone array in the AEDC NFAC (Arnold Engineering Development Complex, National Full Scale Aerodynamics Complex) 40- by 80-Foot Wind Tunnel at NASA Ames Research Center. The spatial resolution of the array was sufficient to distinguish between individual support brackets over the full-scale frequency range of 100 to 2875 Hertz. For conditions representative of landing and take-off configuration, the noise from the brackets dominated other sources near the leading edge. Inclusion of flight-like brackets for select conditions highlights the importance of including the correct number of leading-edge high-lift device brackets with sufficient scale and fidelity. These measurements will support the development of new predictive models.

  20. A 5′ RNA element promotes dengue virus RNA synthesis on a circular genome

    PubMed Central

    Filomatori, Claudia V.; Lodeiro, Maria F.; Alvarez, Diego E.; Samsa, Marcelo M.; Pietrasanta, Lía; Gamarnik, Andrea V.

    2006-01-01

    The mechanisms of RNA replication of plus-strand RNA viruses are still unclear. Here, we identified the first promoter element for RNA synthesis described in a flavivirus. Using dengue virus as a model, we found that the viral RdRp discriminates the viral RNA by specific recognition of a 5′ element named SLA. We demonstrated that RNA–RNA interactions between 5′ and 3′ end sequences of the viral genome enhance dengue virus RNA synthesis only in the presence of an intact SLA. We propose a novel mechanism for minus-strand RNA synthesis in which the viral polymerase binds SLA at the 5′ end of the genome and reaches the site of initiation at the 3′ end via long-range RNA–RNA interactions. These findings provide an explanation for the strict requirement of dengue virus genome cyclization during viral replication. PMID:16882970

  1. Photogrammetry of a 5m Inflatable Space Antenna With Consumer Digital Cameras

    NASA Technical Reports Server (NTRS)

    Pappa, Richard S.; Giersch, Louis R.; Quagliaroli, Jessica M.

    2000-01-01

    This paper discusses photogrammetric measurements of a 5m-diameter inflatable space antenna using four Kodak DC290 (2.1 megapixel) digital cameras. The study had two objectives: 1) Determine the photogrammetric measurement precision obtained using multiple consumer-grade digital cameras and 2) Gain experience with new commercial photogrammetry software packages, specifically PhotoModeler Pro from Eos Systems, Inc. The paper covers the eight steps required using this hardware/software combination. The baseline data set contained four images of the structure taken from various viewing directions. Each image came from a separate camera. This approach simulated the situation of using multiple time-synchronized cameras, which will be required in future tests of vibrating or deploying ultra-lightweight space structures. With four images, the average measurement precision for more than 500 points on the antenna surface was less than 0.020 inches in-plane and approximately 0.050 inches out-of-plane.

  2. Salter-Harris type-IV displaced distal radius fracture in a 5-year-old.

    PubMed

    Huntley, Samuel R; Summers, Spencer H; Stricker, Stephen J

    2016-03-01

    Displaced Salter-Harris type-IV fractures are rare in young children and can result in articular incongruity or premature physeal arrest. We describe a 5-year-old boy who sustained a displaced left distal radial Salter-Harris type-IV fracture. The patient had normal wrist function and physeal growth at the 3-year postoperative follow-up. Our patient is by far the youngest reported child with a displaced Salter-Harris type-IV fracture of the distal radius. Prompt anatomic reduction and fixation of a displaced distal radial Salter-Harris type-IV fracture can result in excellent short-term wrist motion with maintenance of physeal function.

  3. Lepton mixing from the interplay of the alternating group A 5 and CP

    NASA Astrophysics Data System (ADS)

    Di Iura, Andrea; Hagedorn, Claudia; Meloni, Davide

    2015-08-01

    Assuming three generations of Majorana neutrinos, we study the different mixing patterns that arise from the non-trivial breaking of the flavor group A 5 and CP to the residual symmetries Z 3, Z 5 or Z 2 × Z 2 in the charged lepton and to Z 2 × CP in the neutrino sector. All patterns contain only one free parameter θ and thus mixing angles as well as the Dirac and the two Majorana phases are strongly correlated. We perform an analytical and a numerical study of all possible mixing patterns. It turns out that only four patterns can describe the experimentally measured values of the mixing angles for a particular choice of θ well. All of them predict trivial Majorana phases, while the Dirac phase δ is maximal for two patterns and trivial for the two remaining ones. If δ is maximal, also the atmospheric mixing angle is fixed to be maximal.

  4. Characterization of timing jitter in a 5 GHz quantum dot passively mode-locked laser.

    PubMed

    Lin, Chang-Yi; Grillot, Frederic; Li, Yan; Raghunathan, Ravi; Lester, Luke F

    2010-10-11

    The timing jitter performance of a 5 GHz quantum dot passively mode-locked laser is investigated at different harmonics in the RF spectrum. The necessity of measuring the phase noise at relatively large harmonic numbers is motivated experimentally in the context of determining the corner frequency, its correlation to the RF linewidth, and the related white noise plateau level. The single-sideband phase noise with an integrated timing jitter of 211 fs (4-80 MHz) is reported. An all-microwave technique has been used to determine a pulse-to-pulse rms timing jitter of 96 fs/cycle. This low timing jitter value makes the chip-scale quantum dot mode-locked laser an attractive source for low noise applications such as optical clocking and sampling. PMID:20941093

  5. Synthesis and Bioactivities of Novel Pyrazole Oxime Derivatives Containing a 5-Trifluoromethylpyridyl Moiety.

    PubMed

    Dai, Hong; Chen, Jia; Li, Hong; Dai, Baojiang; He, Haibing; Fang, Yuan; Shi, Yujun

    2016-01-01

    In this study, in order to find novel biologically active pyrazole oxime compounds, a series of pyrazole oxime derivatives containing a 5-trifluoromethylpyridyl moiety were synthesized. Preliminary bioassays indicated that most title compounds were found to display good to excellent acaricidal activity against Tetranychus cinnabarinus at a concentration of 200 μg/mL, and some designed compounds still showed excellent acaricidal activity against Tetranychus cinnabarinus at the concentration of 10 μg/mL, especially since the inhibition rates of compounds 8e, 8f, 8l, 8m, 8n, 8p, and 8q were all 100.00%. Interestingly, some target compounds exhibited moderate to good insecticidal activities against Plutella xylostella and Aphis craccivora at a concentration of 200 μg/mL; furthermore, compounds 8e and 8l possessed outstanding insecticidal activities against Plutella xylostella under the concentration of 50 μg/mL. PMID:26927054

  6. Building-up a Smile in a 5-Year-Old Child: A Case Report.

    PubMed

    Marwaha, Mohita; Bhat, Manohar; Singh Nanda, Kanwar Deep

    2012-05-01

    A variety of therapeutic modalities, from removable partial dentures to conventional fixed space maintainer can be used for the replacement of traumatically missing or carious lost primary anterior teeth. Dentistry has advanced to a point where it is undesirable for children to be partially edentulous or to have unattractive anterior teeth. The introduction of new materials and adhesive systems in dentistry, offers a new reconstructive alternative for severely destroyed or lost primary anterior teeth. The purpose of this article was to present a clinical case of four primary anterior teeth replacement by means of fiber-reinforced composite bridge. This technique offers a conservative, esthetic and noninvasive treatment. It can be considered, as a long- lasting reversible provisional treatment. How to cite this article: Marwaha M, Bhat M, Nanda KDS. Building-up a Smile in a 5-Year-Old Child: A Case Report. Int J Clin Pediatr Dent 2012;5(2):151-154.

  7. Building-up a Smile in a 5-Year-Old Child: A Case Report

    PubMed Central

    Bhat, Manohar; Singh Nanda, Kanwar Deep

    2012-01-01

    ABSTRACT A variety of therapeutic modalities, from removable partial dentures to conventional fixed space maintainer can be used for the replacement of traumatically missing or carious lost primary anterior teeth. Dentistry has advanced to a point where it is undesirable for children to be partially edentulous or to have unattractive anterior teeth. The introduction of new materials and adhesive systems in dentistry, offers a new reconstructive alternative for severely destroyed or lost primary anterior teeth. The purpose of this article was to present a clinical case of four primary anterior teeth replacement by means of fiber-reinforced composite bridge. This technique offers a conservative, esthetic and noninvasive treatment. It can be considered, as a long- lasting reversible provisional treatment. How to cite this article: Marwaha M, Bhat M, Nanda KDS. Building-up a Smile in a 5-Year-Old Child: A Case Report. Int J Clin Pediatr Dent 2012;5(2):151-154. PMID:25206158

  8. Increased risk of cancer after Bell's palsy: a 5-year follow-up study.

    PubMed

    Sheu, Jau-Jiuan; Keller, Joseph J; Lin, Herng-Ching

    2012-11-01

    Reactivation of latent herpes simplex virus (HSV) type I or varicella-zoster virus (VZV) has been recognized as the most common pathomechanism underlying Bell's palsy. There is also increased reactivation of HSV or VZV in patients with immunosuppressed states and in cancer patients. The purpose of this study was to investigate the risk for cancer during a 5-year follow-up period after diagnosis of Bell's palsy by using a population-based dataset in Taiwan. We used data from the "Longitudinal Health Insurance Database". We identified 2,618 patients with Bell's palsy as the study cohort and randomly selected 13,090 patients to be used as a comparison cohort. Cox proportional hazards regression was performed to compare the 5-year risk of subsequent cancer between the study and comparison cohorts. We found that the incidence of cancer was 1.55 (95 % CI 1.35-1.78) per 100 person-years for patients with Bell's palsy and 1.09 (95 % CI 1.02-1.18) per 100 person-years for comparison patients. After censoring cases that died from non-cancer causes during the follow-up period and adjusting for urbanization, monthly income, geographic region, and diabetes, the hazard ratio (HR) for cancer during the 5-year follow-up period for patients with Bell's palsy was 1.43 times that for comparison patients (95 % CI 1.22-1.73). There was a particularly increased risk of oral cancer (HR = 2.49; 95 % CI 1.54-4.03) for patients with Bell's palsy compared with the other patients. We conclude that patients with Bell's palsy were at significant risk of cancer during a 5-year follow-up period after diagnosis.

  9. A 5-year scientometric analysis of research centers affiliated to Tehran University of Medical Sciences

    PubMed Central

    Yazdani, Kamran; Rahimi-Movaghar, Afarin; Nedjat, Saharnaz; Ghalichi, Leila; Khalili, Malahat

    2015-01-01

    Background: Since Tehran University of Medical Sciences (TUMS) has the oldest and highest number of research centers among all Iranian medical universities, this study was conducted to evaluate scientific output of research centers affiliated to Tehran University of Medical Sciences (TUMS) using scientometric indices and the affecting factors. Moreover, a number of scientometric indicators were introduced. Methods: This cross-sectional study was performed to evaluate a 5-year scientific performance of research centers of TUMS. Data were collected through questionnaires, annual evaluation reports of the Ministry of Health, and also from Scopus database. We used appropriate measures of central tendency and variation for descriptive analyses. Moreover, uni-and multi-variable linear regression were used to evaluate the effect of independent factors on the scientific output of the centers. Results: The medians of the numbers of papers and books during a 5-year period were 150.5 and 2.5 respectively. The median of the "articles per researcher" was 19.1. Based on multiple linear regression, younger age centers (p=0.001), having a separate budget line (p=0.016), and number of research personnel (p<0.001) had a direct significant correlation with the number of articles while real properties had a reverse significant correlation with it (p=0.004). Conclusion: The results can help policy makers and research managers to allocate sufficient resources to improve current situation of the centers. Newly adopted and effective scientometric indices are is suggested to be used to evaluate scientific outputs and functions of these centers. PMID:26157724

  10. Dynamic changes in prefrontal cortex gene expression following lysergic acid diethylamide administration.

    PubMed

    Nichols, Charles D; Garcia, Efrain E; Sanders-Bush, Elaine

    2003-03-17

    Lysergic acid diethylamide (LSD) is a psychoactive drug that transiently alters human perception, behavior, and mood at extremely low doses. Certain aspects of the behavior elicited by acute doses of LSD closely resemble symptoms of mental disorders such as schizophrenia. Characterizing gene expression profiles after LSD will be important for understanding how it alters behavior, and will lead to novel insights into disorders, such as schizophrenia, whose behavioral symptoms resemble the temporary effects of hallucinogenic drugs. We previously identified a small collection of genes within the rat prefrontal cortex that respond to LSD. Many of the products of these genes are involved in the process of synaptic plasticity. In the current report, we present a detailed analysis of the expression of these genes within the brain using RNase protection analysis. We find that the gene response to LSD is quite dynamic. The expression of some genes increases rapidly and decreases rapidly, while other genes change more gradually. Dose-response studies show two classes of expression; gene expression maximally stimulated at lower doses, versus gene expression that continues to rise at the higher doses. The role of the 5-HT(1A) and 5-HT(2A) receptor in mediating the increases in gene expression was examined in a series of experiments using receptor specific antagonists. Most expression increases were due to activation of the 5-HT(2A) receptor, however expression of two genes had neither a 5-HT(1A) nor a 5-HT(2A) receptor component.

  11. Annexin A5 haplotype M2 is not a risk factor for recurrent spontaneous abortion in Northern Europe: is there sufficient evidence?

    PubMed

    Markoff, Arseni; Kurahashi, Hiroki; Grandone, Elvira; Bogdanova, Nadja

    2016-05-01

    The M2 haplotype of the annexin A5 gene is a well-recognized predisposition factor for recurrent spontaneous abortion (RSA). A recent publication by Nagirnaja et al. (2015) in PLoS One discusses the risk role of the M2 haplotype for RSA in cases compared with controls of North European extraction and arrives at a negative result. As a number of previous and fairly recent studies have supported the proposed involvement of the M2 haplotype in the cause of idiopathic RSA, this commentary aims to highlight problematic issues in the above publication. It is the opinion of the authors that the study by Nagirnaja et al. (2015) does not generate adequate proof of the absence of RSA risk, attributable to carriage of the M2 haplotype.

  12. Gene structure and expression

    SciTech Connect

    Hawkins, J. )

    1990-01-01

    This book describes the structure of genes in molecular terms and summarizes present knowledge about how their activity is regulated. It covers a range of topics, including a review of the structure and replication of DNA, transcription and translation, prokaryotic and eukaryotic gene organization and expression, retroviruses and oncogenes. The book also includes a chapter on the methodology of DNA manipulation including sections on site-directed mutagenesis, the polymerase chain reaction, reporter genes and restriction fragment length polymorphisms. The hemoglobin gene system and the genetics of the proteins of the immune system are presented in the latter half of the book to show the structure and expression of the most well-studied systems in higher eukaryotes. The final chapter reviews the differences between prokaryotic and the eukaryotic genomes.

  13. GeneLab

    NASA Technical Reports Server (NTRS)

    Berrios, Daniel C.; Thompson, Terri G.

    2015-01-01

    NASA GeneLab is expected to capture and distribute omics data and experimental and process conditions most relevant to research community in their statistical and theoretical analysis of NASAs omics data.

  14. Epigenetics and gene expression.

    PubMed

    Gibney, E R; Nolan, C M

    2010-07-01

    Transcription, translation and subsequent protein modification represent the transfer of genetic information from the archival copy of DNA to the short-lived messenger RNA, usually with subsequent production of protein. Although all cells in an organism contain essentially the same DNA, cell types and functions differ because of qualitative and quantitative differences in their gene expression. Thus, control of gene expression is at the heart of differentiation and development. Epigenetic processes, including DNA methylation, histone modification and various RNA-mediated processes, are thought to influence gene expression chiefly at the level of transcription; however, other steps in the process (for example, translation) may also be regulated epigenetically. The following paper will outline the role epigenetics is believed to have in influencing gene expression.

  15. "Bad genes" & criminal responsibility.

    PubMed

    González-Tapia, María Isabel; Obsuth, Ingrid

    2015-01-01

    The genetics of the accused is trying to break into the courts. To date several candidate genes have been put forward and their links to antisocial behavior have been examined and documented with some consistency. In this paper, we focus on the so called "warrior gene", or the low-activity allele of the MAOA gene, which has been most consistently related to human behavior and specifically to violence and antisocial behavior. In preparing this paper we had two objectives. First, to summarize and analyze the current scientific evidence, in order to gain an in depth understanding of the state of the issue and determine whether a dominant line of generally accepted scientific knowledge in this field can be asserted. Second, to derive conclusions and put forward recommendations related to the use of genetic information, specifically the presence of the low-activity genotype of the MAOA gene, in modulation of criminal responsibility in European and US courts.

  16. "Bad genes" & criminal responsibility.

    PubMed

    González-Tapia, María Isabel; Obsuth, Ingrid

    2015-01-01

    The genetics of the accused is trying to break into the courts. To date several candidate genes have been put forward and their links to antisocial behavior have been examined and documented with some consistency. In this paper, we focus on the so called "warrior gene", or the low-activity allele of the MAOA gene, which has been most consistently related to human behavior and specifically to violence and antisocial behavior. In preparing this paper we had two objectives. First, to summarize and analyze the current scientific evidence, in order to gain an in depth understanding of the state of the issue and determine whether a dominant line of generally accepted scientific knowledge in this field can be asserted. Second, to derive conclusions and put forward recommendations related to the use of genetic information, specifically the presence of the low-activity genotype of the MAOA gene, in modulation of criminal responsibility in European and US courts. PMID:25708001

  17. Vaginal gene therapy.

    PubMed

    Rodríguez-Gascón, Alicia; Del Pozo-Rodríguez, Ana; Isla, Arantxazu; Solinís, María Angeles

    2015-09-15

    In the last years, vaginal gene therapy has gained increasing attention mainly for the treatment and control of sexually transmitted infections. DNA delivery has been also suggested to improve reproductive outcomes for women with deficiencies in the female reproductive tract. Although no product has reached clinical phase, preclinical investigations reveal the potential of the vaginal tract as an effective administration route for gene delivery. This review focuses on the main advantages and challenges of vaginal gene therapy, and on the most used nucleic acid delivery systems, including viral and non-viral vectors. Additionally, the advances in the application of vaginal gene therapy for the treatment and/or prevention of infectious diseases such as the human immunodeficiency virus (HIV), the human papillomavirus (HPV) or the herpes simplex virus (HSV) are presented.

  18. miR-199a-5p regulates β1 integrin through Ets-1 to suppress invasion in breast cancer.

    PubMed

    Li, Wentong; Wang, Hui; Zhang, Jinbao; Zhai, Limin; Chen, Weijuan; Zhao, Chunling

    2016-07-01

    Increasing evidence has revealed that miR-199a-5p is actively involved in tumor invasion and metastasis as well as in the decline of breast cancer tissues. In this research, overexpression of miR-199a-5p weakened motility and invasion of breast cancer cells MCF-7 and MDA-MB-231. Upregulation of Ets-1 increased breast cancer cell invasion, but the mechanism by which miR-199a-5p modulates activation of Ets-1 in breast cancer was not clarified. We investigated the relationship between miR-199a-5p and Ets-1 on the basis of 158 primary breast cancer case specimens, and the results showed that Ets-1 expression was inversely correlated with endogenous miR-199a-5p. Overexpression of miR-199a-5p reduced the mRNA and protein levels of Ets-1 in MCF-7 and MDA-MB-231 cells, whereas anti-miR-199a-5p elevated Ets-1. siRNA-mediated Ets-1 knockdown phenocopied the inhibition invasion of miR-199a-5p in vitro. Moreover, luciferase reporter assay revealed that miR-199a-5p directly targeted 3'-UTR of Ets-1 mRNA. This research revealed that miR-199a-5p could descend the levels of β1 integrin by targeting 3'-UTR of Ets-1 to alleviate the invasion of breast cancer via FAK/Src/Akt/mTOR signaling pathway. Our results provide insight into the regulation of β1 integrin through miR-199a-5p-mediated Ets-1 silence and will help in designing new therapeutic strategies to inhibit signal pathways induced by miR-199a-5p in breast cancer invasion.

  19. Evidence for homosexuality gene

    SciTech Connect

    Pool, R.

    1993-07-16

    A genetic analysis of 40 pairs of homosexual brothers has uncovered a region on the X chromosome that appears to contain a gene or genes for homosexuality. When analyzing the pedigrees of homosexual males, the researcheres found evidence that the trait has a higher likelihood of being passed through maternal genes. This led them to search the X chromosome for genes predisposing to homosexuality. The researchers examined the X chromosomes of pairs of homosexual brothers for regions of DNA that most or all had in common. Of the 40 sets of brothers, 33 shared a set of five markers in the q28 region of the long arm of the X chromosome. The linkage has a LOD score of 4.0, which translates into a 99.5% certainty that there is a gene or genes in this area that predispose males to homosexuality. The chief researcher warns, however, that this one site cannot explain all instances of homosexuality, since there were some cases where the trait seemed to be passed paternally. And even among those brothers where there was no evidence that the trait was passed paternally, seven sets of brothers did not share the Xq28 markers. It seems likely that homosexuality arises from a variety of causes.

  20. [Integrons: gene collectors].

    PubMed

    Di Conza, J A; Gutkind, G O

    2010-01-01

    Integrons gained great interest due to their participation in resistance gene recruitment and expression. Their basic structure includes a fragment that encodes an integrase (intI) followed by a recognition sequence (attI) into which they may incorporate gene cassettes (encoding resistance mechanisms). A promoter (Pc) embedded within the integrase gene controls the transcription of integrated resistance markers, as these genes do not have their own promoters. When in cassettes, resistance genes are flanked by specific sequences (attC), which are recognized by the integrase that, by site specific recombination, incorporates them after attI in proper orientation for their expression. In the past, integrons were classified according to their sequence homology; currently they are classified according to their location. In general, they are divided into "mobile" integrons (those associated with insertion sequences, transposons and/or plasmids, being most of them associated with resistance mechanisms), and chromosomally-located "super" integrons with large arrangements of cassette genes. "Mobile" class 1 integrons are the most abundant in clinical isolates and are generally associated with Tn21 subgroup transposons, followed by class 2, derived primarily from Tn7. These elements are not mobile themselves, but their association with mobile platforms that facilitate horizontal transfer, explains their wide distribution among bacteria. This review also attempts to describe the mobile integrons described so far in Argentina.

  1. Pentamidine blocks the interaction between mutant S100A5 and RAGE V domain and inhibits the RAGE signaling pathway.

    PubMed

    Cho, Ching Chang; Chou, Ruey Hwang; Yu, Chin

    2016-08-19

    The human S100 protein family contains small, dimeric and acidic proteins that contain two EF-hand motifs and bind calcium. When S100A5 binds calcium, its conformation changes and promotes interaction with the target protein. The extracellular domain of RAGE (Receptor of Advanced Glycation End products) contain three domains: C1, C2 and V. The RAGE V domain is the target protein of S100A5 that promotes cell survival, growth and differentiation by activating several signaling pathways. Pentamidine is an apoptotic and antiparasitic drug that is used to treat or prevent pneumonia. Here, we found that pentamidine interacts with S100A5 using HSQC titration. We elucidated the interactions of S100A5 with RAGE V domain and pentamidine using fluorescence and NMR spectroscopy. We generated two binary models-the S100A5-RAGE V domain and S100A5-Pentamidine complex-and then observed that the pentamidine and RAGE V domain share a similar binding region in mS100A5. We also used the WST-1 assay to investigate the bioactivity of S100A5, RAGE V domain and pentamidine. These results indicated that pentamidine blocks the binding between S100A5 and RAGE V domain. This finding is useful for the development of new anti-proliferation drugs.

  2. Pentamidine blocks the interaction between mutant S100A5 and RAGE V domain and inhibits the RAGE signaling pathway.

    PubMed

    Cho, Ching Chang; Chou, Ruey Hwang; Yu, Chin

    2016-08-19

    The human S100 protein family contains small, dimeric and acidic proteins that contain two EF-hand motifs and bind calcium. When S100A5 binds calcium, its conformation changes and promotes interaction with the target protein. The extracellular domain of RAGE (Receptor of Advanced Glycation End products) contain three domains: C1, C2 and V. The RAGE V domain is the target protein of S100A5 that promotes cell survival, growth and differentiation by activating several signaling pathways. Pentamidine is an apoptotic and antiparasitic drug that is used to treat or prevent pneumonia. Here, we found that pentamidine interacts with S100A5 using HSQC titration. We elucidated the interactions of S100A5 with RAGE V domain and pentamidine using fluorescence and NMR spectroscopy. We generated two binary models-the S100A5-RAGE V domain and S100A5-Pentamidine complex-and then observed that the pentamidine and RAGE V domain share a similar binding region in mS100A5. We also used the WST-1 assay to investigate the bioactivity of S100A5, RAGE V domain and pentamidine. These results indicated that pentamidine blocks the binding between S100A5 and RAGE V domain. This finding is useful for the development of new anti-proliferation drugs. PMID:27297108

  3. Associations between DNA methylation and schizophrenia-related intermediate phenotypes - a gene set enrichment analysis.

    PubMed

    Hass, Johanna; Walton, Esther; Wright, Carrie; Beyer, Andreas; Scholz, Markus; Turner, Jessica; Liu, Jingyu; Smolka, Michael N; Roessner, Veit; Sponheim, Scott R; Gollub, Randy L; Calhoun, Vince D; Ehrlich, Stefan

    2015-06-01

    Multiple genetic approaches have identified microRNAs as key effectors in psychiatric disorders as they post-transcriptionally regulate expression of thousands of target genes. However, their role in specific psychiatric diseases remains poorly understood. In addition, epigenetic mechanisms such as DNA methylation, which affect the expression of both microRNAs and coding genes, are critical for our understanding of molecular mechanisms in schizophrenia. Using clinical, imaging, genetic, and epigenetic data of 103 patients with schizophrenia and 111 healthy controls of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia, we conducted gene set enrichment analysis to identify markers for schizophrenia-associated intermediate phenotypes. Genes were ranked based on the correlation between DNA methylation patterns and each phenotype, and then searched for enrichment in 221 predicted microRNA target gene sets. We found the predicted hsa-miR-219a-5p target gene set to be significantly enriched for genes (EPHA4, PKNOX1, ESR1, among others) whose methylation status is correlated with hippocampal volume independent of disease status. Our results were strengthened by significant associations between hsa-miR-219a-5p target gene methylation patterns and hippocampus-related neuropsychological variables. IPA pathway analysis of the respective predicted hsa-miR-219a-5p target genes revealed associated network functions in behavior and developmental disorders. Altered methylation patterns of predicted hsa-miR-219a-5p target genes are associated with a structural aberration of the brain that has been proposed as a possible biomarker for schizophrenia. The (dys)regulation of microRNA target genes by epigenetic mechanisms may confer additional risk for developing psychiatric symptoms. Further study is needed to understand possible interactions between microRNAs and epigenetic changes and their impact on risk for brain-based disorders such as schizophrenia. PMID:25598502

  4. Associations between DNA methylation and schizophrenia-related intermediate phenotypes - a gene set enrichment analysis.

    PubMed

    Hass, Johanna; Walton, Esther; Wright, Carrie; Beyer, Andreas; Scholz, Markus; Turner, Jessica; Liu, Jingyu; Smolka, Michael N; Roessner, Veit; Sponheim, Scott R; Gollub, Randy L; Calhoun, Vince D; Ehrlich, Stefan

    2015-06-01

    Multiple genetic approaches have identified microRNAs as key effectors in psychiatric disorders as they post-transcriptionally regulate expression of thousands of target genes. However, their role in specific psychiatric diseases remains poorly understood. In addition, epigenetic mechanisms such as DNA methylation, which affect the expression of both microRNAs and coding genes, are critical for our understanding of molecular mechanisms in schizophrenia. Using clinical, imaging, genetic, and epigenetic data of 103 patients with schizophrenia and 111 healthy controls of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia, we conducted gene set enrichment analysis to identify markers for schizophrenia-associated intermediate phenotypes. Genes were ranked based on the correlation between DNA methylation patterns and each phenotype, and then searched for enrichment in 221 predicted microRNA target gene sets. We found the predicted hsa-miR-219a-5p target gene set to be significantly enriched for genes (EPHA4, PKNOX1, ESR1, among others) whose methylation status is correlated with hippocampal volume independent of disease status. Our results were strengthened by significant associations between hsa-miR-219a-5p target gene methylation patterns and hippocampus-related neuropsychological variables. IPA pathway analysis of the respective predicted hsa-miR-219a-5p target genes revealed associated network functions in behavior and developmental disorders. Altered methylation patterns of predicted hsa-miR-219a-5p target genes are associated with a structural aberration of the brain that has been proposed as a possible biomarker for schizophrenia. The (dys)regulation of microRNA target genes by epigenetic mechanisms may confer additional risk for developing psychiatric symptoms. Further study is needed to understand possible interactions between microRNAs and epigenetic changes and their impact on risk for brain-based disorders such as schizophrenia.

  5. Identification of four soybean reference genes for gene expression normalization

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Gene expression analysis requires the use of reference genes stably expressed independently of specific tissues or environmental conditions. Housekeeping genes (e.g., actin, tubulin, ribosomal, polyubiquitin and elongation factor 1-alpha) are commonly used as reference genes with the assumption tha...

  6. 5. OVERHEAD VIEW OF GENE CAMP LOOKING SOUTH. GENE PUMP ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    5. OVERHEAD VIEW OF GENE CAMP LOOKING SOUTH. GENE PUMP PLANT IS AT CENTER WITH ADMINISTRATIVE COMPLEX IN FOREGROUND AND RESIDENTIAL AREA BEYOND PLANT. - Gene Pump Plant, South of Gene Wash Reservoir, 2 miles west of Whitsett Pump Plant, Parker Dam, San Bernardino County, CA

  7. Regulatory domain or CpG site variation in SLC12A5, encoding the chloride transporter KCC2, in human autism and schizophrenia

    PubMed Central

    Merner, Nancy D.; Chandler, Madison R.; Bourassa, Cynthia; Liang, Bo; Khanna, Arjun R.; Dion, Patrick; Rouleau, Guy A.; Kahle, Kristopher T.

    2015-01-01

    Many encoded gene products responsible for neurodevelopmental disorders (NDs) like autism spectrum disorders (ASD), schizophrenia (SCZ), intellectual disability (ID), and idiopathic generalized epilepsy (IGE) converge on networks controlling synaptic function. An increase in KCC2 (SLC12A5) Cl− transporter activity drives the developmental GABA excitatory-inhibitory sequence, but the role of KCC2 in human NDs is essentially unknown. Here, we report two rare, non-synonymous (NS), functionally-impairing variants in the KCC2 C-terminal regulatory domain (CTRD) in human ASD (R952H and R1049C) and SCZ (R952H) previously linked with IGE and familial febrile seizures, and another novel NS KCC2 variant in ASD (R1048W) with highly-predicted pathogenicity. Exome data from 2517 simplex families in the ASD Simon Simplex Collection (SSC) revealed significantly more KCC2 CTRD variants in ASD cases than controls, and interestingly, these were more often synonymous and predicted to disrupt or introduce a CpG site. Furthermore, full gene analysis showed ASD cases are more likely to contain rare KCC2 variants affecting CpG sites than controls. These data suggest genetically-encoded dysregulation of KCC2-dependent GABA signaling may contribute to multiple human NDs. PMID:26528127

  8. A 5-year-old white girl with Prader-Willi syndrome and a submicroscopic deletion of chromosome 15q11q13

    SciTech Connect

    Butler, M.G.; Christian, S.L.; Kubota, T.; Ledbetter, D.H.

    1996-10-16

    We report on a 5-year-old white girl with Prader-Willi syndrome (PWS) and a submicroscopic deletion of 15q11q13 of approximately 100-200 kb in size. High resolution chromosome analysis was normal but fluorescence in situ hybridization (FISH), Southern hybridization, and microsatellite data from the 15q11q13 region demonstrated that the deletion was paternal in origin and included the SNRPN, PAR-5, and PAR-7 genes from the proximal to distal boundaries of the deletion segment. SNRPN and PW71B methylation studies showed an abnormal pattern consistent with the diagnosis of PWS and supported the presence of a paternal deletion of 15q11q13 or an imprinting mutation. Biparental (normal) inheritance of PW71B (D15S63 locus) and a deletion of the SNRPN gene were observed by microsatellite, quantitative Southern hybridization, and/or FISH analyses. Our patient met the diagnostic criteria for PWS, but has no reported behavior problems, hyperphagia, or hypopigmentation. Our patient further supports SNRPN and possibly other genomic sequences which are deleted as the cause of the phenotype recognized in PWS patients. 21 refs., 7 figs.

  9. Regulatory domain or CpG site variation in SLC12A5, encoding the chloride transporter KCC2, in human autism and schizophrenia.

    PubMed

    Merner, Nancy D; Chandler, Madison R; Bourassa, Cynthia; Liang, Bo; Khanna, Arjun R; Dion, Patrick; Rouleau, Guy A; Kahle, Kristopher T

    2015-01-01

    Many encoded gene products responsible for neurodevelopmental disorders (NDs) like autism spectrum disorders (ASD), schizophrenia (SCZ), intellectual disability (ID), and idiopathic generalized epilepsy (IGE) converge on networks controlling synaptic function. An increase in KCC2 (SLC12A5) Cl(-) transporter activity drives the developmental GABA excitatory-inhibitory sequence, but the role of KCC2 in human NDs is essentially unknown. Here, we report two rare, non-synonymous (NS), functionally-impairing variants in the KCC2 C-terminal regulatory domain (CTRD) in human ASD (R952H and R1049C) and SCZ (R952H) previously linked with IGE and familial febrile seizures, and another novel NS KCC2 variant in ASD (R1048W) with highly-predicted pathogenicity. Exome data from 2517 simplex families in the ASD Simon Simplex Collection (SSC) revealed significantly more KCC2 CTRD variants in ASD cases than controls, and interestingly, these were more often synonymous and predicted to disrupt or introduce a CpG site. Furthermore, full gene analysis showed ASD cases are more likely to contain rare KCC2 variants affecting CpG sites than controls. These data suggest genetically-encoded dysregulation of KCC2-dependent GABA signaling may contribute to multiple human NDs. PMID:26528127

  10. Hox genes and study of Hox genes in crustacean

    NASA Astrophysics Data System (ADS)

    Hou, Lin; Chen, Zhijuan; Xu, Mingyu; Lin, Shengguo; Wang, Lu

    2004-12-01

    Homeobox genes have been discovered in many species. These genes are known to play a major role in specifying regional identity along the anterior-posterior axis of animals from a wide range of phyla. The products of the homeotic genes are a set of evolutionarily conserved transcription factors that control elaborate developmental processes and specify cell fates in metazoans. Crustacean, presenting a variety of body plans not encountered in any other class or phylum of the Metazoa, has been shown to possess a single set of homologous Hox genes like insect. The ancestral crustacean Hox gene complex comprised ten genes: eight homologous to the hometic Hox genes and two related to nonhomeotic genes presented within the insect Hox complexes. The crustacean in particular exhibits an abundant diversity segment specialization and tagmosis. This morphological diversity relates to the Hox genes. In crustacean body plan, different Hox genes control different segments and tagmosis.

  11. Mutations in the Na+/Citrate Cotransporter NaCT (SLC13A5) in Pediatric Patients with Epilepsy and Developmental Delay

    PubMed Central

    Klotz, Jenna; Porter, Brenda E; Colas, Claire; Schlessinger, Avner; Pajor, Ana M

    2016-01-01

    Mutations in the SLC13A5 gene that codes for the Na+/citrate cotransporter, NaCT, are associated with early onset epilepsy, developmental delay and tooth dysplasia in children. In this study, we identify additional SLC13A5 mutations in nine epilepsy patients from six families. To better characterize the syndrome, families with affected children answered questions about the scope of illness and the treatment strategies. Currently, there are no effective treatments, but some antiepileptic drugs targeting the γ-aminobutyric acid system reduce seizure frequency. Acetazolamide, a carbonic anhydrase inhibitor and atypical antiseizure medication, decreases seizures in four patients. In contrast to previous reports, the ketogenic diet and fasting resulted in worsening of symptoms. The effects of the mutations on NaCT transport function and protein expression were examined by transient transfections of COS-7 cells. There was no transport activity from any of the mutant transporters, although some of the mutant transporter proteins were present on the plasma membrane. The structural model of NaCT suggests that these mutations can affect helix packing or substrate binding. We tested various treatments, including chemical chaperones and low temperatures, but none improved transport function in the NaCT mutants. Interestingly, coexpression of NaCT and the mutants results in decreased protein expression and activity of the wild-type transporter, indicating functional interaction. In conclusion, this study has identified additional SLC13A5 mutations in patients with chronic epilepsy starting in the neonatal period, with the mutations producing inactive Na+/citrate transporters. PMID:27261973

  12. Blunt abdominal trauma. A 5-year analysis of 870 patients requiring celiotomy.

    PubMed Central

    Cox, E F

    1984-01-01

    This study represents the experience with blunt trauma to the abdomen of patients from a major regional trauma center. Eight hundred and seventy patients with blunt abdominal trauma are reviewed, representing 12.89% of the total admissions over a 5-year period. The motor vehicle continues to be the major cause (89.5%) of injury to these patients. Thirty per cent had positive blood alcohol. Intra-abdominal injuries in this group necessitating operative intervention were based on the use of peritoneal lavage. Negative celiotomies occurred in 10.2% of these patients. Of the injuries incurred, the spleen was involved 42%, the liver 35.6%, the serosa, diaphragm, bowel, and blood vessels were involved to a lesser extent. Only 0.4% of the patients suffered direct injury to the stomach, duodenum, and pancreas, data which should preclude routine exploration of retroperitoneal structures unless by obvious retroperitoneal injury is noted. Additional surgical intervention for associated injuries was seen in 50.54% of this patient group. PMID:6712323

  13. Development of a 5.5 m diameter vertical axis wind turbine, phase 3

    NASA Astrophysics Data System (ADS)

    Dekitsch, A.; Etzler, C. C.; Fritzsche, A.; Lorch, G.; Mueller, W.; Rogalla, K.; Schmelzle, J.; Schuhwerk, W.; Vollan, A.; Welte, D.

    1982-06-01

    In continuation of development of a 5.5 m diameter vertical axis windmill that consists in conception, building, and wind tunnel testing, a Darrieus rotor windpowered generator feeding an isolated network under different wind velocity conditions and with optimal energy conversion efficiency was designed built, and field tested. The three-bladed Darrieus rotor tested in the wind tunnel was equiped with two variable pitch Savonius rotors 2 m in diameter. By means of separate measures of the aerodynamic factors and the energy consumption, effect of revisions and optimizations on different elements was assessed. Pitch adjustement of the Savonius blades, lubrication of speed reducer, rotor speed at cut-in of generator field excitation, time constant of field excitation, stability conditions, switch points of ohmic resistors which combined with a small electric battery simulated a larger isolated network connected with a large storage battery, were investigated. Fundamentals for the economic series production of windpowered generators with Darrieus rotors for the control and the electric conversion system are presented.

  14. Cognitive influence of a 5-h ENERGY® shot: Are effects perceived or real?

    PubMed

    Buckenmeyer, Philip J; Bauer, Jeffery A; Hokanson, James F; Hendrick, Joy L

    2015-12-01

    With the gain in popularity and use of 'functional energy drinks' (FEDs), manufacturers of these beverages have been making greater claims as to their benefits on a number of performance factors including mental alertness, energy, and physical performance. Few experimental studies have been conducted on FEDs, and no study to date has examined their effects over time. This study looked at the effects of consumption of a 5-h ENERGY® shot (5-HES) on various cognitive functions across five hours on 24 college-aged students using a double-blind, cross-over, placebo-based design. Participants completed a series of five computer-based tests before ingesting the beverage (either 5-HES or placebo) and then completed the tests for each of the next five hours (morning to midday). One week later, they repeated the process with the other beverage. While 90% of participants subjectively thought that the 5-HES was effective at one-hour post-ingestion, no evidence was found to support an enhanced effect on recognition, reaction time, short-term and working memory, or attention capacity. In conclusion, the 5-h Energy Shot® did not significantly improve short- or long-term cognitive function for selected computer-based tasks despite a high level of perception that it was working effectively compared to a placebo with college-aged participants.

  15. Design and Fabrication of a 5-kWe Free-Piston Stirling Power Conversion System

    NASA Technical Reports Server (NTRS)

    Chapman, Peter A.; Walter, Thomas J.; Brandhorst, Henry W., Jr.

    2008-01-01

    Progress in the design and fabrication of a 5-kWe free-piston Stirling power conversion system is described. A scaled-down version of the successful 12.5-kWe Component Test Power Converter (CTPC) developed under NAS3-25463, this single cylinder prototype incorporates cost effective and readily available materials (steel versus beryllium) and components (a commercial linear alternator). The design consists of a displacer suspended on internally pumped gas bearings and a power piston/alternator supported on flexures. Non-contacting clearance seals are used between internal volumes. Heat to and from the prototype is supplied via pumped liquid loops passing through shell and tube heat exchangers. The control system incorporates several novel ideas such as a pulse start capability and a piston stroke set point control strategy that provides the ability to throttle the engine to match the required output power. It also ensures stable response to various disturbances such as electrical load variations while providing useful data regarding the position of both power piston and displacer. All design and analysis activities are complete and fabrication is underway. Prototype test is planned for summer 2008 at Foster-Miller to characterize the dynamics and steady-state operation of the prototype and determine maximum power output and system efficiency. Further tests will then be performed at Auburn University to determine start-up and shutdown characteristics and assess transient response to temperature and load variations.

  16. Opening switches for a 5 MJ, 1 MA energy storage transformer

    NASA Astrophysics Data System (ADS)

    Clements, Neal D.; Johnson, Donald E.

    1991-01-01

    Two possible switch topologies used to switch the primary of an energy storage transformer are compared. A series-connected semiconductor/vacuum interrupter switch and an all-solid-state switch are sized for a 5-MJ energy storage transformer. Gate-turn-off (GTO) thyristors are used as the semiconductor switches. Total mass estimates, operating characteristics, and applicability to a space-based pulsed power system are discussed. Both designs store the commutation energy in capacitors. The commutation energy is then dissipated in resistors after switching has occurred. The capacitor mass is shown to dominate the total switch mass. Therefore, the mass of both switches is approximately equal. The advantages of the all-solid-state switch include high reliability, no moving parts, proven design, and a high probability of future mass reduction with new semiconductor device developments. The all-solid-state switch has a higher On-state power dissipation than the vacuum interrupter switch. It is suggested that the advantages of the all-solid-state switch outweigh the disadvantages of the higher power dissipation.

  17. Quantitative Proteomic Profiling the Molecular Signatures of Annexin A5 in Lung Squamous Carcinoma Cells

    PubMed Central

    Zhang, Liyuan; Gong, Linlin; Qi, Xiaoyu; Li, Huizhen; Wang, Faming; Chi, Xinming; Jiang, Yulin; Shao, Shujuan

    2016-01-01

    Lung cancer remains the leading cancer killer around the world. It’s crucial to identify newer mechanism-based targets to effectively manage lung cancer. Annexin A5 (ANXA5) is a protein kinase C inhibitory protein and calcium dependent phospholipid-binding protein, which may act as an endogenous regulator of various pathophysiological processes. However, its molecular mechanism in lung cancer remains poorly understood. This study was designed to determine the mechanism of ANXA5 in lung cancer with a hope to obtain useful information to provide a new therapeutic target. We used a stable isotope dimethyl labeling based quantitative proteomic method to identify differentially expressed proteins in NSCLC cell lines after ANXA5 transfection. Out of 314 proteins, we identified 26 and 44 proteins that were down- and up-regulated upon ANXA5 modulation, respectively. The IPA analysis revealed that glycolysis and gluconeogenesis were the predominant pathways modulated by ANXA5. Multiple central nodes, namely HSPA5, FN1, PDIA6, ENO1, ALDOA, JUP and KRT6A appeared to occupy regulatory nodes in the protein-protein networks upon ANXA5 modulation. Taken together, ANXA5 appears to have pleotropic effects, as it modulates multiple key signaling pathways, supporting the potential usefulness of ANXA5 as a potential target in lung cancer. This study might provide a new insight into the mechanism of ANXA5 in lung cancer. PMID:27684953

  18. Survival Rate of Short, Locking Taper Implants with a Plateau Design: A 5-Year Retrospective Study

    PubMed Central

    Demiralp, Kemal Özgür; Akbulut, Nihat; Kursun, Sebnem; Argun, Didem; Bagis, Nilsun; Orhan, Kaan

    2015-01-01

    Background. Short implants have become popular in the reconstruction of jaws, especially in cases with limited bone height. Shorter implants, those with locking tapers and plateau root shapes, tend to have longer survival times. We retrospectively investigated the cumulative survival rates of Bicon short implants (<8 mm) according to patient variables over a 5-year period. Materials and Methods. This study included 111 consecutively treated patients with 371 implants supporting fixed or removable prosthetics. Data were evaluated to acquire cumulative survival rates according to gender, age, tobacco use, surgical procedure, bone quality, and restoration type. Statistics were performed using chi-square, Mann-Whitney, and Kruskal Wallis H tests. Results. The survival rate was 97.3% with, on average, 22.8 months of follow-up. Patients older than 60 years had higher failure rate than the other age groups (P < 0.05). Placed region, age, and bone quality had adverse effects on survival rate in the <8 mm implant group with statistically significant difference (P < 0.05). Conclusions. Approximately 23-month follow-up data indicate that short implants with locking tapers and plateau-type roots have comparable survival rates as other types of dental implants. However, due to limitations of study, these issues remain to be further investigated in future randomized controlled clinical trials. PMID:25961004

  19. The Treatment of Parasomnias with Hypnosis: a 5-Year Follow-Up Study

    PubMed Central

    Hauri, Peter J.; Silber, Michael H.; Boeve, Bradley F.

    2007-01-01

    Study Objectives: This study involves a replication and extension of a previous one reported by Hurwitz et al (1991) on the treatment of certain parasomnias with hypnosis. Methods: Thirty-six patients (17 females), mean age 32.7 years (range 6–71). Four were children aged 6 to 16. All had chronic, “functionally autonomous” (self-sustaining) parasomnias. All underwent 1 or 2 hypnotherapy sessions and were then followed by questionnaire for 5 years. Results: Of the 36 patients, 45.4% were symptom-free or at least much improved at the 1-month follow-up, 42.2% at the 18-month follow-up, and 40.5% at the 5-year follow-up. Conclusions: One or 2 sessions of hypnotherapy might be an efficient first-line therapy for patients with certain types of parasomnias. Citation: Hauri PJ; Silber MH; Boeve BF. The treatment of parasomnias with hypnosis: a 5-year follow-up study. J Clin Sleep Med 2007;3(4):369-373. PMID:17694725

  20. Development of a 5 MW reference gearbox for offshore wind turbines: 5 MW reference gearbox

    SciTech Connect

    Nejad, Amir Rasekhi; Guo, Yi; Gao, Zhen; Moan, Torgeir

    2015-07-27

    This paper presents detailed descriptions, modeling parameters and technical data of a 5MW high-speed gearbox developed for the National Renewable Energy Laboratory offshore 5MW baseline wind turbine. The main aim of this paper is to support the concept studies and research for large offshore wind turbines by providing a baseline gearbox model with detailed modeling parameters. This baseline gearbox follows the most conventional design types of those used in wind turbines. It is based on the four-point supports: two main bearings and two torque arms. The gearbox consists of three stages: two planetary and one parallel stage gears. The gear ratios among the stages are calculated in a way to obtain the minimum gearbox weight. The gearbox components are designed and selected based on the offshore wind turbine design codes and validated by comparison to the data available from large offshore wind turbine prototypes. All parameters required to establish the dynamic model of the gearbox are then provided. Moreover, a maintenance map indicating components with high to low probability of failure is shown. The 5 MW reference gearbox can be used as a baseline for research on wind turbine gearboxes and comparison studies. It can also be employed in global analysis tools to represent a more realistic model of a gearbox in a coupled analysis.

  1. Prevalence of Candida dubliniensis among cancer patients in Kuwait: a 5-year retrospective study.

    PubMed

    Mokaddas, Eiman; Khan, Zia U; Ahmad, Suhail

    2011-07-01

    Despite close genetic and phenotypic relationship of Candida dubliniensis with Candida albicans, its role in human disease is mostly restricted to oral colonisation, particularly among HIV-infected patients. The prevalence of C. dubliniensis in association with other disease conditions has been infrequently reported. In this study, we present data on the prevalence of C. dubliniensis among yeast species isolated from cancer patients over a 5-year period. A total of 1445 yeast isolates recovered from respiratory specimens, blood, urine and oral swabs were analysed. Candida dubliniensis isolates were provisionally identified by phenotypic methods and their identity was further confirmed by species-specific amplification and/or sequencing of internally transcribed spacer region of rDNA. Antifungal susceptibility for fluconazole was determined by Etest. The number of isolates identified as C. dubliniensis, C. albicans and other yeast species were 71 (4.9%), 862 (59.6%) and 512 (35%) respectively. All the C. dubliniensis isolates originated from respiratory (5.9%) or oral (3.2%) specimens with an overall prevalence of 4.9%, and were found to be susceptible to fluconazole. The isolation of C. dubliniensis from respiratory or oral specimens and not from blood or urine specimens suggests that this species has preference to colonise these sites of human body.

  2. Gravitational waves during inflation from a 5D large-scale repulsive gravity model

    NASA Astrophysics Data System (ADS)

    Reyes, Luz M.; Moreno, Claudia; Madriz Aguilar, José Edgar; Bellini, Mauricio

    2012-10-01

    We investigate, in the transverse traceless (TT) gauge, the generation of the relic background of gravitational waves, generated during the early inflationary stage, on the framework of a large-scale repulsive gravity model. We calculate the spectrum of the tensor metric fluctuations of an effective 4D Schwarzschild-de Sitter metric on cosmological scales. This metric is obtained after implementing a planar coordinate transformation on a 5D Ricci-flat metric solution, in the context of a non-compact Kaluza-Klein theory of gravity. We found that the spectrum is nearly scale invariant under certain conditions. One interesting aspect of this model is that it is possible to derive the dynamical field equations for the tensor metric fluctuations, valid not just at cosmological scales, but also at astrophysical scales, from the same theoretical model. The astrophysical and cosmological scales are determined by the gravity-antigravity radius, which is a natural length scale of the model, that indicates when gravity becomes repulsive in nature.

  3. Modification of antisense phosphodiester oligodeoxynucleotides by a 5' cholesteryl moiety increases cellular association and improves efficacy.

    PubMed Central

    Krieg, A M; Tonkinson, J; Matson, S; Zhao, Q; Saxon, M; Zhang, L M; Bhanja, U; Yakubov, L; Stein, C A

    1993-01-01

    Phosphodiester oligodeoxynucleotides bearing a 5' cholesteryl (chol) modification bind to low density lipoprotein (LDL), apparently by partitioning the chol-modified oligonucleotides into the lipid layer. Both HL60 cells and primary mouse spleen T and B cells incubated with fluorescently labeled chol-modified oligonucleotide showed substantially increased cellular association by flow cytometry and increased internalization by confocal microscopy compared to an identical molecule not bearing the chol group. Cellular internalization of chol-modified oligonucleotide occurred at least partially through the LDL receptor; it was increased in mouse spleen cells by cell culture in lipoprotein-deficient medium and/or lovastatin, and it was decreased by culture in high serum medium. To determine whether chol-modified oligonucleotides are more potent antisense agents, we titered antisense unmodified phosphodiester and chol-modified oligonucleotides targeted against a mouse immunosuppressive protein. Murine spleen cells cultured with 20 microM phosphodiester antisense oligonucleotides had a 2-fold increase in RNA synthesis, indicating the expected lymphocyte activation. Antisense chol-modified oligonucleotides showed an 8-fold increase in relative potency: they caused a 2-fold increase in RNA synthesis at just 2.5 microM. The increased efficacy was blocked by heparin and was further increased by cell culture in 1% (vs. 10%) fetal bovine serum, suggesting that the effect may, at least in part, be mediated via the LDL receptor. Antisense chol-modified oligonucleotides are sequence specific and have increased potency as compared to unmodified oligonucleotides. Images PMID:8430072

  4. An uncontrolled examination of a 5-day intensive treatment for pediatric OCD.

    PubMed

    Whiteside, Stephen P; Jacobsen, Amy Brown

    2010-09-01

    This study examined the feasibility of a 5-day intensive treatment for pediatric obsessive-compulsive disorder (OCD). Fifteen children with OCD received a week-long treatment based on exposure and response prevention (ERP). The intervention also emphasized teaching children and parents how to conduct ERP independently at home. All families completed the week-long treatment and symptoms improved significantly as measured by self- and parent-report forms, as well as the Children's Yale-Brown Obsessive-Compulsive Scale, F(2, 22)=45.67, p<.05. Total CY-BOCS scores decreased significantly from pretreatment (M=28.00, SD=4.24) to posttreatment [M=16.00, SD=6.0, F(1, 11)=34.38, p<.05] and from posttreatment to 5-month follow-up [M=11.5, SD=7.3; F(1, 11)=12.94, p<.05]. This level of improvement was consistent with other intensive treatments for pediatric OCD. The study suggests that the 5-day program is a promising treatment for children with OCD who do not have access to local providers.

  5. Outcome and Prognostic Factors for Traumatic Endophthalmitis over a 5-Year Period

    PubMed Central

    Nicoară, Simona Delia; Călinici, Tudor

    2014-01-01

    Purpose. To evaluate the outcome and identify the prognostic factors of traumatic endophthalmitis over a 5-year period. Methods. We reviewed the medical records of all the traumatic endophthalmities that we treated in our department over the last 5 years (2009–2013). We extracted the following parameters: age, gender, wound anatomy, associated ocular lesions, treatment, and initial and final visual acuities. We used the program SPSS version 20.0.0. for the statistical analysis of our data. Results. During the last 5 years, we treated 14 traumatic endophthalmities, representing 46.66% of all types of endophthalmities. The infection rate in open globe injuries was 8.13% and 34.78%, if an intraocular foreign body (IOFB) was associated. All the patients were males with the median age of 37 years. Initial visual acuities varied between light perception and 0.4 and the timing of treatment from a few hours to 10 days. We administered antibiotic and anti-inflammatory drugs, systemically and intravitreally, in all cases. We performed pars plana vitrectomy in 64.28% of cases. In 57.14% of cases, the final visual acuity was 0.1 or more. Conclusions. IOFBs increased significantly the risk for endophthalmitis. The worse prognostic factors were retinal detachment at presentation and delayed treatment. This trial is registered with IRCT2014082918966N1. PMID:25302113

  6. Bacillus subtilis TRAP binds to its RNA target by a 5' to 3' directional mechanism.

    PubMed

    Barbolina, Maria V; Li, Xiufeng; Gollnick, Paul

    2005-01-28

    TRAP is an 11 subunit RNA-binding protein that regulates expression of the Bacillus subtilis trpEDCFBA operon by transcription attenuation and translation control mechanisms. Tryptophan-activated TRAP acts by binding to a site in the 5'-untranslated leader region of trp mRNA consisting of 11 (G/U)AG repeats. We used mung bean nuclease footprinting to analyze the interaction of TRAP with several artificial binding sites composed of 11 GAG repeats in nucleic acids that lack secondary structure. Affinities for individual repeats within a binding site did not vary significantly. In contrast, the association rate constants were highest for repeats at the 5' end and lowest for those at the 3' end of all binding sites tested. These results indicate that TRAP binds to its RNA targets by first associating with one or more repeat at the 5' end of its binding site followed by wrapping the remainder of binding site around the protein in a 5' to 3' direction. This directional binding is novel among RNA-binding proteins. We suggest that this mechanism of binding is important for TRAP-mediated transcription attenuation control of the trp operon. PMID:15588817

  7. Gallstone disease in a teaching hospital, Addis Ababa: a 5-year review.

    PubMed

    Ersumo, Tessema

    2006-01-01

    There are not many studies of gallbladder disease in Africa. The disease appears to be not uncommon in Ethiopia. To determine the prevalence and evaluate the management of gallstone disease in a central teaching hospital, a 5-year retrospective study was undertaken in 747 patients surgically treated for gallbladder disease in the period 1995-99 in Tikur Anbessa Hospital, Addis Ababa. The sex ratio (M:F) was 1:5, narrower ratio in complicated cholelithiasis. The mean age was 42 years. About 80% of patients were in the age group between 30 and 60 years. The median duration of symptoms at admission was 2 years. Abdominal pain, in 96% of cases situated in the right upper quadrant (RUQ) and usually aching type, was the most frequent presenting symptom; RUQ tenderness was the most common sign. Clinically, 29.4% of patients were categorized obese. Gallstone detection rate by ultrasound was about 96% but cholecystitis appeared to be overlooked. At operation, about 77% of cases had features of chronic cholecystitis, 2% acalculous cholecystitis. Majority of the stones were grossly cholesterol stones. Cholecystectomy was performed in 99% of cases, most often through the oblique subcostal and transverse routes. The overall in-hospital mortality rate was 0.4%. Nearly 87% of cases had postoperative course without incident. The etiologic factors and the type of gallstones, we believe, are not different from that of the developed world. Cholecystectomy is a safe and most effective procedure that provides ultimate cure for symptomatic gallstone disease. PMID:17447363

  8. Statistical fault diagnosis of wind turbine drivetrain applied to a 5MW floating wind turbine

    NASA Astrophysics Data System (ADS)

    Ghane, Mahdi; Nejad, Amir R.; Blanke, Mogens; Gao, Zhen; Moan, Torgeir

    2016-09-01

    Deployment of large scale wind turbine parks, in particular offshore, requires well organized operation and maintenance strategies to make it as competitive as the classical electric power stations. It is important to ensure systems are safe, profitable, and cost-effective. In this regards, the ability to detect, isolate, estimate, and prognose faults plays an important role. One of the critical wind turbine components is the gearbox. Failures in the gearbox are costly both due to the cost of the gearbox itself and also due to high repair downtime. In order to detect faults as fast as possible to prevent them to develop into failure, statistical change detection is used in this paper. The Cumulative Sum Method (CUSUM) is employed to detect possible defects in the downwind main bearing. A high fidelity gearbox model on a 5-MW spar-type wind turbine is used to generate data for fault-free and faulty conditions of the bearing at the rated wind speed and the associated wave condition. Acceleration measurements are utilized to find residuals used to indirectly detect damages in the bearing. Residuals are found to be nonGaussian, following a t-distribution with multivariable characteristic parameters. The results in this paper show how the diagnostic scheme can detect change with desired false alarm and detection probabilities.

  9. Serious anaphylactic shock induced by hemocoagulase agkistrodon during anesthesia in a 5-year-old child.

    PubMed

    Xu, Ying-Yi; Li, Bi-Lian; Jin, Yu-Lin; Wang, Zi-Xin; Song, Xing-Rong; Ni, Jin

    2015-01-01

    We report a case of serious anaphylactic shock in a 5-year-old child undergoing scheduled surgery blank space of a right femoral intramedullary nail removal. The boy had undergone right femoral elastic intramedullary nail fixation surgery 14 months prior, but had no history of allergies. Within 5 minutes of intravenous bonus injection of hemocoagulase agkistrodon (HCA) 1 unit, a widespread transient diffuse erythema was seen on the front of his chest. After 20 minutes, sudden, profound cardiovascular collapse occurred. The child was treated effectively and sent to a ward 5 hours later. In this period, he received intravenously infused 200 ml hydroxyethyl starch solution and epinephrine at a rate of 0.05-0.01 μg kg(-1) min(-1). Total amount of dexamethasone sodium phosphate 14 mg was used. To the best of our knowledge, few case reports of HCA-induced anaphylactic shock in children exist. Our report will, therefore, increase awareness of the allergic potential of HCA among pediatric anesthesiologists. PMID:26064413

  10. Functional Interactions between BKCaα-Subunit and Annexin A5: Implications in Apoptosis

    PubMed Central

    2016-01-01

    Proteomic studies have suggested a biochemical interaction between α subunit of the large conductance, voltage- and Ca2+-activated potassium channel (BKCaα), and annexin A5 (ANXA5), which we verify here by coimmunoprecipitation and double labelling immunocytochemistry. The observation that annexin is flipped to the outer membrane leaflet of the plasma membrane during apoptosis, together with the knowledge that the intracellular C-terminal of BKCaα contains both Ca2+-binding and a putative annexin-binding motif, prompted us to investigate the functional consequences of this protein partnership to cell death. Membrane biotinylation demonstrated that ANXA5 was flipped to the outer membrane leaflet of HEK 293 cells early in serum deprivation-evoked apoptosis. As expected, serum deprivation caused caspase-3/7 activation and this was accentuated in BKCaα expressing HEK 293 cells. The functional consequences of ANXA5 partnership with BKCaα were striking, with ANXA5 knockdown causing an increase and ANXA5 overexpression causing a decrease, in single BKCa channel Ca2+-sensitivity, measured in inside-out membrane patches by patch-clamp. Taken together, these data suggest a novel model of the early stages of apoptosis where membrane flippage results in removal of the inhibitory effect of ANXA5 on K+ channel activity with the consequent amplification of Ca2+ influx and augmented activation of caspases. PMID:27738490

  11. Systemic treatment with a 5HT1a agonist induces anti-oxidant protection and preserves the retina from mitochondrial oxidative stress.

    PubMed

    Biswal, Manas R; Ahmed, Chulbul M; Ildefonso, Cristhian J; Han, Pingyang; Li, Hong; Jivanji, Hiral; Mao, Haoyu; Lewin, Alfred S

    2015-11-01

    Chronic oxidative stress contributes to age related diseases including age related macular degeneration (AMD). Earlier work showed that the 5-hydroxy-tryptamine 1a (5HT1a) receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) protects retinal pigment epithelium (RPE) cells from hydrogen peroxide treatment and mouse retinas from oxidative insults including light injury. In our current experiments, RPE derived cells subjected to mitochondrial oxidative stress were protected from cell death by the up-regulation of anti-oxidant enzymes and of the metal ion chaperone metallothionein. Differentiated RPE cells were resistant to oxidative stress, and the expression of genes for protective proteins was highly increased by oxidative stress plus drug treatment. In mice treated with 8-OH-DPAT, the same genes (MT1, HO1, NqO1, Cat, Sod1) were induced in the neural retina, but the drug did not affect the expression of Sod2, the gene for manganese superoxide dismutase. We used a mouse strain deleted for Sod2 in the RPE to accelerate age-related oxidative stress in the retina and to test the impact of 8-OH-DPAT on the photoreceptor and RPE degeneration developed in these mice. Treatment of mice with daily injections of the drug led to increased electroretinogram (ERG) amplitudes in dark-adapted mice and to a slight improvement in visual acuity. Most strikingly, in mice treated with a high dose of the drug (5 mg/kg) the structure of the RPE and Bruch's membrane and the normal architecture of photoreceptor outer segments were preserved. These results suggest that systemic treatment with this class of drugs may be useful in preventing geographic atrophy, the advanced form of dry AMD, which is characterized by RPE degeneration.

  12. GeneCards Version 3: the human gene integrator.

    PubMed

    Safran, Marilyn; Dalah, Irina; Alexander, Justin; Rosen, Naomi; Iny Stein, Tsippi; Shmoish, Michael; Nativ, Noam; Bahir, Iris; Doniger, Tirza; Krug, Hagit; Sirota-Madi, Alexandra; Olender, Tsviya; Golan, Yaron; Stelzer, Gil; Harel, Arye; Lancet, Doron

    2010-08-05

    GeneCards (www.genecards.org) is a comprehensive, authoritative compendium of annotative information about human genes, widely used for nearly 15 years. Its gene-centric content is automatically mined and integrated from over 80 digital sources, resulting in a web-based deep-linked card for each of >73,000 human gene entries, encompassing the following categories: protein coding, pseudogene, RNA gene, genetic locus, cluster and uncategorized. We now introduce GeneCards Version 3, featuring a speedy and sophisticated search engine and a revamped, technologically enabling infrastructure, catering to the expanding needs of biomedical researchers. A key focus is on gene-set analyses, which leverage GeneCards' unique wealth of combinatorial annotations. These include the GeneALaCart batch query facility, which tabulates user-selected annotations for multiple genes and GeneDecks, which identifies similar genes with shared annotations, and finds set-shared annotations by descriptor enrichment analysis. Such set-centric features address a host of applications, including microarray data analysis, cross-database annotation mapping and gene-disorder associations for drug targeting. We highlight the new Version 3 database architecture, its multi-faceted search engine, and its semi-automated quality assurance system. Data enhancements include an expanded visualization of gene expression patterns in normal and cancer tissues, an integrated alternative splicing pattern display, and augmented multi-source SNPs and pathways sections. GeneCards now provides direct links to gene-related research reagents such as antibodies, recombinant proteins, DNA clones and inhibitory RNAs and features gene-related drugs and compounds lists. We also portray the GeneCards Inferred Functionality Score annotation landscape tool for scoring a gene's functional information status. Finally, we delineate examples of applications and collaborations that have benefited from the GeneCards suite. Database

  13. GeneCards Version 3: the human gene integrator.

    PubMed

    Safran, Marilyn; Dalah, Irina; Alexander, Justin; Rosen, Naomi; Iny Stein, Tsippi; Shmoish, Michael; Nativ, Noam; Bahir, Iris; Doniger, Tirza; Krug, Hagit; Sirota-Madi, Alexandra; Olender, Tsviya; Golan, Yaron; Stelzer, Gil; Harel, Arye; Lancet, Doron

    2010-01-01

    GeneCards (www.genecards.org) is a comprehensive, authoritative compendium of annotative information about human genes, widely used for nearly 15 years. Its gene-centric content is automatically mined and integrated from over 80 digital sources, resulting in a web-based deep-linked card for each of >73,000 human gene entries, encompassing the following categories: protein coding, pseudogene, RNA gene, genetic locus, cluster and uncategorized. We now introduce GeneCards Version 3, featuring a speedy and sophisticated search engine and a revamped, technologically enabling infrastructure, catering to the expanding needs of biomedical researchers. A key focus is on gene-set analyses, which leverage GeneCards' unique wealth of combinatorial annotations. These include the GeneALaCart batch query facility, which tabulates user-selected annotations for multiple genes and GeneDecks, which identifies similar genes with shared annotations, and finds set-shared annotations by descriptor enrichment analysis. Such set-centric features address a host of applications, including microarray data analysis, cross-database annotation mapping and gene-disorder associations for drug targeting. We highlight the new Version 3 database architecture, its multi-faceted search engine, and its semi-automated quality assurance system. Data enhancements include an expanded visualization of gene expression patterns in normal and cancer tissues, an integrated alternative splicing pattern display, and augmented multi-source SNPs and pathways sections. GeneCards now provides direct links to gene-related research reagents such as antibodies, recombinant proteins, DNA clones and inhibitory RNAs and features gene-related drugs and compounds lists. We also portray the GeneCards Inferred Functionality Score annotation landscape tool for scoring a gene's functional information status. Finally, we delineate examples of applications and collaborations that have benefited from the GeneCards suite. Database

  14. The novel putative bile acid transporter SLC10A5 is highly expressed in liver and kidney

    SciTech Connect

    Fernandes, Carla F.; Godoy, Jose R.; Doering, Barbara; Cavalcanti, Marcia C.O.; Bergmann, Martin; Petzinger, Ernst; Geyer, Joachim . E-mail: Joachim.M.Geyer@vetmed.uni-giessen.de

    2007-09-14

    Here we report the identification, cloning, and characterization of SLC10A5, which is a new member of Solute Carrier Family 10 (SLC10), also known as the 'sodium/bile acid cotransporter family'. Expression of SLC10A5/Slc10a5 was examined by quantitative real-time PCR and revealed its highest expression levels in liver and kidney in humans, rat and mouse. In rat liver and kidney, Slc10a5 expression was localized by in situ hybridization to hepatocytes and proximal tubules, respectively. A SLC10A5-FLAG fusion protein was expressed in HEK293 cells and showed an apparent molecular weight of 42 kDa after immunoprecipitation. When expressed in Xenopus laevis oocytes, the SLC10A5-FLAG protein was detected in the oocyte's plasma membrane but showed no transport activity for taurocholate, cholate, estrone-3-sulfate, or dehydroepiandrosterone sulfate. As bile acid carriers are the most related carriers to SLC10A5 though, we strongly suppose that SLC10A5 is an orphan carrier with yet non-identified substrates.

  15. 26 CFR 1.512(a)-5T - Questions and answers relating to the unrelated business taxable income of organizations...

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... income of organizations described in paragraphs (9), (17) or (20) of Section 501(c) (temporary). Q-1... business taxable income of organizations described in paragraphs (9), (17) or (20) of Section 501(c) (temporary). 1.512(a)-5T Section 1.512(a)-5T Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF...

  16. 26 CFR 1.512(a)-5T - Questions and answers relating to the unrelated business taxable income of organizations...

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... income of organizations described in paragraphs (9), (17) or (20) of Section 501(c) (temporary). Q-1... business taxable income of organizations described in paragraphs (9), (17) or (20) of Section 501(c) (temporary). 1.512(a)-5T Section 1.512(a)-5T Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF...

  17. 26 CFR 1.512(a)-5T - Questions and answers relating to the unrelated business taxable income of organizations...

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... income of organizations described in paragraphs (9), (17) or (20) of Section 501(c) (temporary). Q-1... business taxable income of organizations described in paragraphs (9), (17) or (20) of Section 501(c) (temporary). 1.512(a)-5T Section 1.512(a)-5T Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF...

  18. 26 CFR 1.512(a)-5T - Questions and answers relating to the unrelated business taxable income of organizations...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... income of organizations described in paragraphs (9), (17) or (20) of Section 501(c) (temporary). Q-1... business taxable income of organizations described in paragraphs (9), (17) or (20) of Section 501(c) (temporary). 1.512(a)-5T Section 1.512(a)-5T Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF...

  19. 26 CFR 1.263A-5 - Exception for qualified creative expenses incurred by certain free-lance authors, photographers...

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 3 2013-04-01 2013-04-01 false Exception for qualified creative expenses incurred by certain free-lance authors, photographers, and artists. 1.263A-5 Section 1.263A-5 Internal... certain free-lance authors, photographers, and artists....

  20. 26 CFR 1.263A-5 - Exception for qualified creative expenses incurred by certain free-lance authors, photographers...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 3 2010-04-01 2010-04-01 false Exception for qualified creative expenses incurred by certain free-lance authors, photographers, and artists. 1.263A-5 Section 1.263A-5 Internal...-lance authors, photographers, and artists....

  1. 26 CFR 1.263A-5 - Exception for qualified creative expenses incurred by certain free-lance authors, photographers...

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 3 2014-04-01 2014-04-01 false Exception for qualified creative expenses incurred by certain free-lance authors, photographers, and artists. 1.263A-5 Section 1.263A-5 Internal... certain free-lance authors, photographers, and artists....

  2. 26 CFR 1.263A-5 - Exception for qualified creative expenses incurred by certain free-lance authors, photographers...

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 3 2012-04-01 2012-04-01 false Exception for qualified creative expenses incurred by certain free-lance authors, photographers, and artists. 1.263A-5 Section 1.263A-5 Internal... certain free-lance authors, photographers, and artists....

  3. 26 CFR 1.263A-5 - Exception for qualified creative expenses incurred by certain free-lance authors, photographers...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 3 2011-04-01 2011-04-01 false Exception for qualified creative expenses incurred by certain free-lance authors, photographers, and artists. 1.263A-5 Section 1.263A-5 Internal... certain free-lance authors, photographers, and artists....

  4. 75 FR 38979 - Endangered and Threatened Species; Initiation of a 5-Year Review of the Eastern Distinct...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-07

    ... for the eastern Distinct Population Segment of the Steller sea lion (75 FR 37385). NMFS inadvertently... of a 5-Year Review of the Eastern Distinct Population Segment of the Steller Sea Lion AGENCY... of a 5-year review of the eastern Distinct Population Segment (DPS) of the Steller Sea...

  5. Neighboring Genes Show Correlated Evolution in Gene Expression.

    PubMed

    Ghanbarian, Avazeh T; Hurst, Laurence D

    2015-07-01

    When considering the evolution of a gene's expression profile, we commonly assume that this is unaffected by its genomic neighborhood. This is, however, in contrast to what we know about the lack of autonomy between neighboring genes in gene expression profiles in extant taxa. Indeed, in all eukaryotic genomes genes of similar expression-profile tend to cluster, reflecting chromatin level dynamics. Does it follow that if a gene increases expression in a particular lineage then the genomic neighbors will also increase in their expression or is gene expression evolution autonomous? To address this here we consider evolution of human gene expression since the human-chimp common ancestor, allowing for both variation in estimation of current expression level and error in Bayesian estimation of the ancestral state. We find that in all tissues and both sexes, the change in gene expression of a focal gene on average predicts the change in gene expression of neighbors. The effect is highly pronounced in the immediate vicinity (<100 kb) but extends much further. Sex-specific expression change is also genomically clustered. As genes increasing their expression in humans tend to avoid nuclear lamina domains and be enriched for the gene activator 5-hydroxymethylcytosine, we conclude that, most probably owing to chromatin level control of gene expression, a change in gene expression of one gene likely affects the expression evolution of neighbors, what we term expression piggybacking, an analog of hitchhiking.

  6. [BIOINFORMATIC SEARCH AND PHYLOGENETIC ANALYSIS OF THE CELLULOSE SYNTHASE GENES OF FLAX (LINUM USITATISSIMUM)].

    PubMed

    Pydiura, N A; Bayer, G Ya; Galinousky, D V; Yemets, A I; Pirko, Ya V; Podvitski, T A; Anisimova, N V; Khotyleva, L V; Kilchevsky, A V; Blume, Ya B

    2015-01-01

    A bioinformatic search of sequences encoding cellulose synthase genes in the flax genome, and their comparison to dicots orthologs was carried out. The analysis revealed 32 cellulose synthase gene candidates, 16 of which are highly likely to encode cellulose synthases, and the remaining 16--cellulose synthase-like proteins (Csl). Phylogenetic analysis of gene products of cellulose synthase genes allowed distinguishing 6 groups of cellulose synthase genes of different classes: CesA1/10, CesA3, CesA4, CesA5/6/2/9, CesA7 and CesA8. Paralogous sequences within classes CesA1/10 and CesA5/6/2/9 which are associated with the primary cell wall formation are characterized by a greater similarity within these classes than orthologous sequences. Whereas the genes controlling the biosynthesis of secondary cell wall cellulose form distinct clades: CesA4, CesA7, and CesA8. The analysis of 16 identified flax cellulose synthase gene candidates shows the presence of at least 12 different cellulose synthase gene variants in flax genome which are represented in all six clades of cellulose synthase genes. Thus, at this point genes of all ten known cellulose synthase classes are identify in flax genome, but their correct classification requires additional research. PMID:26638491

  7. [BIOINFORMATIC SEARCH AND PHYLOGENETIC ANALYSIS OF THE CELLULOSE SYNTHASE GENES OF FLAX (LINUM USITATISSIMUM)].

    PubMed

    Pydiura, N A; Bayer, G Ya; Galinousky, D V; Yemets, A I; Pirko, Ya V; Podvitski, T A; Anisimova, N V; Khotyleva, L V; Kilchevsky, A V; Blume, Ya B

    2015-01-01

    A bioinformatic search of sequences encoding cellulose synthase genes in the flax genome, and their comparison to dicots orthologs was carried out. The analysis revealed 32 cellulose synthase gene candidates, 16 of which are highly likely to encode cellulose synthases, and the remaining 16--cellulose synthase-like proteins (Csl). Phylogenetic analysis of gene products of cellulose synthase genes allowed distinguishing 6 groups of cellulose synthase genes of different classes: CesA1/10, CesA3, CesA4, CesA5/6/2/9, CesA7 and CesA8. Paralogous sequences within classes CesA1/10 and CesA5/6/2/9 which are associated with the primary cell wall formation are characterized by a greater similarity within these classes than orthologous sequences. Whereas the genes controlling the biosynthesis of secondary cell wall cellulose form distinct clades: CesA4, CesA7, and CesA8. The analysis of 16 identified flax cellulose synthase gene candidates shows the presence of at least 12 different cellulose synthase gene variants in flax genome which are represented in all six clades of cellulose synthase genes. Thus, at this point genes of all ten known cellulose synthase classes are identify in flax genome, but their correct classification requires additional research.

  8. Saporin suicide gene therapy.

    PubMed

    Zarovni, Natasa; Vago, Riccardo; Fabbrini, Maria Serena

    2009-01-01

    New genes useful in suicide gene therapy are those encoding toxins such as plant ribosome-inactivating proteins (RIPs), which can irreversibly block protein synthesis, triggering apoptotic cell death. Plasmids expressing a cytosolic saporin (SAP) gene from common soapwort (Saponaria officinalis) are generated by placing the region encoding the mature plant toxin under the control of strong viral promoters and may be placed under tumor-specific promoters. The ability of the resulting constructs to inhibit protein synthesis is tested in cultured tumor cells co-transfected with a luciferase reporter gene. SAP expression driven by the cytomegalovirus (CMV) promoter (pCI-SAP) demonstrates that only 10 ng ofplasmid DNA per 1.6 x 10(4) B16 melanoma cells drastically reduces luciferase reporter activity to 18% of that in control cells (1). Direct intratumoral injections are performed in an aggressive melanoma model. B16 melanoma-bearing mice injected with pCI-SAP complexed with lipofectamine or N-(2,3-dioleoyloxy-1-propyl) trimethylammonium methyl sulfate (DOTAP) show a noteworthy attenuation in tumor growth, and this effect is significantly augmented by repeated administrations of the DNA complexes. Here, we describe in detail this cost-effective and safe suicide gene approach. PMID:19565907

  9. On sports and genes.

    PubMed

    Zilberman-Schapira, Gili; Chen, Jieming; Gerstein, Mark

    2012-12-01

    Our genes influence our athletic ability. However, the causal genetic factors and mechanisms, and the extent of their effects, remain largely elusive. Many studies investigate this association between specific genes and athletic performance. Such studies have increased in number over the past few years, as recent developments and patents in DNA sequencing have made large amounts of sequencing data available for such analysis. In this paper, we consider four of the most intensively studied genes in relation to athletic ability: angiotensin I-converting enzyme, alpha-actinin 3, peroxismose proliferator-activator receptor alpha and nitric oxide synthase 3. We investigate the connection between genotype and athletic phenotype in the context of these four genes in various sport fields and across different ethnicities and genders. We do an extensive literature survey on these genes and the polymorphisms (single nucleotide polymorphisms or indels) found to be associated with athletic performance. We also present, for each of these polymorphisms, the allele frequencies in the different ethnicities reported in the pilot phase of the 1000 Genomes Project - arguably the largest human genome-sequencing endeavor to date. We discuss the considerable success, and significant drawbacks, of past research along these lines, and propose interesting directions for future research.

  10. Hox genes and evolution

    PubMed Central

    Hrycaj, Steven M.; Wellik, Deneen M.

    2016-01-01

    Hox proteins are a deeply conserved group of transcription factors originally defined for their critical roles in governing segmental identity along the antero-posterior (AP) axis in Drosophila. Over the last 30 years, numerous data generated in evolutionarily diverse taxa have clearly shown that changes in the expression patterns of these genes are closely associated with the regionalization of the AP axis, suggesting that Hox genes have played a critical role in the evolution of novel body plans within Bilateria. Despite this deep functional conservation and the importance of these genes in AP patterning, key questions remain regarding many aspects of Hox biology. In this commentary, we highlight recent reports that have provided novel insight into the origins of the mammalian Hox cluster, the role of Hox genes in the generation of a limbless body plan, and a novel putative mechanism in which Hox genes may encode specificity along the AP axis. Although the data discussed here offer a fresh perspective, it is clear that there is still much to learn about Hox biology and the roles it has played in the evolution of the Bilaterian body plan. PMID:27239281

  11. LQTS gene LOVD database.

    PubMed

    Zhang, Tao; Moss, Arthur; Cong, Peikuan; Pan, Min; Chang, Bingxi; Zheng, Liangrong; Fang, Quan; Zareba, Wojciech; Robinson, Jennifer; Lin, Changsong; Li, Zhongxiang; Wei, Junfang; Zeng, Qiang; Qi, Ming

    2010-11-01

    The Long QT Syndrome (LQTS) is a group of genetically heterogeneous disorders that predisposes young individuals to ventricular arrhythmias and sudden death. LQTS is mainly caused by mutations in genes encoding subunits of cardiac ion channels (KCNQ1, KCNH2,SCN5A, KCNE1, and KCNE2). Many other genes involved in LQTS have been described recently(KCNJ2, AKAP9, ANK2, CACNA1C, SCNA4B, SNTA1, and CAV3). We created an online database(http://www.genomed.org/LOVD/introduction.html) that provides information on variants in LQTS-associated genes. As of February 2010, the database contains 1738 unique variants in 12 genes. A total of 950 variants are considered pathogenic, 265 are possible pathogenic, 131 are unknown/unclassified, and 292 have no known pathogenicity. In addition to these mutations collected from published literature, we also submitted information on gene variants, including one possible novel pathogenic mutation in the KCNH2 splice site found in ten Chinese families with documented arrhythmias. The remote user is able to search the data and is encouraged to submit new mutations into the database. The LQTS database will become a powerful tool for both researchers and clinicians. PMID:20809527

  12. LQTS gene LOVD database.

    PubMed

    Zhang, Tao; Moss, Arthur; Cong, Peikuan; Pan, Min; Chang, Bingxi; Zheng, Liangrong; Fang, Quan; Zareba, Wojciech; Robinson, Jennifer; Lin, Changsong; Li, Zhongxiang; Wei, Junfang; Zeng, Qiang; Qi, Ming

    2010-11-01

    The Long QT Syndrome (LQTS) is a group of genetically heterogeneous disorders that predisposes young individuals to ventricular arrhythmias and sudden death. LQTS is mainly caused by mutations in genes encoding subunits of cardiac ion channels (KCNQ1, KCNH2,SCN5A, KCNE1, and KCNE2). Many other genes involved in LQTS have been described recently(KCNJ2, AKAP9, ANK2, CACNA1C, SCNA4B, SNTA1, and CAV3). We created an online database(http://www.genomed.org/LOVD/introduction.html) that provides information on variants in LQTS-associated genes. As of February 2010, the database contains 1738 unique variants in 12 genes. A total of 950 variants are considered pathogenic, 265 are possible pathogenic, 131 are unknown/unclassified, and 292 have no known pathogenicity. In addition to these mutations collected from published literature, we also submitted information on gene variants, including one possible novel pathogenic mutation in the KCNH2 splice site found in ten Chinese families with documented arrhythmias. The remote user is able to search the data and is encouraged to submit new mutations into the database. The LQTS database will become a powerful tool for both researchers and clinicians.

  13. Gene therapy for brain tumors.

    PubMed

    Bansal, K; Engelhard, H H

    2000-09-01

    "Gene therapy" can be defined as the transfer of genetic material into a patient's cells for therapeutic purposes. To date, a diverse and creative assortment of treatment strategies utilizing gene therapy have been devised, including gene transfer for modulating the immune system, enzyme prodrug ("suicide gene") therapy, oncolytic therapy, replacement/therapeutic gene transfer, and antisense therapy. For malignant glioma, gene-directed prodrug therapy using the herpes simplex virus thymidine kinase gene was the first gene therapy attempted clinically. A variety of different strategies have now been pursued experimentally and in clinical trials. Although, to date, gene therapy for brain tumors has been found to be reasonably safe, concerns still exist regarding issues related to viral delivery, transduction efficiency, potential pathologic response of the brain, and treatment efficacy. Improved viral vectors are being sought, and potential use of gene therapy in combination with other treatments is being investigated.

  14. How old is my gene?

    PubMed Central

    Capra, John A.; Stolzer, Maureen; Durand, Dannie; Pollard, Katherine S.

    2013-01-01

    Gene functions, interactions, disease associations, and ecological distributions are all correlated with gene age. However, it is challenging to estimate the intricate series of evolutionary events leading to a modern day gene and then reduce this history to a single age estimate. Focusing on eukaryotic gene families, we introduce a framework in which to compare current strategies for quantifying gene age, discuss key differences between these methods, and highlight several common problems. We argue that genes with complex evolutionary histories do not have a single well-defined age. As a result, care must be taken to articulate the goals and assumptions of any analysis that uses gene age estimates. Recent algorithmic advances offer the promise of gene age estimates that are fast, accurate, and consistent across gene families. This will enable a shift to integrated genome-wide analyses of all events in gene evolutionary histories in the near future. PMID:23915718

  15. Gene therapy prospects--intranasal delivery of therapeutic genes.

    PubMed

    Podolska, Karolina; Stachurska, Anna; Hajdukiewicz, Karolina; Małecki, Maciej

    2012-01-01

    Gene therapy is recognized to be a novel method for the treatment of various disorders. Gene therapy strategies involve gene manipulation on broad biological processes responsible for the spreading of diseases. Cancer, monogenic diseases, vascular and infectious diseases are the main targets of gene therapy. In order to obtain valuable experimental and clinical results, sufficient gene transfer methods are required. Therapeutic genes can be administered into target tissues via gene carriers commonly defined as vectors. The retroviral, adenoviral and adeno-associated virus based vectors are most frequently used in the clinic. So far, gene preparations may be administered directly into target organs or by intravenous, intramuscular, intratumor or intranasal injections. It is common knowledge that the number of gene therapy clinical trials has rapidly increased. However, some limitations such as transfection efficiency and stable and long-term gene expression are still not resolved. Consequently, great effort is focused on the evaluation of new strategies of gene delivery. There are many expectations associated with intranasal delivery of gene preparations for the treatment of diseases. Intranasal delivery of therapeutic genes is regarded as one of the most promising forms of pulmonary gene therapy research. Gene therapy based on inhalation of gene preparations offers an alternative way for the treatment of patients suffering from such lung diseases as cystic fibrosis, alpha-1-antitrypsin defect, or cancer. Experimental and first clinical trials based on plasmid vectors or recombinant viruses have revealed that gene preparations can effectively deliver therapeutic or marker genes to the cells of the respiratory tract. The noninvasive intranasal delivery of gene preparations or conventional drugs seems to be very encouraging, although basic scientific research still has to continue.

  16. GeneCards Version 3: the human gene integrator

    PubMed Central

    Safran, Marilyn; Dalah, Irina; Alexander, Justin; Rosen, Naomi; Iny Stein, Tsippi; Shmoish, Michael; Nativ, Noam; Bahir, Iris; Doniger, Tirza; Krug, Hagit; Sirota-Madi, Alexandra; Olender, Tsviya; Golan, Yaron; Stelzer, Gil; Harel, Arye; Lancet, Doron

    2010-01-01

    GeneCards (www.genecards.org) is a comprehensive, authoritative compendium of annotative information about human genes, widely used for nearly 15 years. Its gene-centric content is automatically mined and integrated from over 80 digital sources, resulting in a web-based deep-linked card for each of >73 000 human gene entries, encompassing the following categories: protein coding, pseudogene, RNA gene, genetic locus, cluster and uncategorized. We now introduce GeneCards Version 3, featuring a speedy and sophisticated search engine and a revamped, technologically enabling infrastructure, catering to the expanding needs of biomedical researchers. A key focus is on gene-set analyses, which leverage GeneCards’ unique wealth of combinatorial annotations. These include the GeneALaCart batch query facility, which tabulates user-selected annotations for multiple genes and GeneDecks, which identifies similar genes with shared annotations, and finds set-shared annotations by descriptor enrichment analysis. Such set-centric features address a host of applications, including microarray data analysis, cross-database annotation mapping and gene-disorder associations for drug targeting. We highlight the new Version 3 database architecture, its multi-faceted search engine, and its semi-automated quality assurance system. Data enhancements include an expanded visualization of gene expression patterns in normal and cancer tissues, an integrated alternative splicing pattern display, and augmented multi-source SNPs and pathways sections. GeneCards now provides direct links to gene-related research reagents such as antibodies, recombinant proteins, DNA clones and inhibitory RNAs and features gene-related drugs and compounds lists. We also portray the GeneCards Inferred Functionality Score annotation landscape tool for scoring a gene’s functional information status. Finally, we delineate examples of applications and collaborations that have benefited from the GeneCards suite

  17. FunGene: the functional gene pipeline and repository

    PubMed Central

    Fish, Jordan A.; Chai, Benli; Wang, Qiong; Sun, Yanni; Brown, C. Titus; Tiedje, James M.; Cole, James R.

    2013-01-01

    Ribosomal RNA genes have become the standard molecular markers for microbial community analysis for good reasons, including universal occurrence in cellular organisms, availability of large databases, and ease of rRNA gene region amplification and analysis. As markers, however, rRNA genes have some significant limitations. The rRNA genes are often present in multiple copies, unlike most protein-coding genes. The slow rate of change in rRNA genes means that multiple species sometimes share identical 16S rRNA gene sequences, while many more species share identical sequences in the short 16S rRNA regions commonly analyzed. In addition, the genes involved in many important processes are not distributed in a phylogenetically coherent manner, potentially due to gene loss or horizontal gene transfer. While rRNA genes remain the most commonly used markers, key genes in ecologically important pathways, e.g., those involved in carbon and nitrogen cycling, can provide important insights into community composition and function not obtainable through rRNA analysis. However, working with ecofunctional gene data requires some tools beyond those required for rRNA analysis. To address this, our Functional Gene Pipeline and Repository (FunGene; http://fungene.cme.msu.edu/) offers databases of many common ecofunctional genes and proteins, as well as integrated tools that allow researchers to browse these collections and choose subsets for further analysis, build phylogenetic trees, test primers and probes for coverage, and download aligned sequences. Additional FunGene tools are specialized to process coding gene amplicon data. For example, FrameBot produces frameshift-corrected protein and DNA sequences from raw reads while finding the most closely related protein reference sequence. These tools can help provide better insight into microbial communities by directly studying key genes involved in important ecological processes. PMID:24101916

  18. Intraoperative assessment of ovarian tumors: a 5-year review with assessment of discrepant diagnostic cases.

    PubMed

    Stewart, Colin J R; Brennan, Barbara A; Hammond, Ian G; Leung, Yee C; McCartney, Anthony J

    2006-07-01

    Frozen section is often requested in the intraoperative assessment of patients, presenting with ovarian masses, to provide guidance for appropriate surgical management. To assess the accuracy of frozen section and identify causes of diagnostic error, we reviewed 914 consecutive ovarian frozen sections performed over a 5-year period in 2 laboratories; one of which provides a general surgical pathology service and, the other, a specialist gynecologic pathology service. Cases, in which there were significant diagnostic discrepancies between the intraoperative and the final histological diagnoses, were reviewed. The series included 552 benign lesions (60.4%), 96 borderline (atypical proliferating) epithelial tumors (10.5%), and 266 malignancies (29.1%). The overall accuracy of frozen section diagnosis was 95.3%. There were 43 cases with diagnostic discrepancy; 20 (3.8% cases) of which were reported in the specialist laboratory and 23 (5.9% cases) in the general laboratory. Underdiagnosis of tumor type accounted for 32 of 43 discrepant cases and was most frequent in borderline mucinous tumors. The most common cause of overdiagnosis was the misinterpretation of serous cystadenofibroma as borderline serous tumor. Slide review of the 41 assessable cases indicated that sampling error, pathologist misinterpretation, and suboptimal slide preparations contributed to misdiagnoses in 17, 23, and 9 tumors, respectively (in 9 cases, 2 factors were contributory), whereas no specific error was identified in the remaining case. Technical factors and pathologist misinterpretation were more common in the general pathology laboratory. This study confirms that ovarian frozen section is a generally reliable technique, but there are problematic areas, particularly involving the assessment of borderline tumors.

  19. Shoot growth in aseptically cultivated daylily and haplopappus plantlets after a 5-day spaceflight.

    PubMed

    Levine, H G; Krikorian, A D

    1992-01-01

    Plantlets of daylily (Hemerocallis cv. Autumn Blaze) regenerated from cell suspensions, and 4 clonal populations of Haplopappus gracilis were aseptically cultivated aboard the Shuttle "Discovery" during a 5-day mission within NASA's Plant Growth Unit (PGU) apparatus. Daylily was selected as a representative herbaceous perennial monocotyledon and the haplopappus clones represented an annual dicotyledon. The latter included 4 strains with different physiological and morphological characteristics: two aseptic seedling clones (each generated from a single seedling) and two tissue culture-derived lines. Mean daily growth rates for the primary shoots of all plantlets averaged 4.13 mm day-1 (SD = 2.20) for the flight experiment and 4.68 mm day-1 (SD = 2.59) for the ground control. Comparable growth rates calculated by summing both the primary and secondary shoots for all plantlets were 5.94 mm day-1 (SD = 2.89) for the flight experiment and 6.38 mm day-1 (SD = 3.71) for the control. Statistically significant differences existed between: (1) flight vs control primary shoot growth (the controls growing more than plantlets subjected to spaceflight conditions), (2) the different populations (the daylily gaining more shoot material than any of the haplopappus populations and the haplopappus seedling clones outperforming the tissue culture-derived haplopappus lines), and (3) the individual Plant Growth Chambers contained within the PGU. The data suggest that some spaceflight-associated factor(s) increased the tendency for primary shoot apices to degrade or senesce, resulting in the release of apical dominance and permitting the emergence of axillary branches, which subsequently partially compensated for the reduced primary axis growth. In addition to spaceflight-associated factors, the physiologically diverse nature of the experimental material as well as environmental heterogeneities within the culture apparatus contributed to the variation in growth results. The findings

  20. Task Specific Frequencies of Neck Motion Measured in Healthy Young Adults over a 5 Day Period

    PubMed Central

    Cobian, Daniel G.; Sterling, Andrew C.; Anderson, Paul A.; Heiderscheit, Bryan C.

    2010-01-01

    Study Design Observational cohort design. Objective To quantify the frequencies and magnitudes of neck motion during daily activities in healthy subjects. Summary of Background Data Previous studies have measured the maximum excursions during re-created ADLs in lab settings, but there is a lack of information available on frequencies and excursions of neck motion with ADLs in non-artificial settings. Methods Ten healthy young adults were fitted with a portable motion measurement device that recorded movement about each primary axis. Participants were instructed to wear the unit continuously over a 5-day period and record their daily activities with corresponding times. After the collection period, subjects' activity logs were analyzed and data were partitioned into five categories which provided the most primary representation of ADLs: athletics, work, travel, sleep, and miscellaneous. Each category was further divided into increasingly specific activities (e.g. running and walking). Frequency of motions within 5° increments was determined and an hourly rate was calculated for each activity. Median motion about each axis for each activity was also determined. Results The total number of movements per hour for all axes, regardless of amplitude, was highest during athletic activity and lowest during sleeping. The majority of movements (92% of athletic activity, 90% of work) required less than 25° of lateral bending, while greater range of movement requirements were observed for flexion-extension and axial rotation. The median range of motion along all axes was highest for athletic activity and lowest for sleeping. Conclusions The results of this study provide a baseline of the frequency and magnitude of neck motion during normal ADLs for the specified population. These findings can assist physicians and physical therapists in determining the extent of disability and identifying activities that will likely be problematic for patients with limited cervical motion

  1. Traditional endodontic surgery versus modern technique: a 5-year controlled clinical trial.

    PubMed

    Tortorici, Silvia; Difalco, Paolo; Caradonna, Luigi; Tetè, Stefano

    2014-05-01

    In this study, we compared outcomes of traditional apicoectomy versus modern apicoectomy, by means of a controlled clinical trial with a 5-year follow-up. The study investigated 938 teeth in 843 patients. On the basis of the procedure performed, the teeth were grouped in 3 groups. Differences between the groups were the method of osteotomy (type of instruments used), type of preparation of retrograde cavity (different apicoectomy angles and instruments used for root-end preparation), and root-end filling material used (gray mineral trioxide aggregate or silver amalgam). Outcome (tooth healing) was estimated after 1 and 5 years, postoperatively. Clinical success rates after 1 year were 67% (306 teeth), 90% (186 teeth), and 94% (256 teeth) according to traditional apicoectomy (group 1), modern microsurgical apicoectomy using burns for osteotomy (group 2) or using piezo-osteotomy (group 3), respectively. After 1 year, group comparison results were statistically significant (P < 0.0001). Linear trend test was also statistically significant (P < 0.0001), pointing out larger healing from group 1 to group 3. After 5 years, teeth were classified into 2 groups on the basis of root-end filling material used. Clinical success was 90.8% (197 teeth) in the silver amalgam group versus 96% (309 teeth) in the mineral trioxide aggregate group (P < 0.00214). Multiple logistic regression analysis found that surgical technique was independently associated to tooth healing. In conclusion, modern apicoectomy resulted in a probability of success more than 5 times higher (odds ratio, 5.20 [95% confidence interval, 3.94-6.92]; P < 0.001) compared with the traditional technique. PMID:24469371

  2. The relationship between overactivity and opioid use in chronic pain: a 5-day observational study.

    PubMed

    Andrews, Nicole Emma; Strong, Jenny; Meredith, Pamela Joy; Fleming, Julia Ann

    2016-02-01

    With increasing concerns about the potential harm of long-term opioid therapy, there is a need for the development and implementation of alternative treatment strategies for patients with chronic pain who have been using opioids for a prolonged period of time. Based on the findings from a recent qualitative investigation that suggested there may be a bidirectional association between opioid reliance and habitual overactivity behaviour (activity engagement that significantly exacerbates pain), this study was designed to quantitatively investigate the association between opioid use and habitual overactivity over a 5-day period in a group of chronic pain patients. Participants provided a list of their prescribed pain medication, completed a self-report measure of habitual overactivity, and then commenced 5 days of data collection. Data collection required participants to wear an activity monitor and to complete a diary that detailed their daily activities and the time at which they took medication. Individuals reporting higher levels of habitual overactivity were more likely to be prescribed opioids. In addition, higher levels of habitual overactivity were associated with more frequent pro re nata ("as needed") opioid use over the 5 days, and with a discrepancy between the prescribed and actual oral morphine-equivalent daily dose, where more medication was taken than was prescribed. There was no predominant context for pro re nata use. The results of this study support the idea that habitual overactivity behaviour may play a role in the development of reliance on opioid medication and that such an association may provide a potential treatment target for opioid therapy rationalisation.

  3. Shoot growth in aseptically cultivated daylily and haplopappus plantlets after a 5-day spaceflight

    NASA Technical Reports Server (NTRS)

    Levine, H. G.; Krikorian, A. D.

    1992-01-01

    Plantlets of daylily (Hemerocallis cv. Autumn Blaze) regenerated from cell suspensions, and 4 clonal populations of Haplopappus gracilis were aseptically cultivated aboard the Shuttle "Discovery" during a 5-day mission within NASA's Plant Growth Unit (PGU) apparatus. Daylily was selected as a representative herbaceous perennial monocotyledon and the haplopappus clones represented an annual dicotyledon. The latter included 4 strains with different physiological and morphological characteristics: two aseptic seedling clones (each generated from a single seedling) and two tissue culture-derived lines. Mean daily growth rates for the primary shoots of all plantlets averaged 4.13 mm day-1 (SD = 2.20) for the flight experiment and 4.68 mm day-1 (SD = 2.59) for the ground control. Comparable growth rates calculated by summing both the primary and secondary shoots for all plantlets were 5.94 mm day-1 (SD = 2.89) for the flight experiment and 6.38 mm day-1 (SD = 3.71) for the control. Statistically significant differences existed between: (1) flight vs control primary shoot growth (the controls growing more than plantlets subjected to spaceflight conditions), (2) the different populations (the daylily gaining more shoot material than any of the haplopappus populations and the haplopappus seedling clones outperforming the tissue culture-derived haplopappus lines), and (3) the individual Plant Growth Chambers contained within the PGU. The data suggest that some spaceflight-associated factor(s) increased the tendency for primary shoot apices to degrade or senesce, resulting in the release of apical dominance and permitting the emergence of axillary branches, which subsequently partially compensated for the reduced primary axis growth. In addition to spaceflight-associated factors, the physiologically diverse nature of the experimental material as well as environmental heterogeneities within the culture apparatus contributed to the variation in growth results. The findings

  4. Accelerated radiation damage test facility using a 5 MV tandem ion accelerator

    NASA Astrophysics Data System (ADS)

    Wady, P. T.; Draude, A.; Shubeita, S. M.; Smith, A. D.; Mason, N.; Pimblott, S. M.; Jimenez-Melero, E.

    2016-01-01

    We have developed a new irradiation facility that allows to perform accelerated damage tests of nuclear reactor materials at temperatures up to 400 °C using the intense proton (<100 μA) and heavy ion (≈10 μA) beams produced by a 5 MV tandem ion accelerator. The dedicated beam line for radiation damage studies comprises: (1) beam diagnosis and focusing optical components, (2) a scanning and slit system that allows uniform irradiation of a sample area of 0.5-6 cm2, and (3) a sample stage designed to be able to monitor in-situ the sample temperature, current deposited on the sample, and the gamma spectrum of potential radio-active nuclides produced during the sample irradiation. The beam line capabilities have been tested by irradiating a 20Cr-25Ni-Nb stabilised stainless steel with a 3 MeV proton beam to a dose level of 3 dpa. The irradiation temperature was 356 °C, with a maximum range in temperature values of ±6 °C within the first 24 h of continuous irradiation. The sample stage is connected to ground through an electrometer to measure accurately the charge deposited on the sample. The charge can be integrated in hardware during irradiation, and this methodology removes uncertainties due to fluctuations in beam current. The measured gamma spectrum allowed the identification of the main radioactive nuclides produced during the proton bombardment from the lifetimes and gamma emissions. This dedicated radiation damage beam line is hosted by the Dalton Cumbrian Facility of the University of Manchester.

  5. Fulminate Hepatic Failure in a 5 Year Old Female after Inappropriate Acetaminophen Treatment

    PubMed Central

    Kasmi, Irena; Sallabanda, Sashenka; Kasmi, Gentian

    2015-01-01

    BACKGROUND: Acetaminophen is a drug widely used in children because of its safety and efficacy. Although the risk of its toxicity is lower in children such reactions occur in pediatric patients from intentional overdoses and less frequently attributable to unintended inappropriate dosing. The aim of reporting this case is to attract the attention to the risk of the acetaminophen toxicity when administered in high doses. CASE PRESENTATION: We report here a 5 year old girl who developed fulminate liver failure with renal impairment and acute pancreatitis, as a result of acetaminophen toxicity caused from unintentional repeated supratherapeutic ingestion, with a total administered dose of 4800 mg in three consecutive days, 1600 mg/day, approximately 90 mg/kg/day. The blood level of acetaminophen after 10 hours of the last administered dose was 32 mg/l. The patient presented with high fever, jaundice, lethargic, agitating with abdominal pain accompanied by encephalopathy. The liver function test revealed with high level of alanine aminotransferase 5794 UI/l and aspartate aminotransferase 6000 UI/l. Early initiation of oral N-acetylcysteine (NAC) after biochemical evidence of liver toxicity was beneficial with rapid improvement of liver enzymes, hepatic function and encephalopathy. During the course of the illness the child developed acute pancreatitis with hyperamylasemia 255 UI/L and hyperlypasemia 514 UI/L. Patient totally recovered within 29 days. CONCLUSION: Healthcare providers should considered probable acetaminophen toxicity in any child who has received the drug and presented with liver failure. When there is a high index of suspicion of acetaminophen toxicity NAC should be initiated and continued until there are no signs of hepatic dysfunction. PMID:27275268

  6. A 5-year study of attachment loss and tooth loss in community-dwelling older adults.

    PubMed

    Beck, J D; Sharp, T; Koch, G G; Offenbacher, S

    1997-08-01

    Tooth loss is a widely recognized endpoint measure for the effects of periodontal diseases and the impact of periodontal therapy. In fact, traditional clinical measures of periodontal status often are considered to be surrogate endpoints in that they are assumed to be related to tooth loss. However, the strength of the relationship between attachment loss and tooth loss in a representative population of untreated subjects has not been studied extensively. The purpose of this paper is to present the trends in attachment loss over a 5-yr period in a population of community-dwelling elderly blacks and whites. Specifically, this paper presents attachment loss trends both at the person and tooth level to address the following issues; 1) whether teeth that experience attachment loss during 1 time period are more likely to be lost at the next time period; and 2) given similar levels of attachment loss, why are some people more likely to lose teeth? In 1988, the University of North Carolina School of Dentistry initiated the Piedmont 65+ Dental Study, which was designed to elicit 800 dentate respondents in the 5-country area who were examined again at 18, 36 and 60 months. Our findings indicated that teeth with poorer attachment level at baseline had a higher probability of being lost during the next 5 yr and teeth that experienced attachment loss during a time period were more likely to be lost during the next time period than teeth without additional attachment loss. In addition, it appears that there are person-level characteristics associated with increasing tendency towards tooth loss in people with similar periodontal status, a finding that may clarify the relationship between attachment loss and tooth loss. PMID:9379319

  7. Results of a 5-Week Schedule of Modern Total Skin Electron Beam Radiation Therapy

    SciTech Connect

    Morris, Stephen Lloyd; McGovern, Mark; Bayne, Sally; Wain, Mary; Child, Fiona; Whittaker, Sean

    2013-08-01

    Purpose: To report the outcomes of a 5-week schedule of total skin electron beam radiation therapy (TSEB) for mycosis fungoides (MF). Methods: Over 5 years, 41 patients with confirmed MF were treated with a modern TSEB technique delivering 30 Gy in 20 fractions over 5 weeks to the whole skin surface. Data were collected prospectively and entered into the skin tumor unit research database. Skin modified skin weighted assessment tool score data were collected to determine response, duration of response, survival, and toxicity. The outcomes were analyzed according to the patient's stage before TSEB, prognostic factors, and adjuvant treatments. Results: Seventeen patients were stage 1B, 19 were stage IIB, 3 were stage III, and 2 were stage IV. The overall response rate was 95%, with a complete response rate of 51%. Seventy-six percent of patients had relapsed at median follow-up of 18 months. The median time to relapse was 12 months, to systemic therapy was 15 months, and to modified skin weighted assessment tool progression above baseline was 44 months. The complete response rate was 59% in stage IB and 47% in stage IIB patients. The median time to skin relapse was longer in stage IB compared with stage IIB, 18 months versus 9 months. The median time to systemic therapy was longer in stage IB compared with stage IIB, >56 months versus 8 months. The median overall survival was 35 months: >56 months for stage IB, 25 months for stage IIB, 46 months for stage III, and 23.5 months for stage IV. Fifteen patients received adjuvant psoralen + ultraviolet A treatment with no difference seen in the time to relapse. Conclusions: This 5-week schedule of TSEB for MF has a high response rate with comparable duration of response to other regimens. Future studies are needed to find adjuvant and combination treatments to improve the duration of response.

  8. Human DNA repair genes.

    PubMed

    Wood, R D; Mitchell, M; Sgouros, J; Lindahl, T

    2001-02-16

    Cellular DNA is subjected to continual attack, both by reactive species inside cells and by environmental agents. Toxic and mutagenic consequences are minimized by distinct pathways of repair, and 130 known human DNA repair genes are described here. Notable features presently include four enzymes that can remove uracil from DNA, seven recombination genes related to RAD51, and many recently discovered DNA polymerases that bypass damage, but only one system to remove the main DNA lesions induced by ultraviolet light. More human DNA repair genes will be found by comparison with model organisms and as common folds in three-dimensional protein structures are determined. Modulation of DNA repair should lead to clinical applications including improvement of radiotherapy and treatment with anticancer drugs and an advanced understanding of the cellular aging process. PMID:11181991

  9. Frequent gene conversion between human red and green opsin genes.

    PubMed

    Zhao, Z; Hewett-Emmett, D; Li, W H

    1998-04-01

    To study the evolution of human X-linked red and green opsin genes, genomic sequences in large regions of the two genes were compared. The divergences in introns 3, 4, and 5 and the 3' flanking sequence of the two genes are significantly lower than those in exons 4 and 5. The homogenization mechanism of introns and the 3' flanking sequence of human red and green opsin genes is probably gene conversion, which also occurred in exons 1 and 6. At least one gene conversion event occurred in each of three regions (1, 3, and 5) in the sequences compared. In conclusion, gene conversion has occurred frequently between human red and green opsin genes, but exons 2, 3, 4, and 5 have been maintained distinct between the two genes by natural selection.

  10. Neighboring Genes Show Correlated Evolution in Gene Expression

    PubMed Central

    Ghanbarian, Avazeh T.; Hurst, Laurence D.

    2015-01-01

    When considering the evolution of a gene’s expression profile, we commonly assume that this is unaffected by its genomic neighborhood. This is, however, in contrast to what we know about the lack of autonomy between neighboring genes in gene expression profiles in extant taxa. Indeed, in all eukaryotic genomes genes of similar expression-profile tend to cluster, reflecting chromatin level dynamics. Does it follow that if a gene increases expression in a particular lineage then the genomic neighbors will also increase in their expression or is gene expression evolution autonomous? To address this here we consider evolution of human gene expression since the human-chimp common ancestor, allowing for both variation in estimation of current expression level and error in Bayesian estimation of the ancestral state. We find that in all tissues and both sexes, the change in gene expression of a focal gene on average predicts the change in gene expression of neighbors. The effect is highly pronounced in the immediate vicinity (<100 kb) but extends much further. Sex-specific expression change is also genomically clustered. As genes increasing their expression in humans tend to avoid nuclear lamina domains and be enriched for the gene activator 5-hydroxymethylcytosine, we conclude that, most probably owing to chromatin level control of gene expression, a change in gene expression of one gene likely affects the expression evolution of neighbors, what we term expression piggybacking, an analog of hitchhiking. PMID:25743543

  11. Genes and Vocal Learning

    PubMed Central

    White, Stephanie A.

    2009-01-01

    Could a mutation in a single gene be the evolutionary lynchpin supporting the development of human language? A rare mutation in the molecule known as FOXP2 discovered in a human family seemed to suggest so, and its sequence phylogeny reinforced a Chomskian view that language emerged wholesale in humans. Spurred by this discovery, research in primates, rodents and birds suggests that FoxP2 and other language-related genes are interactors in the neuromolecular networks that underlie subsystems of language, such symbolic understanding, vocal learning and theory of mind. The whole picture will only come together through comparative and integrative study into how the human language singularity evolved. PMID:19913899

  12. The gene tree delusion.

    PubMed

    Springer, Mark S; Gatesy, John

    2016-01-01

    Higher-level relationships among placental mammals are mostly resolved, but several polytomies remain contentious. Song et al. (2012) claimed to have resolved three of these using shortcut coalescence methods (MP-EST, STAR) and further concluded that these methods, which assume no within-locus recombination, are required to unravel deep-level phylogenetic problems that have stymied concatenation. Here, we reanalyze Song et al.'s (2012) data and leverage these re-analyses to explore key issues in systematics including the recombination ratchet, gene tree stoichiometry, the proportion of gene tree incongruence that results from deep coalescence versus other factors, and simulations that compare the performance of coalescence and concatenation methods in species tree estimation. Song et al. (2012) reported an average locus length of 3.1 kb for the 447 protein-coding genes in their phylogenomic dataset, but the true mean length of these loci (start codon to stop codon) is 139.6 kb. Empirical estimates of recombination breakpoints in primates, coupled with consideration of the recombination ratchet, suggest that individual coalescence genes (c-genes) approach ∼12 bp or less for Song et al.'s (2012) dataset, three to four orders of magnitude shorter than the c-genes reported by these authors. This result has general implications for the application of coalescence methods in species tree estimation. We contend that it is illogical to apply coalescence methods to complete protein-coding sequences. Such analyses amalgamate c-genes with different evolutionary histories (i.e., exons separated by >100,000 bp), distort true gene tree stoichiometry that is required for accurate species tree inference, and contradict the central rationale for applying coalescence methods to difficult phylogenetic problems. In addition, Song et al.'s (2012) dataset of 447 genes includes 21 loci with switched taxonomic names, eight duplicated loci, 26 loci with non-homologous sequences that are

  13. The gene tree delusion.

    PubMed

    Springer, Mark S; Gatesy, John

    2016-01-01

    Higher-level relationships among placental mammals are mostly resolved, but several polytomies remain contentious. Song et al. (2012) claimed to have resolved three of these using shortcut coalescence methods (MP-EST, STAR) and further concluded that these methods, which assume no within-locus recombination, are required to unravel deep-level phylogenetic problems that have stymied concatenation. Here, we reanalyze Song et al.'s (2012) data and leverage these re-analyses to explore key issues in systematics including the recombination ratchet, gene tree stoichiometry, the proportion of gene tree incongruence that results from deep coalescence versus other factors, and simulations that compare the performance of coalescence and concatenation methods in species tree estimation. Song et al. (2012) reported an average locus length of 3.1 kb for the 447 protein-coding genes in their phylogenomic dataset, but the true mean length of these loci (start codon to stop codon) is 139.6 kb. Empirical estimates of recombination breakpoints in primates, coupled with consideration of the recombination ratchet, suggest that individual coalescence genes (c-genes) approach ∼12 bp or less for Song et al.'s (2012) dataset, three to four orders of magnitude shorter than the c-genes reported by these authors. This result has general implications for the application of coalescence methods in species tree estimation. We contend that it is illogical to apply coalescence methods to complete protein-coding sequences. Such analyses amalgamate c-genes with different evolutionary histories (i.e., exons separated by >100,000 bp), distort true gene tree stoichiometry that is required for accurate species tree inference, and contradict the central rationale for applying coalescence methods to difficult phylogenetic problems. In addition, Song et al.'s (2012) dataset of 447 genes includes 21 loci with switched taxonomic names, eight duplicated loci, 26 loci with non-homologous sequences that are

  14. Huntington's disease gene located.

    PubMed

    Kolata, G

    1983-11-25

    Investigators have found a restriction enzyme marker, a piece of DNA that can be located with recombinant DNA techniques, that is so close to the Huntington's disease gene that its presence can be used as an indicator for that gene. If this marker is used as a diagnostic test for Huntington's disease, people at risk for getting the disease will be able to learn whether or not they will in fact develop the disease. The ability to predict the inevitable onset of this progressive, degenerative disease raises ethical questions about counseling, screening, and disclosure of risk status to patients and family members.

  15. Identification of p53-target genes in Danio rerio.

    PubMed

    Mandriani, Barbara; Castellana, Stefano; Rinaldi, Carmela; Manzoni, Marta; Venuto, Santina; Rodriguez-Aznar, Eva; Galceran, Juan; Nieto, M Angela; Borsani, Giuseppe; Monti, Eugenio; Mazza, Tommaso; Merla, Giuseppe; Micale, Lucia

    2016-01-01

    To orchestrate the genomic response to cellular stress signals, p53 recognizes and binds to DNA containing specific and well-characterized p53-responsive elements (REs). Differences in RE sequences can strongly affect the p53 transactivation capacity and occur even between closely related species. Therefore, the identification and characterization of a species-specific p53 Binding sistes (BS) consensus sequence and of the associated target genes may help to provide new insights into the evolution of the p53 regulatory networks across different species. Although p53 functions were studied in a wide range of species, little is known about the p53-mediated transcriptional signature in Danio rerio. Here, we designed and biochemically validated a computational approach to identify novel p53 target genes in Danio rerio genome. Screening all the Danio rerio genome by pattern-matching-based analysis, we found p53 RE-like patterns proximal to 979 annotated Danio rerio genes. Prioritization analysis identified a subset of 134 candidate pattern-related genes, 31 of which have been investigated in further biochemical assays. Our study identified runx1, axin1, traf4a, hspa8, col4a5, necab2, and dnajc9 genes as novel direct p53 targets and 12 additional p53-controlled genes in Danio rerio genome. The proposed combinatorial approach resulted to be highly sensitive and robust for identifying new p53 target genes also in additional animal species. PMID:27581768

  16. Identification of p53-target genes in Danio rerio

    PubMed Central

    Mandriani, Barbara; Castellana, Stefano; Rinaldi, Carmela; Manzoni, Marta; Venuto, Santina; Rodriguez-Aznar, Eva; Galceran, Juan; Nieto, M. Angela; Borsani, Giuseppe; Monti, Eugenio; Mazza, Tommaso; Merla, Giuseppe; Micale, Lucia

    2016-01-01

    To orchestrate the genomic response to cellular stress signals, p53 recognizes and binds to DNA containing specific and well-characterized p53-responsive elements (REs). Differences in RE sequences can strongly affect the p53 transactivation capacity and occur even between closely related species. Therefore, the identification and characterization of a species-specific p53 Binding sistes (BS) consensus sequence and of the associated target genes may help to provide new insights into the evolution of the p53 regulatory networks across different species. Although p53 functions were studied in a wide range of species, little is known about the p53-mediated transcriptional signature in Danio rerio. Here, we designed and biochemically validated a computational approach to identify novel p53 target genes in Danio rerio genome. Screening all the Danio rerio genome by pattern-matching-based analysis, we found p53 RE-like patterns proximal to 979 annotated Danio rerio genes. Prioritization analysis identified a subset of 134 candidate pattern-related genes, 31 of which have been investigated in further biochemical assays. Our study identified runx1, axin1, traf4a, hspa8, col4a5, necab2, and dnajc9 genes as novel direct p53 targets and 12 additional p53-controlled genes in Danio rerio genome. The proposed combinatorial approach resulted to be highly sensitive and robust for identifying new p53 target genes also in additional animal species. PMID:27581768

  17. Identification of p53-target genes in Danio rerio.

    PubMed

    Mandriani, Barbara; Castellana, Stefano; Rinaldi, Carmela; Manzoni, Marta; Venuto, Santina; Rodriguez-Aznar, Eva; Galceran, Juan; Nieto, M Angela; Borsani, Giuseppe; Monti, Eugenio; Mazza, Tommaso; Merla, Giuseppe; Micale, Lucia

    2016-01-01

    To orchestrate the genomic response to cellular stress signals, p53 recognizes and binds to DNA containing specific and well-characterized p53-responsive elements (REs). Differences in RE sequences can strongly affect the p53 transactivation capacity and occur even between closely related species. Therefore, the identification and characterization of a species-specific p53 Binding sistes (BS) consensus sequence and of the associated target genes may help to provide new insights into the evolution of the p53 regulatory networks across different species. Although p53 functions were studied in a wide range of species, little is known about the p53-mediated transcriptional signature in Danio rerio. Here, we designed and biochemically validated a computational approach to identify novel p53 target genes in Danio rerio genome. Screening all the Danio rerio genome by pattern-matching-based analysis, we found p53 RE-like patterns proximal to 979 annotated Danio rerio genes. Prioritization analysis identified a subset of 134 candidate pattern-related genes, 31 of which have been investigated in further biochemical assays. Our study identified runx1, axin1, traf4a, hspa8, col4a5, necab2, and dnajc9 genes as novel direct p53 targets and 12 additional p53-controlled genes in Danio rerio genome. The proposed combinatorial approach resulted to be highly sensitive and robust for identifying new p53 target genes also in additional animal species.

  18. Immunohistochemical localization of annexin a5 in the mammary gland of rats: up-regulation of expression by pup removal.

    PubMed

    Rieanrakwong, Duangjai; Yonezawa, Tomohiro; Kurusu, Shiro; Kawaminami, Mitsumori

    2010-01-01

    The distribution of annexin A5, a cytosolic protein related to gonadotropin releasing hormone action, was examined in the mammary gland of rats by immunohistochemistry with special reference to changes by lactation. Annexin A5 was observed in the interstitial tissues but not alveolar cells in virgin rats, while mammary epithelial cells became positive for annexin A5 in pregnant rats. The intensity of annexin A5 was decreased in lactating rats and dramatically increased after weaning, especially on the nucleus. When pups were removed from their dam at mid-lactation (day 10), annexin A5 was also increased on day 12. Apoptotic epithelial cells detected by terminal deoxynucleotidyl transferase nick end labeling were simultaneously increased. Annexin A5 mRNA expression of mammary tissues was increased after pup removal. These results are the first to demonstrate the distribution of annexin A5 in the mammary glands of lactating rats, and the enhanced expression in mammary epithelial cells after lactation suggests its involvement in mammary epithelial cell involution.

  19. CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma

    PubMed Central

    Noll, Elisa M.; Eisen, Christian; Stenzinger, Albrecht; Espinet, Elisa; Muckenhuber, Alexander; Klein, Corinna; Vogel, Vanessa; Klaus, Bernd; Nadler, Wiebke; Rösli, Christoph; Lutz, Christian; Kulke, Michael; Engelhardt, Jan; Zickgraf, Franziska M.; Espinosa, Octavio; Schlesner, Matthias; Jiang, Xiaoqi; Kopp-Schneider, Annette; Neuhaus, Peter; Bahra, Marcus; Sinn, Bruno V.; Eils, Roland; Giese, Nathalia A.; Hackert, Thilo; Strobel, Oliver; Werner, Jens; Büchler, Markus W.; Weichert, Wilko; Trumpp, Andreas; Sprick, Martin R.

    2016-01-01

    Although subtypes of pancreatic ductal adenocarcinoma (PDAC) were described, this malignancy is clinically still treated as a single disease. Here, we present patient-derived models representing the full spectrum of previously identified quasi-mesenchymal (QM-PDA), classical and exocrine-like PDAC subtypes, and identify two markers—HNF1A and KRT81—that enable stratification of tumors into different subtypes by immunohistochemistry. Individuals bearing tumors of these subtypes show significant differences in overall survival and their tumors differ in drug sensitivity, with the exocrine-like subtype being resistant to tyrosine kinase inhibitors and paclitaxel. Cytochrome P450 3A5 (CYP3A5) metabolizes these compounds in tumors of the exocrine-like subtype, and pharmacological or shRNA-mediated CYP3A5 inhibition sensitizes tumor cells to these drugs. Whereas hepatocyte nuclear factor 4 alpha (HNF4A) controls basal expression of CYP3A5, drug-induced CYP3A5 upregulation is mediated by the nuclear receptor NR1I2. CYP3A5 also contributes to acquired drug resistance in QM-PDA and classical PDAC, and is highly expressed in several additional malignancies. These findings designate CYP3A5 as predictor of therapy response and as a tumor cell-autonomous detoxification mechanism that must be overcome to prevent drug resistance. PMID:26855150

  20. CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma.

    PubMed

    Noll, Elisa M; Eisen, Christian; Stenzinger, Albrecht; Espinet, Elisa; Muckenhuber, Alexander; Klein, Corinna; Vogel, Vanessa; Klaus, Bernd; Nadler, Wiebke; Rösli, Christoph; Lutz, Christian; Kulke, Michael; Engelhardt, Jan; Zickgraf, Franziska M; Espinosa, Octavio; Schlesner, Matthias; Jiang, Xiaoqi; Kopp-Schneider, Annette; Neuhaus, Peter; Bahra, Marcus; Sinn, Bruno V; Eils, Roland; Giese, Nathalia A; Hackert, Thilo; Strobel, Oliver; Werner, Jens; Büchler, Markus W; Weichert, Wilko; Trumpp, Andreas; Sprick, Martin R

    2016-03-01

    Although subtypes of pancreatic ductal adenocarcinoma (PDAC) have been described, this malignancy is clinically still treated as a single disease. Here we present patient-derived models representing the full spectrum of previously identified quasi-mesenchymal (QM-PDA), classical and exocrine-like PDAC subtypes, and identify two markers--HNF1A and KRT81--that enable stratification of tumors into different subtypes by using immunohistochemistry. Individuals with tumors of these subtypes showed substantial differences in overall survival, and their tumors differed in drug sensitivity, with the exocrine-like subtype being resistant to tyrosine kinase inhibitors and paclitaxel. Cytochrome P450 3A5 (CYP3A5) metabolizes these compounds in tumors of the exocrine-like subtype, and pharmacological or short hairpin RNA (shRNA)-mediated CYP3A5 inhibition sensitizes tumor cells to these drugs. Whereas hepatocyte nuclear factor 4, alpha (HNF4A) controls basal expression of CYP3A5, drug-induced CYP3A5 upregulation is mediated by the nuclear receptor NR1I2. CYP3A5 also contributes to acquired drug resistance in QM-PDA and classical PDAC, and it is highly expressed in several additional malignancies. These findings designate CYP3A5 as a predictor of therapy response and as a tumor cell-autonomous detoxification mechanism that must be overcome to prevent drug resistance. PMID:26855150