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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

    USDA-ARS?s Scientific Manuscript database

    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. APOA5 gene variation interacts with dietary fat intake to modulate obesity and circulating triglycerides in a Mediterranean population

    USDA-ARS?s Scientific Manuscript database

    APOA5 is one of the strongest regulators of plasma TG concentrations; nevertheless, its mechanisms of action are poorly characterized. Genetic variability at the APOA5 locus has also been associated with increased cardiovascular disease risk; however, this predisposition could be attenuated in the c...

  3. Association of APOA5 -1131T>C and S19W gene polymorphisms with both mild hypertriglyceridemia and hyperchylomicronemia in type 2 diabetic patients.

    PubMed

    Charriere, Sybil; Bernard, Sophie; Aqallal, Mahdi; Merlin, Micheline; Billon, Stéphane; Perrot, Laurence; Le Coquil, Elodie; Sassolas, Agnès; Moulin, Philippe; Marcais, Christophe

    2008-08-01

    Two minor apolipoprotein A5 (APOA5) gene haplotypes, represented by -1131T>C and S19W polymorphisms, are strong determinants of plasma triglyceride (TG) concentration variability across human populations. Hypertriglyceridemia is frequent in type 2 diabetes (T2D) and hyperchylomicronemia is not uncommon. We investigated the association of -1131T>C and S19W polymorphisms with diabetic dyslipidemia in 400 Caucasian T2D patients divided in 2 groups: group N with 130 normotriglyceridemics (TG<90th percentile) and group M with 270 moderately hypertriglyceridemics. A third group of 51 diabetic patients (group H) with history of hyperchylomicronemia (TG>15 mM) was also studied. The -1131C allele was more frequent in both mild and severe hypertriglyceridemia (20.6% vs 9.8% vs 5.0%, group H vs M vs N, p<0.001). The 19W allele was more frequent only in patients with hyperchylomicronemia (14.0% vs 6.5% vs 6.1%, group H vs M vs N, p=0.001). In group N+M, the -1131C allele was associated with higher TG (+13%, p=0.034) and lower HDLc (-10%, p=0.004). The 19W allele was only associated with lower HDLc (-9%, p=0.022). These results suggest that in T2D APOA5 polymorphisms contribute to modulate dyslipidemia. Both -1131T>C and S19W polymorphisms are associated with hyperchylomicronemia and only -1131T>C polymorphism with mild hypertriglyceridemia.

  4. 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 havemore » 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.« less

  5. APOA5 genotype modulates 2-y changes in lipid profile in response to weight-loss diet intervention: the Pounds Lost Trial.

    PubMed

    Zhang, Xiaomin; Qi, Qibin; Bray, George A; Hu, Frank B; Sacks, Frank M; Qi, Lu

    2012-10-01

    The apolipoprotein A5 gene (APOA5) is a major gene that regulates lipid metabolism and is modulated by dietary factors. A novel variant rs964184 in APOA5 was identified to be associated with lipids in genome-wide association studies. We examined whether this variant modified changes in lipid concentrations in response to a 2-y weight-loss diet intervention in a randomized trial. The current analyses were secondary analyses of a data set from the Pounds Lost Trial. We genotyped APOA5 rs964184 in 734 overweight or obese adults who were randomly assigned to one of 4 diets that differed in percentages of energy derived from fat, protein, and carbohydrate for 2 y. We evaluated changes in fasting serum concentrations of total cholesterol (TC), LDL cholesterol, HDL cholesterol, and triglyceride from baseline to 2 y of follow-up. After a 2-y dietary intervention, we showed significant interactions between the APOA5 rs964184 polymorphism and dietary fat intake (low compared with high) in the determination of changes in TC, LDL cholesterol, and HDL cholesterol (P-interaction = 0.007, 0.017, and 0.006, respectively). In the low-fat intake group (20% of energy derived from fat), carriers of the risk allele (G allele) exhibited greater reductions in TC and LDL cholesterol than did noncarriers (P = 0.036 and 0.039, respectively), whereas in the high-fat diet group (40% of energy derived from fat), participants with the G allele had a greater increase in HDL cholesterol than did participants without this allele (P = 0.038). Our data showed better improvement in lipid profiles from long-term low-fat diet intake in the APOA5 rs964184 risk allele.

  6. Sequence Analysis of APOA5 Among the Kuwaiti Population Identifies Association of rs2072560, rs2266788, and rs662799 With TG and VLDL Levels

    PubMed Central

    Jasim, Anfal A.; Al-Bustan, Suzanne A.; Al-Kandari, Wafa; Al-Serri, Ahmad; AlAskar, Huda

    2018-01-01

    Common variants of Apolipoprotein A5 (APOA5) have been associated with lipid levels yet very few studies have reported full sequence data from various ethnic groups. The purpose of this study was to analyse the full APOA5 gene sequence to identify variants in 100 healthy Kuwaitis of Arab ethnicities and assess their association with variation in lipid levels in a cohort of 733 samples. Sanger method was used in the direct sequencing of the full 3.7 Kb APOA5 and multiple sequence alignment was used to identify variants. The complete APOA5 sequence in Kuwaiti Arabs has been deposited in GenBank (KJ401315). A total of 20 reported single nucleotide polymorphisms (SNPs) were identified. Two novel SNPs were also identified: a synonymous 2197G>A polymorphism at genomic position 116661525 and a 3′ UTR 3222 C>T polymorphism at genomic position 116660500 based on human genome assembly GRCh37/hg:19. Five SNPs along with the two novel SNPs were selected for validation in the cohort. Association of those SNPs with lipid levels was tested and minor alleles of three SNPs (rs2072560, rs2266788, and rs662799) were found significantly associated with TG and VLDL levels. This is the first study to report the full APOA5 sequence and SNPs in an Arab ethnic group. Analysis of the variants identified and comparison to other populations suggests a distinctive genetic component in Arabs. The positive association observed for rs2072560 and rs2266788 with TG and VLDL levels confirms their role in lipid metabolism. PMID:29686695

  7. Structural and functional analysis of APOA5 mutations identified in patients with severe hypertriglyceridemia[S

    PubMed Central

    Mendoza-Barberá, Elena; Julve, Josep; Nilsson, Stefan K.; Lookene, Aivar; Martín-Campos, Jesús M.; Roig, Rosa; Lechuga-Sancho, Alfonso M.; Sloan, John H.; Fuentes-Prior, Pablo; Blanco-Vaca, Francisco

    2013-01-01

    During the diagnosis of three unrelated patients with severe hypertriglyceridemia, three APOA5 mutations [p.(Ser232_Leu235)del, p.Leu253Pro, and p.Asp332ValfsX4] were found without evidence of concomitant LPL, APOC2, or GPIHBP1 mutations. The molecular mechanisms by which APOA5 mutations result in severe hypertriglyceridemia remain poorly understood, and the functional impairment/s induced by these specific mutations was not obvious. Therefore, we performed a thorough structural and functional analysis that included follow-up of patients and their closest relatives, measurement of apoA-V serum concentrations, and sequencing of the APOA5 gene in 200 nonhyperlipidemic controls. Further, we cloned, overexpressed, and purified both wild-type and mutant apoA-V variants and characterized their capacity to activate LPL. The interactions of recombinant wild-type and mutated apoA-V variants with liposomes of different composition, heparin, LRP1, sortilin, and SorLA/LR11 were also analyzed. Finally, to explore the possible structural consequences of these mutations, we developed a three-dimensional model of full-length, lipid-free human apoA-V. A complex, wide array of impairments was found in each of the three mutants, suggesting that the specific residues affected are critical structural determinants for apoA-V function in lipoprotein metabolism and, therefore, that these APOA5 mutations are a direct cause of hypertriglyceridemia. PMID:23307945

  8. Modulation of phenotypic expression of APOA5 Q97X and L242P mutations.

    PubMed

    Charrière, S; Cugnet, C; Guitard, M; Bernard, S; Groisne, L; Charcosset, M; Pruneta-Deloche, V; Merlin, M; Billon, S; Delay, M; Sassolas, A; Moulin, P; Marçais, C

    2009-11-01

    To provide phenotypic and functional data in new patients with APOA5 mutations and to identify genetic and metabolic factors influencing their phenotypic expression. By sequencing APOA5 gene in a cohort of 286 hyperchylomicronemic subjects, free of LPL or APOC2 mutations, we identified 4 unrelated carriers of the Q97X mutation (3 heterozygotes and 1 homozygote) and one heterozygote with a new L242P mutation. Postheparin LPL activity level was reduced by about 50% in Q97X heterozygotes and more than 90% in the Q97X homozygote, but was normal in the L242P patient after resolution of hyperchylomicronemia. Plasma apoAV was undetectable in the Q97X homozygote and in the normal range in the L242P and Q97X heterozygous carriers. In Western blot studies, the association of apoAV with plasma lipoproteins was altered in Q97X heterozygous carriers but not in the L242P carrier. Hyperchylomicronemic heterozygotes for both mutations carried an additional APOA5 variant haplotype and/or APOE variant (E2 or E4). Type 2 diabetes or metabolic syndrome were not a major phenotypic determinant. The L242P mutation was present in a hyperchylomicronemic proband but its causal involvement remains to be established. The Q97X mutation was clearly involved in hyperchylomicronemia with evidence of concomitant altered intravascular lipolysis, and a complete apoAV deficiency in the homozygote. The phenotypic expression variability of APOA5 mutations was mostly influenced by compound heterozygosity with APOA5 variant haplotypes plus additional genetic factors, and in a lesser extent by the metabolic environment.

  9. Association between sequence variant of c.553 G > T in the apolipoprotein A5 gene and metabolic syndrome, insulin resistance, and carotid atherosclerosis.

    PubMed

    Chien, Kuo-Liong; Hsu, Hsiu-Ching; Chen, Yen-Ching; Su, Ta-Chen; Lee, Yuan-Teh; Chen, Ming-Fong

    2009-09-01

    Common polymorphism of the apolipoprotein A5 gene (APOA5, c.553G>T) related to metabolic syndrome components, insulin resistance, and carotid atherosclerosis remains unclear. We investigated the associations of the APOA5 c.553G>T gene with various metabolic syndrome components and carotid artery atherosclerosis among family members. A total of 661 participants who provided complete genotyping and carotid artery measures were included in this study. Participants with APOA5 c.553T carrier (GT and TT) were more likely to have higher levels of triglycerides and apolipoprotein B, as well as lower levels of high-density lipoprotein (HDL) cholesterol, than participants with the GG genotype. Individuals who carried T alleles had an increased risk of a high level of triglycerides (multivariate odds ratio [OR], 3.86; 95% confidence interval [CI], 1.98-7.55; P<0.0001) and low levels of HDL cholesterol (OR, 2.32; 95% CI, 1.40-3.86; P=0.0012) compared with those without T alleles. The age was an effect modifier for the association between APOA5 genotype and smoking, alcohol drinking, obesity, and lipid profiles, including total, HDL, and low-density lipoprotein (LDL) cholesterol; triglycerides; and apolipoproteins. In addition, the association between APOA5 genotype and hypertriglyceridemia was significant only in adult groups (OR, 3.53; 95% CI, 1.79-6.94), and the association between APOA5 genotype and low HDL cholesterol was stable in young adolescents (OR, 2.39; 95% CI, 1.19-4.78) and adults (OR, 2.20; 95% CI, 1.17-4.15). Our findings indicated that the APOA5 c.553G>T polymorphism is associated with high triglycerides and low HDL cholesterol but not with other metabolic syndrome components or carotid atherosclerosis in this ethnic Chinese population.

  10. Association of rs662799 in APOA5 with CAD in Chinese Han population.

    PubMed

    Chen, Hua; Ding, Shifang; Zhou, Mi; Wu, Xiayin; Liu, Xi; Wu, Yun; Liu, Dechao

    2018-01-08

    CAD (Coronary Artery Disease) is a complex disease that influenced by various environmental and genetic factors. Previous studies have found many single nucleotide polymorphisms (SNPs) associated with the risk of CAD occurrence. However, the results are inconsistent. In this study, we aim to investigate genetic etiology in Chinese Han population by analysis of 7 SNPs in lipid metabolism pathway that previously has been reported to be associated with CAD. A total of 631 samples were used in this study, including 435 CAD cases and 196 normal healthy controls. SNP genotyping were conducted via multiplex PCR amplifying followed by NGS (next-generation sequencing). Rs662799 in APOA5 (Apolipoprotein A5) gene was associated with CAD in Chinese Han population (Odds-ratio = 1.374, P-value = 0.03). No significant association was observed between the rest of SNPs and CAD. Stratified association analysis revealed rs5882 was associated with CAD in non-hypertension group (Odds-ratio = 1.593, P-value = 0.023). Rs1800588 was associated with CAD in smoking group (Odds-ratio = 1.603, P-value = 0.035). The minor allele of rs662799 was the risk factor of CAD occurrences in Chinese Han population.

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

    SciTech Connect

    Pennacchio, Len A.; Olivier, Michael; Hubacek, Jaroslav A.

    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 triglyceridemore » 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.« less

  12. An APOA5 3' UTR variant associated with plasma triglycerides triggers APOA5 downregulation by creating a functional miR-485-5p binding site.

    PubMed

    Caussy, Cyrielle; Charrière, Sybil; Marçais, Christophe; Di Filippo, Mathilde; Sassolas, Agnès; Delay, Mireille; Euthine, Vanessa; Jalabert, Audrey; Lefai, Etienne; Rome, Sophie; Moulin, Philippe

    2014-01-02

    APOA5 c.*158C>T (rs2266788), located in the 3' UTR, belongs to APOA5 haplotype 2 (APOA5*2), which is strongly associated with plasma triglyceride levels and modulates the occurrence of both moderate and severe hypertriglyceridemia. Individuals with APOA5*2 display reduced APOA5 expression at the posttranscriptional level. However, the functionality of this haplotype remains unclear. We hypothesized that the hypertriglyceridemic effects of APOA5*2 could involve miRNA regulation in the APOA5 3' UTR. Bioinformatic studies have identified the creation of a potential miRNA binding site for liver-expressed miR-485-5p (MIRN485-5p) in the mutant APOA5 3' UTR with the c.*158C allele. In human embryonic kidney 293T (HEK293T) cells cotransfected with an APOA5 3' UTR luciferase reporter vector and a miR485-5p precursor, c.*158C allele expression was significantly decreased. Moreover, in HuH-7 cells endogenously expressing miR-485-5p, we observed that luciferase activity was significantly lower in the presence of the c.*158C allele than in the presence of the c.*158T allele, which was completely reversed by a miR-485-5p inhibitor. We demonstrated that the rare c.*158C APOA5 allele creates a functional target site for liver-expressed miR-485-5p. Therefore, we propose that the well-documented hypertriglyceridemic effect of APOA5*2 involves an APOA5 posttranscriptional downregulation mediated by miR-485-5p. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  13. An APOA5 3′ UTR Variant Associated with Plasma Triglycerides Triggers APOA5 Downregulation by Creating a Functional miR-485-5p Binding Site

    PubMed Central

    Caussy, Cyrielle; Charrière, Sybil; Marçais, Christophe; Di Filippo, Mathilde; Sassolas, Agnès; Delay, Mireille; Euthine, Vanessa; Jalabert, Audrey; Lefai, Etienne; Rome, Sophie; Moulin, Philippe

    2014-01-01

    APOA5 c.∗158C>T (rs2266788), located in the 3′ UTR, belongs to APOA5 haplotype 2 (APOA5∗2), which is strongly associated with plasma triglyceride levels and modulates the occurrence of both moderate and severe hypertriglyceridemia. Individuals with APOA5∗2 display reduced APOA5 expression at the posttranscriptional level. However, the functionality of this haplotype remains unclear. We hypothesized that the hypertriglyceridemic effects of APOA5∗2 could involve miRNA regulation in the APOA5 3′ UTR. Bioinformatic studies have identified the creation of a potential miRNA binding site for liver-expressed miR-485-5p (MIRN485-5p) in the mutant APOA5 3′ UTR with the c.∗158C allele. In human embryonic kidney 293T (HEK293T) cells cotransfected with an APOA5 3′ UTR luciferase reporter vector and a miR485-5p precursor, c.∗158C allele expression was significantly decreased. Moreover, in HuH-7 cells endogenously expressing miR-485-5p, we observed that luciferase activity was significantly lower in the presence of the c.∗158C allele than in the presence of the c.∗158T allele, which was completely reversed by a miR-485-5p inhibitor. We demonstrated that the rare c.∗158C APOA5 allele creates a functional target site for liver-expressed miR-485-5p. Therefore, we propose that the well-documented hypertriglyceridemic effect of APOA5∗2 involves an APOA5 posttranscriptional downregulation mediated by miR-485-5p. PMID:24387992

  14. Haplotype analysis of the apolipoprotein gene cluster on human chromosome 11

    PubMed Central

    Olivier, Michael; Wang, Xujing; Cole, Regina; Gau, Brian; Kim, Jessica; Rubin, Edward M.; Pennacchio, Len A.

    2009-01-01

    Members of the apolipoprotein gene cluster (APOA1/C3/A4/A5) on human chromosome 11q23 play an important role in lipid metabolism. Polymorphisms in both APOA5 and APOC3 are strongly associated with plasma triglyceride concentrations. The close genomic locations of these two genes as well as their functional similarity have hindered efforts to define whether each gene independently influences human triglyceride concentrations. In this study, we examined the linkage disequilibrium and haplotype structure of 49 SNPs in a 150-kb region spanning the gene cluster. We identified a total of five common APOA5 haplotypes with a frequency of greater than 8% in samples of northern European origin. The APOA5 haplotype block did not extend past the 7 SNPs in the gene and was separated from the other apolipoprotein gene in the cluster by a region of significantly increased recombination. Furthermore, one previously identified triglyceride risk haplotype of APOA5 (APOA5*3) showed no association with three APOC3 SNPs previously associated with triglyceride concentrations, in contrast to the other risk haplotype (APOA5*2), which was associated with all three minor APOC3 SNP alleles. These results highlight the complex genetic relationship between APOA5 and APOC3 and support the notion that APOA5 represents an independent risk gene affecting plasma triglyceride concentrations in humans. PMID:15081120

  15. Consumption of whole grains and legumes modulates the genetic effect of the APOA5 -1131C variant on changes in triglyceride and apolipoprotein A-V concentrations in patients with impaired fasting glucose or newly diagnosed type 2 diabetes

    PubMed Central

    2014-01-01

    Background The apolipoprotein A5 gene (APOA5) -1131 T > C polymorphism is associated with mild hypertriglyceridemia in type 2 diabetic subjects, and interacts with dietary fat in the determination of triglyceride concentrations. We examined whether a substitution of whole grains and legumes for refined rice in a high carbohydrate diet (about 65% of energy derived from carbohydrate) may modify the effect of this variant on changes in apolipoprotein A-V (apoA-V) and triglyceride concentrations. Methods We genotyped the APOA5 -1131 T > C in individuals with impaired fasting glucose (IFG) or newly diagnosed type 2 diabetes, who were randomly assigned to either a group ingesting whole grain and legume meals daily or a control group for 12 weeks. Results After dietary intervention, we observed significant interactions between the APOA5 -1131 T > C polymorphism and carbohydrate sources (whole grains and legumes versus refined rice) in the determination of mean percent changes in triglyceride and apoA-V (P interactions <0.001 and =0.038, respectively). In the refined rice group (n = 93), the carriers of the risk C allele (n = 50) showed a greater increase in the mean percent changes of triglyceride and apoA-V than noncarriers after adjusting for HOMA-IR (P = 0.004 and 0.021, respectively). The whole grain and legume group (n = 92), however, showed a decrease in fasting glucose, HOMA-IR, and triglyceride, and an increase in apoA-V, irrespective of genotype. Conclusions The data showed that the magnitude of the genetic effect of the APOA5 -1131C variant on triglyceride and apoA-V levels was modulated when substituting consumption of whole grains and legumes for refined rice as a carbohydrate source in IFG or diabetic subjects. Trial registration ClinicalTrials.gov: NCT01784952. PMID:24690159

  16. Consumption of whole grains and legumes modulates the genetic effect of the APOA5 -1131C variant on changes in triglyceride and apolipoprotein A-V concentrations in patients with impaired fasting glucose or newly diagnosed type 2 diabetes.

    PubMed

    Kang, Ryungwoo; Kim, Minjoo; Chae, Jey Sook; Lee, Sang-Hyun; Lee, Jong Ho

    2014-04-01

    The apolipoprotein A5 gene (APOA5) -1131 T > C polymorphism is associated with mild hypertriglyceridemia in type 2 diabetic subjects, and interacts with dietary fat in the determination of triglyceride concentrations. We examined whether a substitution of whole grains and legumes for refined rice in a high carbohydrate diet (about 65% of energy derived from carbohydrate) may modify the effect of this variant on changes in apolipoprotein A-V (apoA-V) and triglyceride concentrations. We genotyped the APOA5 -1131 T > C in individuals with impaired fasting glucose (IFG) or newly diagnosed type 2 diabetes, who were randomly assigned to either a group ingesting whole grain and legume meals daily or a control group for 12 weeks. After dietary intervention, we observed significant interactions between the APOA5 -1131 T > C polymorphism and carbohydrate sources (whole grains and legumes versus refined rice) in the determination of mean percent changes in triglyceride and apoA-V (P interactions <0.001 and =0.038, respectively). In the refined rice group (n = 93), the carriers of the risk C allele (n = 50) showed a greater increase in the mean percent changes of triglyceride and apoA-V than noncarriers after adjusting for HOMA-IR (P = 0.004 and 0.021, respectively). The whole grain and legume group (n = 92), however, showed a decrease in fasting glucose, HOMA-IR, and triglyceride, and an increase in apoA-V, irrespective of genotype. The data showed that the magnitude of the genetic effect of the APOA5 -1131C variant on triglyceride and apoA-V levels was modulated when substituting consumption of whole grains and legumes for refined rice as a carbohydrate source in IFG or diabetic subjects. ClinicalTrials.gov: NCT01784952.

  17. Positive Association between APOA5 rs662799 Polymorphism and Coronary Heart Disease: A Case-Control Study and Meta-Analysis

    PubMed Central

    Ye, Huadan; Zhou, Annan; Hong, Qiangxiao; Tang, Linlin; Xu, Xuting; Xin, Yanfei; Jiang, Danjie; Dai, Dongjun; Li, Yirun; Wang, Dao Wen; Duan, Shiwei

    2015-01-01

    Objective Apolipoprotein A5 (APOA5) is associated with plasma triglyceride (TG) levels, a risk factor for coronary heart disease (CHD). This study explored the association between CHD and the APOA5 rs662799 polymorphism. Methods We collected 1,521 samples (783 CHD patients and 738 controls) for this case-control study. Meta-analysis was performed using Review Manager Software and Stata Software. Results Significant differences were observed between CHD cases and controls at the level of both genotype (χ2 = 8.964, df = 2, P = 0.011) and allele (χ2 = 9.180, df = 1, P = 0.002, OR = 1.275, 95% CI = 1.089–1.492). A breakdown analysis by gender showed a significant association of APOA5 rs662799 with CHD in males (χ2 = 7.770, df = 1, P = 0.005; OR = 1.331, 95% CI = 1.088–1.628). An additional meta-analysis using 21378 cases and 28428 controls established that rs662799 is significantly associated with CHD (P < 0.00001). Conclusion Both our case-control study and meta-analysis confirm a significant association between APOA5 rs662799 and CHD. In addition, our results suggest a male-specific association between the APOA5 rs662799 polymorphism and CHD. PMID:26309253

  18. 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

    2015-02-05

    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.

  19. 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. Copyright © 2014 Elsevier Inc. All

  20. Genetic polymorphisms of T-1131C APOA5 and ALOX5AP SG13S114 with the susceptibility of ischaemic stroke in Morocco.

    PubMed

    Diakite, Brehima; Hamzi, Khalil; Hmimech, Wiam; Nadifi, Sellama

    2016-06-01

    Ischaemic stroke is a multifactorial disease. Genetic polymorphisms involved in lipid, inflammatory and thrombotic metabolisms play an important role in the development of ischaemic stroke. The present study aimed to assess the relationship between T1131C APOA5 and SG13S114 ALOX5AP polymorphisms and the risk of ischemic stroke in 175 cases and 201 controls. Genotyping was performed by high resolution melting and polymerase chain reaction restriction fragment length polymorphism methods. In the case of T-1131C APOA5, a modest risk of ischaemic stroke was noticed with CC (OR: 2.86; 95% CI = 1.24-6.58; Pc = 0.039) and C allele (OR: 1.54; 95% CI = 1.01-2.33; Pc = 0.014). For SG13S114 ALOX5AP, a significant association was observed among subjects with TT (OR: 2.57; 95% CI =1.49-4.83; Pc = 0.009) and T allele (OR: 1.59; 95% CI = 1.16-2.19; Pc = 0.008). According to the risk factors of ischaemic stroke, a positive correlation was observed only between SG13S114 variant of ALOX5AP gene and hypertension (Pc = 0.026). Despite lower sample size, T-1131C APOA5 and SG13S114 variants could be considered an independent genetic risk factor of ischaemic stroke in Moroccan population.

  1. Apolipoprotein A5 gene -1131T/C polymorphism is associated with the risk of metabolic syndrome in ethnic Chinese in Taiwan.

    PubMed

    Hsu, Lung-An; Ko, Yu-Lin; Chang, Chi-Jen; Teng, Ming-Sheng; Wu, Semon; Hu, Chiao-Feng

    2008-01-01

    The -1131T>C polymorphism in the apolipoprotein gene A5 (APOA5) was found to be associated with increased levels of plasma triglyceride and decreased levels of high-density lipoprotein cholesterol (HDL-C), which are characteristic dyslipidemic components of metabolic syndrome. This study aimed to identify a link between this polymorphism and the risk of metabolic syndrome. The sample population comprised 615 unrelated subjects, 18.7% of whom had metabolic syndrome. Genotypes were determined via polymerase chain reaction, restriction mapping with MseI, and gel electrophoresis. A significantly higher level of triglycerides and a lower level of HDL-C were noted in carriers of the -1131C allele than in the non-carriers (p<0.001 and p=0.044, respectively). The frequency of the -1131C allele in the metabolic syndrome-affected subjects was significantly higher than that of the group of unaffected subjects (37.4% vs. 27.7%, p=0.004). Even after adjusting for age, gender, smoking, regular exercise, and waist-to-hip ratio, the APOA5 -1131C allele carriers remained significantly associated with an increased risk of metabolic syndrome (OR=1.77, 95% CI, 1.13-2.77; p=0.012). These results indicate that the association of APOA5 -1131T>C polymorphism with dyslipidemia can also contribute to an increased susceptibility to metabolic syndrome in the Chinese, as a result of its effect on triglyceride metabolism.

  2. Association of a genetic variant in the apolipoprotein A5 gene with the metabolic syndrome in Chinese.

    PubMed

    Ong, Kwok Leung; Jiang, Chao Qiang; Liu, Bin; Jin, Ya Li; Tso, Annette W K; Tam, Sidney; Wong, Ka Sing; Tomlinson, Brian; Cheung, Bernard M Y; Lin, Jie Ming; Yue, Xiao Jun; Lam, Karen S L; Lam, Tai Hing; Thomas, Graham Neil

    2011-02-01

    Single nucleotide polymorphisms (SNPs) in the apolipoprotein A5 gene (APOA5) are associated with hypertriglyceridaemia in our population. We studied the associations of SNPs in APOA5 with the metabolic syndrome (MetS) in the Hong Kong and Guangzhou Chinese. We genotyped five tagging SNPs in 1330 unrelated subjects from the Hong Kong Cardiovascular Risk Factor Prevalence Study cohort with follow-up after a median interval of 6·4 years; 1952 subjects from the Guangzhou Biobank Cohort Study-Cardiovascular Disease Subcohort were used to replicate the findings. The MetS was defined according to the consensus criteria proposed jointly by several organizations in 2009. The SNP rs662799 (-1131T>C) was associated with the MetS (odds ratio = 1·47, P = 0·00082) and the number of its components present (regression coefficient = 0·204, P = 4·6 × 10(-5) ) after adjusting for age, sex, smoking, drinking and education in Hong Kong subjects at baseline. Similar association of this SNP was found in Hong Kong subjects at follow-up (P = 0·010 and 0·00021, respectively) and in Guangzhou subjects (P = 0·0041 and 0·017, respectively). The association of rs662799 with the number of the MetS components was significant regardless of age, sex, obesity and alcohol drinking, but almost disappeared after further adjusting for plasma triglycerides. Our results showed that the -1131T>C polymorphism in APOA5 was associated with the MetS because of its strong effect on plasma triglycerides. This may partly explain the higher cardiovascular risk in people with this polymorphism. © 2011 Blackwell Publishing Ltd.

  3. Interaction of dietary fat intake with APOA2, APOA5 and LEPR polymorphisms and its relationship with obesity and dyslipidemia in young subjects.

    PubMed

    Domínguez-Reyes, Teresa; Astudillo-López, Constanza C; Salgado-Goytia, Lorenzo; Muñoz-Valle, José F; Salgado-Bernabé, Aralia B; Guzmán-Guzmán, Iris P; Castro-Alarcón, Natividad; Moreno-Godínez, Ma E; Parra-Rojas, Isela

    2015-09-13

    Diet is an important environmental factor that interacts with genes to modulate the likelihood of developing disorders in lipid metabolism and the relationship between diet and genes in the presence of other chronic diseases such as obesity. The objective of this study was to analyze the interaction of a high fat diet with the APOA2 (rs3813627 and rs5082), APOA5 (rs662799 and rs3135506) and LEPR (rs8179183 and rs1137101) polymorphisms and its relationship with obesity and dyslipidemia in young subjects. The study included 200 young subjects aged 18 to 25 years (100 normal-weight and 100 obese subjects). Dietary fat intake was measured using the frequency food consumption questionnaire. Genotyping of polymorphisms was performed by PCR-RFLP. Individuals carrying the APOA5 56 G/G genotype with a high saturated fatty acid consumption (OR = 2.7, p = 0.006) and/or total fat (OR = 2.4, p = 0.018), associated with an increased risk of obesity. We also found that A/G + G/G genotypes of the 668 A/G polymorphism in the LEPR gene with an intake ≥ 12 g/d of saturated fatty acids, have 2.9 times higher risk of obesity (p = 0.002), 3.8 times higher risk of hypercholesterolemia (p = 0.002) and 2.4 times higher risk of hypertriglyceridemia (p = 0.02), than those with an intake <12 g/d of saturated fatty acids. Similarly, LEPR 668 A/G + G/G carriers with a high fat total intake had 3.0 times higher risk of obesity (p = 0.002) and 4.1 times higher risk of hypercholesterolemia (p = 0.001). Our results suggest that dietary fat intake modifies the effect of APOA5 and LEPR polymorphisms on serum triglycerides, cholesterol levels and obesity in young subjects.

  4. 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

  5. Admixture mapping in two Mexican samples identifies significant associations of locus ancestry with triglyceride levels in the BUD13/ZNF259/APOA5 region and fine mapping points to rs964184 as the main driver of the association signal

    PubMed Central

    Mazurek, Andrew; Sockell, Alexandra; Morris, Andrew P.; Petty, Lauren E.; Hanis, Craig L.; Cox, Nancy J.; Cruz, Miguel

    2017-01-01

    We carried out an admixture mapping study of lipid traits in two samples from Mexico City. Native American locus ancestry was significantly associated with triglyceride levels in a broad region of chromosome 11 overlapping the BUD13, ZNF259 and APOA5 genes. In our fine-mapping analysis of this region using dense genome-wide data, rs964184 is the only marker included in the 99% credible set of SNPs, providing strong support for rs964184 as the causal variant within this region. The frequency of the allele associated with increased triglyceride concentrations (rs964184-G) is between 30–40% higher in Native American populations from Mexico than in European populations. The evidence currently available for this variant indicates that it may be exerting its effect through three potential mechanisms: 1) modification of enhancer activity, 2) regulation of the expression of several genes in cis and/or trans, or 3) modification of the methylation patterns of the promoter of the APOA5 gene. PMID:28245265

  6. Associations of polymorphisms in the apolipoprotein A1/C3/A4/A5 gene cluster with familial combined hyperlipidaemia in Hong Kong Chinese.

    PubMed

    Liu, Zhi-Kai; Hu, Miao; Baum, Larry; Thomas, G Neil; Tomlinson, Brian

    2010-02-01

    Familial combined hyperlipidaemia (FCH) is the most common genetic dyslipidaemia associated with coronary artery disease. Single nucleotide polymorphisms (SNPs) and haplotypes in the APOA1/C3/A4/A5 gene cluster are associated with FCH in Caucasians and with elevated triglycerides (TG) in various ethnic groups. We examined these associations with FCH in Hong Kong Chinese. Fifty-six Chinese FCH patients and 176 unrelated controls were studied. Thirteen SNPs in the APOA1/C3/A4/A5 cluster were genotyped. Four alleles in APOA5 were associated with FCH (P<0.001). The -1131T>C (rs662799) and -3A>G (rs651821) SNPs in APOA5 were in almost complete linkage disequilibrium (LD, r(2)=0.99), and their minor alleles were more frequent (P<0.001) in FCH than controls (0.60 vs. 0.24). The odds ratio (OR) for FCH was 6.2 (95% CI, 2.6-14.8) and 6.1 (2.6-14.6) per copy of -1131C and -3G, respectively, and 24.6 (8.4-72.0) and 24.4 (8.4-70.9) in -1131C and -3G homozygotes, respectively, as compared to wild-type homozygotes. The 1891T>C (rs2266788) SNP was in LD (r(2)=0.68) with -1131T>C and -3A>G, and the minor allele was more frequent in FCH than controls (0.42 vs. 0.19, P<0.001). The 553G>T (rs2075291) nonsynonymous variant was also associated with FCH (0.15 vs. 0.04, P=0.001) and, along with -3A>G (or -1131T>C) and 1891T>C, contributed to haplotypes predicting FCH. The two tightly linked SNPs, -1131T>C and -3A>G polymorphism were significantly associated with lipid traits in all subjects combined, with variant homozygous subjects having higher TG and LDL-C and lower HDL-C levels. Some common polymorphisms and haplotypes in APOA5 are closely associated with FCH in Hong Kong Chinese, and these differ from those found in Caucasians. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

  7. Association of G894T eNOS, 4G/5G PAI and T1131C APOA5 polymorphisms with susceptibility to myocardial infarction in Morocco.

    PubMed

    Hassani Idrissi, Hind; Hmimech, Wiam; Diakite, Brehima; Korchi, Farah; Baghdadi, Dalila; Habbal, Rachida; Nadifi, Sellama

    2016-09-01

    Myocardial infarction (MI) is a common multifactorial disease. Numerous studies have found that genetic plays an essential role in MI occurrence. The main objective of our case-control study is to explore the association of G894T eNOS (rs1799983), 4G/5G PAI (rs1799889) and T1131C APOA5 (rs662799) polymorphisms with MI susceptibility in the Moroccan population. 118 MI patients were recruited vs 184 healthy controls. DNA samples were genotyped by PCR-RFLP method using MboI, BslI and MseI restriction enzymes respectively for the G894T eNOS, 4G/5G PAI and T1131C APOA5 polymorphisms. Our results show that the G894T eNOS was significantly associated with increased risk of MI under the three genetic transmission models (dominant: OR = 1.64, 95% CI = 1.05-2.58, P = 0.003; recessive: OR = 2.15, 95% CI = 0.74-6.16, P = 0.03; additive: OR = 1.54, 95% CI = 1.06-2.23, P = 0.001). The T1131C APOA5 polymorphism was associated to MI risk in recessive and additive models (OR = 1.53, 95% CI = 0.72-3.2, P = 0.04 and OR = 1.78, 95% CI = 1.26-2.51, P = 0.03 respectively). For the 4G/5G PAI variant, even the cases and controls groups were not in Hardy-Weinberg Equilibrium (HWE), the dominant and additive models show a statistically significant association with MI risk (OR = 7.96, 95%CI = 3.83-16.36, P = 0.01 and OR = 1.96, 95% CI = 1.4-2.72, P = 0.03 respectively). Our results suggest that G894T eNOS and T1131C APOA5 polymorphisms may be considered as genetic markers of MI among the Moroccan population. Further studies including larger sample sizes and exploring more genetic associations are needed to confirm our results and to better understand the susceptibility to MI.

  8. 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.

    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 datamore » 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.« less

  9. Tissue-specific DNA methylation profiles regulate liver-specific expression of the APOA1/C3/A4/A5 cluster and can be manipulated with demethylating agents on intestinal cells.

    PubMed

    Guardiola, Montse; Oliva, Iris; Guillaumet, Amy; Martín-Trujillo, Álex; Rosales, Roser; Vallvé, Joan Carles; Sabench, Fàtima; Del Castillo, Daniel; Zaina, Silvio; Monk, David; Ribalta, Josep

    2014-12-01

    The tissue-specific expression profiles of genes within the APOA1/C3/A4/A5 cluster play an important role in lipid metabolism regulation. We hypothesize that the tissue-specific expression of the APOA1/C3/A4/A5 gene cluster will show an inverse pattern with DNA methylation, and that repression in non- or low-expressing tissue, such as the intestine, can be reversed using epigenetic drugs. We analyzed DNA samples from different human adult tissues (liver, intestine, leukocytes, brain, kidney, pancreas, muscle and sperm) using the Infinium HumanMethyation450 BeadChip array. DNA methylation profiles in APOA1/C3/A4/A5 gene cluster were confirmed by bisulfite PCR and pyrosequencing. To determine whether the observed tissue-specific methylation was associated with the expression profile we exposed intestinal TC7/Caco-2 cells to the demethylating agent 5-Aza-2'-deoxycytidine and monitored intestinal APOA1/C3/A4/A5 transcript re-expression by RT-qPCR. The promoters of APOA1, APOC3 and APOA5 genes were less methylated in liver compared to other tissues, and APOA4 gene was highly methylated in most tissues and partially methylated in liver and intestine. In TC7/Caco-2 cells, 5-Aza-2'-deoxycytidine treatment induced a decrease between 37 and 24% in the methylation levels of APOA1/C3/A4/A5 genes and a concomitant re-expression mainly in APOA1, APOA4 and APOA5 genes ranging from 22 to 600%. We have determined the methylation patterns of the APOA1/C3/A4/A5 cluster that may be directly involved in the transcriptional regulation of this cluster. DNA demethylation of intestinal cells increases the RNA levels especially of APOA1, APOA4 and APOA5 genes. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  10. 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

  11. Effects of APOA5 S19W polymorphism on growth, insulin sensitivity and lipoproteins in normoweight neonates

    USDA-ARS?s Scientific Manuscript database

    Apolipoprotein (Apo) A5 is a protein involved in the activation of lipoprotein lipase (LPL) and the metabolism of triglyceride (TG)-rich lipoproteins. LPL plays a major role in the metabolism of TG-rich lipoproteins, and placental LPL activity is known to correlate positively with foetal fat deposit...

  12. Genetic association of APOA5 and APOE with metabolic syndrome and their interaction with health-related behavior in Korean men.

    PubMed

    Son, Ki Young; Son, Ho-Young; Chae, Jeesoo; Hwang, Jinha; Jang, SeSong; Yun, Jae Moon; Cho, BeLong; Park, Jin Ho; Kim, Jong-Il

    2015-09-13

    Genome-wide association studies have been used extensively to identify genetic variants linked to metabolic syndrome (MetS), but most of them have been conducted in non-Asian populations. This study aimed to evaluate the association between MetS and previously studied single nucleotide polymorphisms (SNPs), and their interaction with health-related behavior in Korean men. Seventeen SNPs were genotyped and their association with MetS and its components was tested in 1193 men who enrolled in the study at Seoul National University Hospital. We found that rs662799 near APOA5 and rs769450 in APOE had significant association with MetS and its components. The SNP rs662799 was associated with increased risk of MetS, elevated triglyceride (TG) and low levels of high-density lipoprotein, while rs769450 was associated with a decreased risk of TG. The SNPs showed interactions between alcohol drinking and physical activity, and TG levels in Korean men. We have identified the genetic association and environmental interaction for MetS in Korean men. These results suggest that a strategy of prevention and treatment should be tailored to personal genotype and the population.

  13. The Methylenetetrahydrofolate Reductase C677T (rs1801133) and Apolipoprotein A5-1131T>C (rs662799) Polymorphisms, and Anemia Are Independent Risk Factors for Ischemic Stroke.

    PubMed

    Escobedo, Jorge; Paz-Aragón, Emmanuel; Vega-Rodríguez, Luz Helena; Benítez Sanfeliz, Miguel Alejandro; Estrada-Rodríguez, Humberto; González-Figueroa, Evangelina; Liceaga-Craviotto, María Gabriela; Gutiérrez-Cuevas, Jorge; Valladares-Salgado, Adán; Cruz, Miguel

    2018-05-01

    Although there is adequate knowledge as to the role of traditional cardiovascular risk factors on stroke incidence, knowledge of other risk factors, particularly genetic ones, is still incomplete. To assess the participation of some polymorphisms, along with other modifiable risk factors, a case-control study was conducted. A total of 253 cases were identified in the emergency room of a general regional hospital, with a clinical trait of stroke confirmed by a skull computerized axial tomography scan. In the surgery ward, 253 controls were identified, gender and age (±5 years) matched. Biochemical parameters were measured, and 4 polymorphisms were genotyped by polymerase chain reaction, rs1801133 (methylenetetrahydrofolate reductase [MTHFR]), rs1498373 (dimethylarginine dimethylaminohydrolase type 1 [DDAH1]), rs662799 (apolipoprotein A5 [APOA5]), and rs1799983 (endothelial nitric oxide). Odds ratios were estimated to assess the strength of association, with 95% confidence intervals, both in a matched case-control analysis and in a conditional regression analysis. Cases had higher mean blood pressure and triglycerides and lower hemoglobin levels. Heterozygous and homozygous subjects to the rs1801133 variant of the MTHFR gene had a 3-fold higher risk of stroke. In the dominant model, those with the polymorphism rs662799 of the promoter region for APOA5 had twice the risk of stroke. Anemia increased the risk of stroke 4-fold. Polymorphisms of the genes MTHFR (rs1801133) and APOA5 (rs662799), as well as anemia, are independent risk factors for stroke in Mexicans, together with traditional cardiovascular risk factors such as high triglycerides and high blood pressure. Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  14. Clinical significance of apolipoprotein A5

    PubMed Central

    Tai, E Shyong; Ordovas, Jose M.

    2015-01-01

    Purpose of review We have examined the evidence from recent human studies examining the role of apolipoprotein A-V in triglyceride-rich lipoprotein metabolism and cardiovascular disease risk. Special emphasis was placed on the evidence emerging from the association between genetic variability at the apolipoprotein A5 locus, lipid phenotypes and disease outcomes. Moreover, we address recent reports evaluating apolipoprotein A5 gene–environment interactions in relation to cardiovascular disease and its common risk factors. Recent findings Several genetic association studies have continued to strengthen the position of APOA5 as a major gene that is involved in triglyceride metabolism and modulated by dietary factors and pharmacological therapies. Moreover, genetic variants at this locus have been significantly associated with both coronary disease and stroke risks. Summary Apolipoprotein A-V has an important role in lipid metabolism, specifically for triglyceride-rich lipoproteins. However, its mechanism of action is still poorly understood. Clinical significance at present comes largely from genetic studies showing a consistent association with plasma triglyceride concentrations. Moreover, the effects of common genetic variants on triglyceride concentrations and disease risk are further modulated by other factors such as diet, pharmacological interventions and BMI. Therefore, these genetic variants could be potentially used to predict cardiovascular disease risk and individualize therapeutic options to decrease cardiovascular disease risk. PMID:18607181

  15. Association of apolipoprotein A5 gene -1131T>C polymorphism with the risk of metabolic syndrome in Korean subjects.

    PubMed

    Song, Kwang Hoon; Cha, Seongwon; Yu, Sung-Gon; Yu, Hyunjoo; Oh, Soo A; Kang, Nam-Sik

    2013-01-01

    We assessed the associations between the APOA5  -1131T>C polymorphism and lipid parameters and other risk factors of the metabolic syndrome in Korean subjects. A total of 2,901 participants from 20 oriental medical hospitals in Korea were enrolled between 2006 and 2011. According to the modified National Cholesterol Education Program Adult Treatment Panel III definitions, subjects were classified into the metabolic syndrome group and control group. The APOA5  -1131T>C genotype was significantly associated with serum high-density lipoprotein cholesterol levels (effect = - 1.700 mg/dL, P=6.550-E07) in the total study population after adjustment for differences in age and gender. The association of the APOA5  -1131T>C genotype with serum log-transformed triglyceride was also significant in an additive genetic model (effect = 0.056 mg/dL, P=2.286E-19). After adjustment for age and gender, we determined that the odds ratio for the occurrence of the metabolic syndrome was 1.322 for C-allele carriers in the additive model (95% CI = [1.165 - 1.501], P=1.48E-05). In the current study, we demonstrated that the APOA5  -1131T>C polymorphism is associated with the metabolic syndrome because of its remarkable effect on serum triglyceride levels in Korean subjects.

  16. 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

    Kim, Minjoo; Chae, Jey Sook; Kim, Miri; Lee, Sang-Hyun; Lee, Jong Ho

    2014-04-28

    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. 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. 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. 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.

  17. Exome sequencing identifies SLC24A5 as a candidate gene for nonsyndromic oculocutaneous albinism.

    PubMed

    Wei, Ai-Hua; Zang, Dong-Jie; Zhang, Zhe; Liu, Xuan-Zhu; He, Xin; Yang, Lin; Wang, Yi; Zhou, Zhi-Yong; Zhang, Ming-Rong; Dai, Lan-Lan; Yang, Xiu-Min; Li, Wei

    2013-07-01

    Oculocutaneous albinism (OCA) is a heterogeneous and autosomal recessive disorder with hypopigmentation in the eye, hair, and skin color. Four genes, TYR, OCA2, TYRP1, and SLC45A2, have been identified as causative genes for nonsyndromic OCA1-4, respectively. The genetic identity of OCA5 locus on 4q24 is unknown. Additional unknown OCA genes may exist as at least 5% of OCA patients have not been characterized during mutational screening in several populations. We used exome sequencing with a family-based recessive mutation model to determine that SLC24A5 is a previously unreported candidate gene for nonsyndromic OCA, which we designate as OCA6. Two deleterious mutations in this patient, c.591G>A and c.1361insT, were identified. We found apparent increase of immature melanosomes and less mature melanosomes in the patient's skin melanocytes. However, no defects in the platelet dense granules were observed, excluding typical Hermansky-Pudlak syndrome (HPS), a well-known syndromic OCA. Moreover, the SLC24A5 protein was reduced in steady-state levels in mouse HPS mutants with deficiencies in BLOC-1 and BLOC-2. Our results suggest that SLC24A5 is a previously unreported nonsyndromic OCA candidate gene and that the SLC24A5 transporter is transported into mature melanosomes by HPS protein complexes.

  18. 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.

  19. Methionine-supplemented diet affects the expression of cardiovascular disease-related genes and increases inflammatory cytokines in mice heart and liver.

    PubMed

    Aissa, Alexandre Ferro; Amaral, Catia Lira do; Venancio, Vinicius Paula; Machado, Carla da Silva; Hernandes, Lívia Cristina; Santos, Patrick Wellington da Silva; Curi, Rui; Bianchi, Maria de Lourdes Pires; Antunes, Lusânia Maria Greggi

    2017-01-01

    Some important environmental factors that influence the development of cardiovascular diseases (CVD) include tobacco, excess alcohol, and unhealthy diet. Methionine obtained from the diet participates in the synthesis of DNA, proteins, lipids and affects homocysteine levels, which is associated with the elevated risk for CVD development. Therefore, the aim of this study was to investigate the manner in which dietary methionine might affect cellular mechanisms underlying CVD occurrence. Swiss albino mice were fed either control (0.3% DL-methionine), methionine-supplemented (2% DL-methionine), or a methionine-deprived diet (0% DL-methionine) over a 10-week period. The parameters measured included plasma homocysteine concentrations, oxidative stress by reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio, levels of inflammatory cytokines IL-1ß, TNF-α, and IL-6, as well as expression of genes associated with CVD. The levels of apolipoprotein A5 (APOA5), a regulator of plasma triglycerides, were measured. The methionine-supplemented diet increased oxidative stress by lowering the GSH/GSSG ratio in heart tissues and decreased expression of the genes Apob, Ctgf, Serpinb2, Spp1, Il1b, and Sell, but elevated expression of Thbs4, Tgfb2, Ccr1, and Vegfa. Methionine-deprived diet reduced expression of Col3a1, Cdh5, Fabp3, Bax, and Hbegf and increased expression of Sell, Ccl5, Itga2, Birc3, Msr1, Bcl2a1a, Il1r2, and Selp. Methionine-deprived diet exerted pro-inflammatory consequences as evidenced by elevated levels of cytokines IL-1ß, TNF-α, and IL-6 noted in liver. Methionine-supplemented diet increased hepatic IL-6 and cardiac TNF-α. Both methionine supplementation and deprivation lowered hepatic levels of APOA5. In conclusion, data demonstrated that a methionine-supplemented diet modulated important biological processes associated with high risk of CVD development.

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

    USDA-ARS?s Scientific Manuscript database

    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...

  1. Association study of polymorphisms in the neutral amino acid transporter genes SLC1A4, SLC1A5 and the glycine transporter genes SLC6A5, SLC6A9 with schizophrenia

    PubMed Central

    Deng, Xiangdong; Sagata, Noriaki; Takeuchi, Naoko; Tanaka, Masami; Ninomiya, Hideaki; Iwata, Nakao; Ozaki, Norio; Shibata, Hiroki; Fukumaki, Yasuyuki

    2008-01-01

    Background Based on the glutamatergic dysfunction hypothesis for schizophrenia pathogenesis, we have been performing systematic association studies of schizophrenia with the genes involved in glutametergic transmission. We report here association studies of schizophrenia with SLC1A4, SLC1A5 encoding neutral amino acid transporters ASCT1, ASCT2, and SLC6A5, SLC6A9 encoding glycine transporters GLYT2, GLYT1, respectively. Methods We initially tested the association of 21 single nucleotide polymorphisms (SNPs) distributed in the four gene regions with schizophrenia using 100 Japanese cases-control pairs and examined allele, genotype and haplotype association with schizophrenia. The observed nominal significance were examined in the full-size samples (400 cases and 420 controls). Results We observed nominally significant single-marker associations with schizophrenia in SNP2 (P = 0.021) and SNP3 (P = 0.029) of SLC1A4, SNP1 (P = 0.009) and SNP2 (P = 0.022) of SLC6A5. We also observed nominally significant haplotype associations with schizophrenia in the combinations of SNP2-SNP7 (P = 0.037) of SLC1A4 and SNP1-SNP4 (P = 0.043) of SLC6A5. We examined all of the nominal significance in the Full-size Sample Set, except one haplotype with insufficient LD. The significant association of SNP1 of SLC6A5 with schizophrenia was confirmed in the Full-size Sample Set (P = 0.018). Conclusion We concluded that at least one susceptibility locus for schizophrenia may be located within or nearby SLC6A5, whereas SLC1A4, SLC1A5 and SLC6A9 are unlikely to be major susceptibility genes for schizophrenia in the Japanese population. PMID:18638388

  2. Association study of polymorphisms in the neutral amino acid transporter genes SLC1A4, SLC1A5 and the glycine transporter genes SLC6A5, SLC6A9 with schizophrenia.

    PubMed

    Deng, Xiangdong; Sagata, Noriaki; Takeuchi, Naoko; Tanaka, Masami; Ninomiya, Hideaki; Iwata, Nakao; Ozaki, Norio; Shibata, Hiroki; Fukumaki, Yasuyuki

    2008-07-18

    Based on the glutamatergic dysfunction hypothesis for schizophrenia pathogenesis, we have been performing systematic association studies of schizophrenia with the genes involved in glutametergic transmission. We report here association studies of schizophrenia with SLC1A4, SLC1A5 encoding neutral amino acid transporters ASCT1, ASCT2, and SLC6A5, SLC6A9 encoding glycine transporters GLYT2, GLYT1, respectively. We initially tested the association of 21 single nucleotide polymorphisms (SNPs) distributed in the four gene regions with schizophrenia using 100 Japanese cases-control pairs and examined allele, genotype and haplotype association with schizophrenia. The observed nominal significance were examined in the full-size samples (400 cases and 420 controls). We observed nominally significant single-marker associations with schizophrenia in SNP2 (P = 0.021) and SNP3 (P = 0.029) of SLC1A4, SNP1 (P = 0.009) and SNP2 (P = 0.022) of SLC6A5. We also observed nominally significant haplotype associations with schizophrenia in the combinations of SNP2-SNP7 (P = 0.037) of SLC1A4 and SNP1-SNP4 (P = 0.043) of SLC6A5. We examined all of the nominal significance in the Full-size Sample Set, except one haplotype with insufficient LD. The significant association of SNP1 of SLC6A5 with schizophrenia was confirmed in the Full-size Sample Set (P = 0.018). We concluded that at least one susceptibility locus for schizophrenia may be located within or nearby SLC6A5, whereas SLC1A4, SLC1A5 and SLC6A9 are unlikely to be major susceptibility genes for schizophrenia in the Japanese population.

  3. The -1131T>C polymorphism in the apolipoprotein A5 gene is related to hypertriglyceridemia in Taiwanese aborigines.

    PubMed

    Huang, Meng-Chuan; Wang, Tsu-Nai; Wang, Huan-Sen; Sung, Yi-Ching; Ko, Ying-Chin; Chiang, Hung-Che

    2008-04-01

    The prevalence of hypertriglyceridemia, considered to be an independent risk factor for the development of cardiovascular disease, is high in Taiwanese aborigines. This study was undertaken to examine the effect of the -1131T>C polymorphism in the apolipoprotein A5 gene on serum triglyceride levels in female Taiwanese aborigines. This was a cross-sectional study, and a total of 316 unrelated female Taiwanese aborigines were genotyped at the -1131T>C polymorphism in apolipoprotein A5 using the polymerase chain reaction-restriction fragment length polymorphism method. Serum triglyceride > or = 150 mg/dL was defined as the hypertriglyceridemia group and triglyceride < 150 mg/dL was considered to be the control group. The frequency of the minor C allele was significantly higher in the hypertriglyceridemia group (0.53) than in the control group (0.35) (p < 0.001). The frequency of this rare allele was comparable to that in Japanese and Han Chinese, but was higher than that in Caucasians. In a multiple logistic model adjusted for possible confounders, C allele-containing variants were independently associated with greater risks (CT genotype: OR = 3.28, 95% CI = 1.43-7.56; CC genotype: OR = 5.86, 95% CI = 2.15-15.99) of hypertriglyceridemia than the TT genotype (p < 0.01), notably with the CC homozygote exhibiting the greatest risks. The genotype polymorphisms were also associated with serum triglyceride concentrations in a linear fashion (for trend, p < 0.05). Our results indicate that the -1131T>C polymorphism of the Apo A5 gene influences serum triglyceride levels in female Taiwanese aborigines, and that differences exist in the frequency of the C allele among people of various ethnicities.

  4. Identification of DLG5 and SLC22A5 gene polymorphisms in Malaysian patients with Crohn's disease.

    PubMed

    Chua, Kek Heng; Lian, Lay Hoong; Kee, Boon Pin; Thum, Chooi Mei; Lee, Way Seah; Hilmi, Ida; Goh, Khean Lee

    2011-12-01

    The aim of this study was to investigate the association of DLG5 and SLC22A5 gene polymorphisms with the onset of Crohn's disease (CD) in a Malaysian cohort. Genomic DNA of 80 CD patients and 100 healthy unrelated control individuals was extracted and analyzed via polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) on DLG5 (4136 C/A), DLG5_e26 and SLC22A5 (-207 G/C) genetic polymorphisms. Data obtained from the study were then subjected to statistical analysis to test for risk association. Significant associations of both DLG5 polymorphisms with the development of CD in the Malaysian patients were observed in this study. The homozygous C genotype of the DLG5 polymorphism was significantly related to CD patients (P = 0.0023, OR = 2.5320), while the homozygous A was significant in control individuals (P = 0.0224, OR = 0.4480). In DLG5_e26 polymorphisms, we found a significant distribution of the homozygous insA genotype in CD patients (P = 0.0006, OR = 2.8916), whereas the heterozygous insA/delA genotype was significant in controls (P = 0.0007, OR = 0.3487). We hypothesized that there might be a complex interaction of both alleles, which confered a protective effect against the onset of CD. However, we did not observe any significant correlation of SLC22A5 polymorphisms with this disease. In our study, both polymorphisms in the DLG5 gene were found to be associated with CD patients in Malaysia. Therefore, these loci can be potentially used as susceptibility markers in the Malaysian population. © 2011 The Authors. Journal of Digestive Diseases © 2011 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.

  5. LPL gene mutation as the cause of severe hypertriglyceridemia in the course of ketoacidosis in a patient with newly diagnosed type 1 diabetes mellitus.

    PubMed

    Nocoń-Bohusz, Julita; Wikiera, Beata; Basiak, Aleksander; Śmigiel, Robert; Noczyńska, Anna

    2016-02-18

    Severe hypertriglyceridemia is a condition associated with extremely high triglycerides (TG) plasma concentrations exceeding 1000mg/dl. This condition may result in mutations in genes encoding lipoprotein lipase (LPL), apolipoprotein C2 (APOC2) and apolipoprotein A5 (APOA5) characterized by an autosomal recessive inheritance pattern. A case report of a patient in which clinical picture of type 1 diabetes mellitus (T1DM) was accompanied by diabetic ketoacidosis (DKA) and severe hypertriglyceridemia. A 2.5-year-old boy was admitted to the hospital with ketoacidosis (pH - 7.0, BE - 20mmol/l, HCO3 10mmol/l), glucose level of 850mg%, hyponatremia (Na 100mmol/l) and hyperlipidemia (TG 13493 mg/dl, TC 734 mg/dl). The administered treatment resulted in nearly normal glycemic values and lipid disturbances normalization. This child was diagnosed with a heterozygous mutation of the LPL gene. Currently with an intensive insulin therapy and correct metabolic control of type 1 diabetes mellitus (T1DM), this patient maintains a normal lipid profile. In patient with T1DM the diagnosis of severe hypertriglyceridemia in the course of ketoacidosis should be based on careful interpretation of laboratory tests results. Moreover genetic tests of the patient and his/her immediate relatives blood samples should be performed. © Polish Society for Pediatric Endocrinology and Diabetology.

  6. Novel aberrant splicings caused by a splice site mutation (IVS1a+5g>a) in F7 gene.

    PubMed

    Ding, Qiulan; Wu, Wenman; Fu, Qihua; Wang, Xuefeng; Hu, Yiqun; Wang, Hongli; Wang, Zhenyi

    2005-06-01

    Low FVII coagulant activity (FVII:C 8.2%) and antigen level (FVII:Ag 34.1%) in a 46-year-old Chinese male led to a diagnosis of coagulation factor VII (FVII) deficiency. Compound heterozygous mutations were identified in his F 7 gene:a G to A transition in the 5' donor splice site of intron 1a (IVS1a+5g>a) and a T to G transition at the nucleotide position 10961 in exon 8, resulting in a His to Gln substitution at amino acid residue 348. An analysis of ectopic transcripts of F7 in the leukocytes of the patient reveals that the mutation (IVS1a+5g>a) is associated with two novel aberrant patterns of splicing. The predominant alternative transcript removes exon 2, but retains intron 3, which shifts the reading frame and predicts a premature translation termination at the nucleotide positions 2-4 in intron 3. The minor alternative transcript skips both exon 2 and exon 3 (FVII Delta 2, 3), leading to an in-frame deletion of the propeptide and gamma-carboxylated glutamic acid (Gla) domains of mature FVII protein. In vitro expression studies of the alternative transcript FVII Delta 2,3 by transient transfection of HEK 293 cells with PcDNA 3.1(-) expression vector showed that although the mutant protein could be secreted, no pro-coagulation activity was detected. The coexistence of the two abnormal transcripts and a heterozygous mutation His348Gln, explained the patient's phenotype.

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

    USDA-ARS?s Scientific Manuscript database

    Background: 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...

  8. Whole Blood Gene Expression Profiling Predicts Severe Morbidity and Mortality in Cystic Fibrosis: A 5-year Follow-Up Study.

    PubMed

    Saavedra, Milene T; Quon, Bradley S; Faino, Anna; Caceres, Silvia M; Poch, Katie R; Sanders, Linda A; Malcolm, Kenneth C; Nichols, David P; Sagel, Scott D; Taylor-Cousar, Jennifer L; Leach, Sonia M; Strand, Matthew; Nick, Jerry A

    2018-02-09

    Cystic fibrosis pulmonary exacerbations accelerate pulmonary decline and increase mortality. Previously, we identified a 10-gene leukocyte panel measured directly from whole blood, which indicates response to exacerbation treatment. We hypothesized that molecular characteristics of exacerbations could also predict future disease severity. We tested whether a 10-gene panel measured from whole blood could identify patient cohorts at increased risk for severe morbidity and mortality, beyond standard clinical measures. Transcript abundance for the 10-gene panel was measured from whole blood at the beginning of exacerbation treatment (n=57). A hierarchical cluster analysis of subjects based on their gene expression was performed, yielding four molecular clusters. An analysis of cluster membership and outcomes incorporating an independent cohort (n=21) was completed to evaluate robustness of cluster partitioning of genes to predict severe morbidity and mortality. The four molecular clusters were analyzed for differences in forced expiratory volume in 1 second (FEV1), C-reactive protein (CRP), return to baseline FEV1 after treatment, time to next exacerbation and time to morbidity or mortality events (defined as lung transplant referral, lung transplant, ICU admission for respiratory insufficiency, or death). Clustering based on gene expression discriminated between patient groups with significant differences in FEV1, admission frequency and overall morbidity and mortality. At 5 years, all subjects in Cluster 1 (very low risk) were alive and well, while 90% of subjects in Cluster 4 (high risk) had suffered a major event (p=0.0001). In multivariable analysis, the ability of gene expression to predict clinical outcomes remained significant, despite adjustment for FEV1, gender and admission frequency. The robustness of gene clustering to categorize patients appropriately in terms of clinical characteristics, short and long term clinical outcomes, remained consistent, even

  9. Possible involvement of nuclear factor erythroid 2-related factor 2 in the gene expression of Cyp2b10 and Cyp2a5.

    PubMed

    Ashino, Takashi; Ohkubo-Morita, Haruyo; Yamamoto, Masayuki; Yoshida, Takemi; Numazawa, Satoshi

    2014-01-01

    Cytochrome P450 gene expression is altered by various chemical compounds. In this study, we used nuclear factor erythroid 2-related factor 2 (Nrf2)-deficient (Nrf2(-⧸-)) mice to investigate the involvement of Nrf2 in Cyp2b10 and Cyp2a5 gene expression. Phorone, an Nrf2 activator, strongly increased Cyp2b10 and Cyp2a5 mRNA as well as Nrf2 target genes, including NAD(P)H-quinone oxidoreductase-1 and heme oxygenase-1, in wild-type mouse livers 8 h after treatment. The phorone-induced mRNA levels in Nrf2(-⧸-) mouse livers were lower than that in wild-type mouse livers. Nrf2(-⧸-) mice showed attenuated Cyp2b10 and Cyp2a5 induction by phenobarbital, a classical Cyp2b inducer. These findings suggest that the Nrf2 pathway is involved in Cyp2b10 and Cyp2a5 gene expression.

  10. Aging and calorie restriction regulate the expression of miR-125a-5p and its target genes Stat3, Casp2 and Stard13.

    PubMed

    Makwana, Kuldeep; Patel, Sonal Arvind; Velingkaar, Nikkhil; Ebron, Jey Sabith; Shukla, Girish C; Kondratov, Roman V Kondratov V

    2017-07-31

    Calorie restriction (CR) is a dietary intervention known to delay aging. In order, to understand molecular mechanisms of CR, we analyzed the expression of 983 MicroRNAs (miRNAs) in the liver of female mice after 2 years of 30% CR using micro-array. 16 miRNAs demonstrated significant changes in their expression upon CR in comparison with age-matched control. mmu-miR-125a-5p (miR-125a-5p) was significantly upregulated upon CR, and in agreement with this, the expression of mRNAs for its three predicted target genes: Stat3, Casp2, and Stard13 was significantly downregulated in the liver of CR animals. The expression of precursor miRNA for miR-125a-5p was also upregulated upon CR, which suggests its regulation at the level of transcription. Upon aging miR-125a-5p expression was downregulated while the expression of its target genes was upregulated. Thus, CR prevented age-associated changes in the expression of miR-125a-5p and its targets. We propose that miR-125a-5p dependent downregulation of Stat3, Casp2, and Stard13 contributes to the calorie restriction-mediated delay of aging.

  11. DNA methylation inhibits transcription by RNA polymerase III of a tRNA gene, but not of a 5S rRNA gene.

    PubMed

    Besser, D; Götz, F; Schulze-Forster, K; Wagner, H; Kröger, H; Simon, D

    1990-09-03

    Methylation of cytosine in the DNA inhibits the transcription by RNA polymerase II in higher eukaryotes, but has no influence on RNA polymerase I transcription. The effect on RNA polymerase III was unknown, so far. Two polymerase III genes: a type 1 5S rRNA gene and a type 2 tRNA gene were methylated in vitro with a purified eukaryotic DNA methyltransferase (EC2.1.1.37) and their transcription was analyzed in Xenopus oocytes. The 5S rRNA gene, an oocyte 5S rRNA gene from X. laevis which is subject to developmental inactivation, was not affected by methylation. Conversely, transcription of the tRNA gene was 80% inhibited by methylation with the eukaryotic methyltransferase. HhaI and HpaII methylation left its transcription unaffected.

  12. Distribution of ABCB1, CYP3A5, CYP2C19, and P2RY12 gene polymorphisms in a Mexican Mestizos population.

    PubMed

    Vargas-Alarcón, Gilberto; Ramírez-Bello, Julián; de la Peña, Aurora; Calderón-Cruz, Beatriz; Peña-Duque, Marco Antonio; Martínez-Ríos, Marco Antonio; Ramírez-Fuentes, Silvestre; Pérez-Méndez, Oscar; Fragoso, José Manuel

    2014-10-01

    The aim of the present study was to establish the gene frequency of six polymorphisms of the ABCB1, CYP3A5, CYP2C19, and P2RY12 genes in a population resident of Mexico City. The proteins encoded by these genes have been associated with the absorption, and biotransformation of clopidogrel. The ABCB1 T3435C, CYP3A5 V3 A6986G, P2RY12 G52T, P2RY12 C34T, CYP2C19 V2 and V3 (positions G681A and G636A, respectively), polymorphisms were analyzed by 5' exonuclease TaqMan genotyping assays in a group of 269 healthy unrelated Mexican Mestizo individuals. The CYP2C19 V3 G636A polymorphism was not detected in the Mexican Mestizos population. However, the studied population presented significant differences (P < 0.05) in the distribution of the T3435C, A6986G, G681A, G52T and C34T polymorphisms when compared to reported frequencies of Amerindian of South America, Caucasian, Asian, and African populations. In summary, the distribution of the ABCB1, CYP3A5, CYP2C19, and P2RY12 gene polymorphisms distinguishes to the Mexican Mestizos population from other ethnic groups.

  13. Common variants in the genes of triglyceride and HDL-C metabolism lack association with coronary artery disease in the Pakistani subjects.

    PubMed

    Shahid, Saleem Ullah; Shabana, N A; Cooper, Jackie A; Rehman, Abdul; Humphries, Steve E

    2017-01-31

    Serum Triglyceride (TG) and High Density Lipoprotein (HDL-C) levels are modifiable coronary artery disease (CAD) risk factors. Polymorphisms in the genes regulating TG and HDL-C levels contribute to the development of CAD. The objective of the current study was to investigate the effect of four such single nucleotide polymorphism (SNPs) in the genes for Lipoprotein Lipase (LPL) (rs328, rs1801177), Apolipoprotein A5 (APOA5) (rs66279) and Cholesteryl ester transfer protein (CETP) (rs708272) on HDL-C and TG levels and to examine the association of these SNPs with CAD risk. A total of 640 subjects (415 cases, 225 controls) were enrolled in the study. The SNPs were genotyped by KASPar allelic discrimination technique. Serum HDL-C and TG were determined by spectrophotometric methods. The population under study was in Hardy Weinberg equilibrium and minor allele of SNP rs1801177 was completely absent in the studied subjects. The SNPs were association with TG and HDL-C levels was checked through regression analysis. For rs328, the effect size of each risk allele on TG and HDL-C (mmol/l) was 0.16(0.08) and -0.11(0.05) respectively. Similarly, the effect size of rs662799 for TG and HDL-C was 0.12(0.06) and -0.13(0.0.3) and that of rs708272 was 0.08(0.04) and 0.1(0.03) respectively. The risk allele frequencies of the SNPs were higher in cases than controls, but the difference was not significant (p > 0.05) and SNPs were not associated with CAD risk (p > 0.05). The combined gene score of four SNPs significantly raised TG and lowered HDL-C but did not increase CAD risk. The studied SNPs were associated with TG and HDL-C levels, but not with CAD in Pakistani population under study.

  14. A 5′- Regulatory Region and Two Coding Region Polymorphisms Modulate Promoter Activity and Gene Expression of the Growth Suppressor Gene ZBED6 in Cattle

    PubMed Central

    Huang, Yong-Zhen; Li, Ming-Xun; Wang, Jing; Zhan, Zhao-Yang; Sun, Yu-Jia; Sun, Jia-Jie; Li, Cong-Jun; Lan, Xian-Yong; Lei, Chu-Zhao; Zhang, Chun-Lei; Chen, Hong

    2013-01-01

    Zinc finger, BED-type containing 6 (ZBED6) is an important transcription factor in placental mammals, affecting development, cell proliferation and growth. Polymorphisms in its promoter and coding regions are likely to impact ZBED6 transcription and growth traits. In this study, rapid amplification of 5’ cDNA ends (5'-RACE) analysis revealed two transcription start sites (TSS) for the bovine ZBED6 starting within exon 1 of the ZC3H11A gene (TSS-1) and upstream of the translation start codon of the ZBED6 gene (TSS-2). There was one SNP in the promoter and two missense mutations in the coding region of the bovine ZBED6 by sequencing of the pooled DNA samples (Pool-Seq, n = 100). The promoter and coding region are the key regions for gene function; polymorphisms in these regions can alter gene expression. Quantitative real-time PCR (qPCR) analysis showed that ZBED6 has a broad tissue distribution in cattle and is highly expressed in skeletal muscle. Eleven promoter-detection vectors were constructed, which enabled the cloning of putative promoter sequences and analysis of ZBED6 transcriptional activity by luciferase reporter gene assays. The core region of the basal promoter of bovine ZBED6 is located within region -866 to -556. The activity of WT-826G-pGL3 in driving reporter gene transcription is significantly higher than that of the M-826A-pGL3 construct (P < 0.01). Analysis of gene expression patterns in homozygous full-sibling Chinese Qinchuan cattle showed that the mutant-type Hap-AGG exhibited a lower mRNA level than the wild-type Hap-GCA (P < 0.05) in longissimus dorsi muscle (LDM). Moreover, ZBED6 mRNA expression was low in C2C12 cells overexpressing the mutant-type ZBED6 (pcDNA3.1+-Hap-GG) (P < 0.01). Our results suggest that the polymorphisms in the promoter and coding regions may modulate the promoter activity and gene expression of bovine ZBED6 in the skeletal muscles of these cattle breeds. PMID:24223190

  15. Serotonergic gene polymorphisms (5-HTTLPR, 5HTR1A, 5HTR2A), and population differences in aggression: traditional (Hadza and Datoga) and industrial (Russians) populations compared.

    PubMed

    Butovskaya, Marina L; Butovskaya, Polina R; Vasilyev, Vasiliy A; Sukhodolskaya, Jane M; Fekhredtinova, Dania I; Karelin, Dmitri V; Fedenok, Julia N; Mabulla, Audax Z P; Ryskov, Alexey P; Lazebny, Oleg E

    2018-04-16

    Current knowledge on genetic basis of aggressive behavior is still contradictory. This may be due to the fact that the majority of studies targeting associations between candidate genes and aggression are conducted on industrial societies and mainly dealing with various types of psychopathology and disorders. Because of that, our study was carried on healthy adult individuals of both sex (n = 853). Three populations were examined: two traditional (Hadza and Datoga) and one industrial (Russians), and the association of aggression with the following polymorphisms 5-HTTLPR, rs6295 (5HTR1A gene), and rs6311 (5HTR2A gene) were tested. Aggression was measured as total self-ratings on Buss-Perry Aggression Questionnaire. Distributions of allelic frequencies of 5-HTTLPR and 5HTR1A polymorphisms were significantly different among the three populations. Consequently, the association analyses for these two candidate genes were carried out separately for each population, while for the 5HTR2A polymorphism, it was conducted on the pooled data that made possible to introduce ethnic factor in the ANOVA model. The traditional biometrical approach revealed no sex differences in total aggression in all three samples. The three-way ANOVA (μ + 5-HTTLPR + 5HTR1A + 5HTR2A +ε) with measures of self-reported total aggression as dependent variable revealed significant effect of the second serotonin receptor gene polymorphism for the Hadza sample. For the Datoga, the interaction effect between 5-HTTLPR and 5HTR1A was significant. No significant effects of the used polymorphisms were obtained for Russians. The results of two-way ANOVA with ethnicity and the 5HTR2A polymorphism as main effects and their interactions revealed the highly significant effect of ethnicity, 5HTR2A polymorphism, and their interaction on total aggression. Our data provided obvious confirmation for the necessity to consider the population origin, as well as cultural background of tested individuals, while

  16. Do polymorphisms in MDR1 and CYP3A5 genes influence the risk of cytogenetic relapse in patients with chronic myeloid leukemia on imatinib therapy?

    PubMed

    Harivenkatesh, Natarajan; Kumar, Lalit; Bakhshi, Sameer; Sharma, Atul; Kabra, Madhulika; Velpandian, Thirumurthy; Gogia, Ajay; Shastri, Shivaram S; Gupta, Yogendra Kumar

    2017-09-01

    Influence of polymorphisms in the genes coding for imatinib transporters and metabolizing enzymes on cytogenetic relapse in patients with chronic myeloid leukemia (CML) is not known. One hundred and four patients (52 cases with cytogenetic relapse and 52 controls without relapse) with chronic-phase CML on imatinib therapy and have completed 5 years of follow-up were enrolled. The following single nucleotide polymorphisms (SNPs) were genotyped; C1236T, C3435T, G2677T/A in MDR1 gene and A6986G in CYP3A5 gene, using PCR-RFLP method and validated by direct gene sequencing. Imatinib trough levels were measured using LC-MS/MS. Patients with CC genotype for MDR1-C1236T polymorphism were at significantly higher risk for cytogenetic relapse [OR =4.382, 95% CI (1.145, 16.774), p = .022], while those with TT genotype for MDR1-C3435T polymorphism had significantly lower risk of relapse [OR =0.309, 95% CI (0.134, 0.708), p = .005]. Imatinib trough levels were lower in patients with relapse compared to those without relapse (1551.4 ± 1324.1 vs. 2154.2 ± 1358.3 ng/mL; p = .041). MDR1-C3435T genotype [adjusted-OR: 0.266; 95% CI (0.111, 0.636); p = .003] and trough levels (p = .014) were independent predictors of relapse in multivariate analysis. To conclude, C1236T and C3435T polymorphisms in MDR1 gene and trough levels significantly influence the risk of cytogenetic relapse. MDR1-C3435T genotype might emerge as a potential biomarker to predict the risk of cytogenetic relapse in patients with CML.

  17. Evidence for the association of the SLC22A4 and SLC22A5 genes with Type 1 Diabetes: a case control study

    PubMed Central

    Santiago, Jose Luis; Martínez, Alfonso; de la Calle, Hermenegildo; Fernández-Arquero, Miguel; Figueredo, M Ángeles; de la Concha, Emilio G; Urcelay, Elena

    2006-01-01

    Background Type 1 diabetes (T1D) is a chronic, autoimmune and multifactorial disease characterized by abnormal metabolism of carbohydrate and fat. Diminished carnitine plasma levels have been previously reported in T1D patients and carnitine increases the sensitivity of the cells to insulin. Polymorphisms in the carnitine transporters, encoded by the SLC22A4 and SLC22A5 genes, have been involved in susceptibility to two other autoimmune diseases, rheumatoid arthritis and Crohn's disease. For these reasons, we investigated for the first time the association with T1D of six single nucleotide polymorphisms (SNPs) mapping to these candidate genes: slc2F2, slc2F11, T306I, L503F, OCTN2-promoter and OCTN2-intron. Methods A case-control study was performed in the Spanish population with 295 T1D patients and 508 healthy control subjects. Maximum-likelihood haplotype frequencies were estimated by applying the Expectation-Maximization (EM) algorithm implemented by the Arlequin software. Results When independently analyzed, one of the tested polymorphisms in the SLC22A4 gene at 1672 showed significant association with T1D in our Spanish cohort. The overall comparison of the inferred haplotypes was significantly different between patients and controls (χ2 = 10.43; p = 0.034) with one of the haplotypes showing a protective effect for T1D (rs3792876/rs1050152/rs2631367/rs274559, CCGA: OR = 0.62 (0.41–0.93); p = 0.02). Conclusion The haplotype distribution in the carnitine transporter locus seems to be significantly different between T1D patients and controls; however, additional studies in independent populations would allow to confirm the role of these genes in T1D risk. PMID:16796743

  18. Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients.

    PubMed

    Provenzani, Alessio; Notarbartolo, Monica; Labbozzetta, Manuela; Poma, Paola; Vizzini, Giovanni; Salis, Paola; Caccamo, Chiara; Bertani, Tullio; Palazzo, Ugo; Polidori, Piera; Gridelli, Bruno; D'Alessandro, Natale

    2011-12-01

    Tacrolimus is a substrate of cytochrome P4503A (CYP3A) enzymes as well as of the drug transporter ABCB1. We have investigated the possible influence of CYP3A5 and ABCB1 single nucleotide polymorphisms (SNPs) and other factors (e.g. albumin, hematocrit and steroids) on tacrolimus blood levels achieved in a population of Caucasian liver (n=51) and kidney (n=50) transplant recipients. At 1, 3 and 6 months after transplantation, tacrolimus doses (mg/kg/day) and trough blood levels (C0) were recorded and the weight-adjusted tacrolimus dosage (mg/kg/day) was calculated. Polymerase chain reaction followed by restriction fragment length polymorphism analysis was used for genotyping CYP3A5*1 and *3 [6986A>G] as well as ABCB1 at exons 21 [2677G>T/A] and 26 [3435C>T] in both liver transplant donors and recipients and in kidney transplant recipients. Of the 152 subjects studied, 84.9% showed a CYP3A5*3/*3 genotype. The total frequency of the allelic variant *3 was 93%. For the G2677T/A and C3435T polymorphisms the total frequencies of the allelic variants T/A and T were 44.7 and 46.7%, respectively. At 1, 3 and 6 months after transplantation the dose-adjusted C0 levels were significantly lower in patients with one copy of the *1 allele compared to those homozygous for the *3 allele. In the case of liver transplant patients the tacrolimus dose requirements were dominantly influenced by the polymorphisms of the CYP3A5 gene in the donors. With regard to the ABCB1 SNPs, in general they did not show any appreciable influence on tacrolimus dosing requirements; however, kidney transplant recipients carrying the 2677T/A allele required significantly higher daily tacrolimus doses than subjects homozygous for the wild-type allele. Identification of CYP3A5 single nucleotide polymorphisms prior to transplantation could contribute to evaluate the appropriate initial dosage of tacrolimus in the patients.

  19. Nucleoside Triphosphate Phosphohydrolase I (NPH I) Functions as a 5′ to 3′ Translocase in Transcription Termination of Vaccinia Early Genes*

    PubMed Central

    Hindman, Ryan; Gollnick, Paul

    2016-01-01

    Vaccinia virus early genes are transcribed immediately upon infection. Nucleoside triphosphate phosphohydrolase I (NPH I) is an essential component of the early gene transcription complex. NPH I hydrolyzes ATP to release transcripts during transcription termination. The ATPase activity of NPH I requires single-stranded (ss) DNA as a cofactor; however, the source of this cofactor within the transcription complex is not known. Based on available structures of transcription complexes it has been hypothesized that the ssDNA cofactor is obtained from the unpaired non-template strand within the transcription bubble. In vitro transcription on templates that lack portions of the non-template strand within the transcription bubble showed that the upstream portion of the transcription bubble is required for efficient NPH I-mediated transcript release. Complementarity between the template and non-template strands in this region is also required for NPH I-mediated transcript release. This observation complicates locating the source of the ssDNA cofactor within the transcription complex because removal of the non-template strand also disrupts transcription bubble reannealing. Prior studies have shown that ssRNA binds to NPH I, but it does not activate ATPase activity. Chimeric transcription templates with RNA in the non-template strand confirm that the source of the ssDNA cofactor for NPH I is the upstream portion of the non-template strand in the transcription bubble. Consistent with this conclusion we also show that isolated NPH I acts as a 5′ to 3′ translocase on single-stranded DNA. PMID:27189950

  20. Sequence analysis of a 5.1 kbp region of the Spodoptera frugiperda multicapsid nucleopolyhedrovirus genome that comprises a functional ecdysteroid UDP-glucosyltransferase (egt) gene.

    PubMed

    Tumilasci, Vanessa Fonseca; Leal, Elcio; Zanotto, Paolo Marinho Andrade; Luque, Teresa; Wolff, José Luiz Caldas

    2003-10-01

    The ecdysteroid UDP-glucosyltransferase gene from the Spodoptera frugiperda multicapsid nucleopolyhedrovirus (SfMNPV) was identified using degenerate primers whose sequence were derived from conserved regions of the EGT proteins encoded by other baculoviruses. Analysis of the gene sequence revealed the presence of an open reading frame (ORF) with potential to encode a polypeptide of 525 amino acids. Promoter sequences typical of baculovirus genes were found in the 5' region of this ORF. A polyadenylation signal was identified downstream the translation stop codon. A transient expression assay showed that the product of this ORF was able to conjugate glucose from UDP-glucose with ecdysone confirming that the gene identified was indeed the SfMNPV egt gene. The SfMNPV egt gene and the sequences of other baculovirus egt genes were used to infer a phylogenetic tree. The nucleotide sequence of the entire BamHI fragment that contains the SfMNPV egt gene was determined. Search of the available sequence databases suggested that, besides the egt gene, this region contains 5 ORFs similar to the baculovirus genes gp37 (fusolin), to ptp2 and to ORFs 28, 29, and 30 of Spodoptera exigua multicapsid nucleopolyhedrovirus. Both the phylogenetic analysis of the egt genes and the gene order of the region that flanks the egt gene indicated that SfMNPV is closely related to the baculoviruses that infects S. exigua and Mamestra configurata.

  1. Deletion at the SLC1A1 glutamate transporter gene co-segregates with schizophrenia and bipolar schizoaffective disorder in a 5-generation family.

    PubMed

    Myles-Worsley, Marina; Tiobech, Josepha; Browning, Sharon R; Korn, Jeremy; Goodman, Sarah; Gentile, Karen; Melhem, Nadine; Byerley, William; Faraone, Stephen V; Middleton, Frank A

    2013-03-01

    Growing evidence for genetic overlap between schizophrenia (SCZ) and bipolar disorder (BPD) suggests that causal variants of large effect on disease risk may cross traditional diagnostic boundaries. Extended multigenerational families with both SCZ and BPD cases can be a valuable resource for discovery of shared biological pathways because they can reveal the natural evolution of the underlying genetic disruptions and their phenotypic expression. We investigated a deletion at the SLC1A1 glutamate transporter gene originally identified as a copy number variant exclusively carried by members of a 5-generation Palauan family. Using an expanded sample of 21 family members, quantitative PCR confirmed the deletion in all seven individuals with psychosis, three "obligate-carrier" parents and one unaffected sibling, while four marry-in parents were non-carriers. Linkage analysis under an autosomal dominant model generated a LOD-score of 3.64, confirming co-segregation of the deletion with psychosis. For more precise localization, we determined the approximate deletion end points using alignment of next-generation sequencing data for one affected deletion-carrier and then designed PCR amplicons to span the entire deletion locus. These probes established that the deletion spans 84,298 bp, thus eliminating the entire promoter, the transcription start site, and the first 59 amino acids of the protein, including the first transmembrane Na(2+)/dicarboxylate symporter domain, one of the domains that perform the glutamate transport action. Discovery of this functionally relevant SLC1A1 mutation and its co-segregation with psychosis in an extended multigenerational pedigree provides further support for the important role played by glutamatergic transmission in the pathophysiology of psychotic disorders. Copyright © 2013 Wiley Periodicals, Inc.

  2. Characterization by yeast artificial chromosome cloning of the linked apolipoprotein(a) and plasminogen genes and identification of the apolipoprotein(a) 5' flanking region.

    PubMed Central

    Malgaretti, N; Acquati, F; Magnaghi, P; Bruno, L; Pontoglio, M; Rocchi, M; Saccone, S; Della Valle, G; D'Urso, M; LePaslier, D

    1992-01-01

    The apoprotein(a) [apo(a)] gene encodes a protein component of the circulating lipoprotein(a) [Lp(a)]. The apo(a) gene is highly homologous to the plasminogen gene. It encodes one of the most polymorphic human proteins, due to variability in the number of repetitions of structures called kringles. In addition, Lp(a) levels vary among individuals by more than two orders of magnitude, the high levels being highly correlated with predisposition to early atherosclerotic disease. To better understand the genetics and function of the apo(a) gene, we have cloned in yeast artificial chromosome vectors DNA fragments comprising the linked apo(a) and plasminogen genes and other members of the plasminogen family. By a combination of pulsed-field gel electrophoresis and genome walking experiments, we have identified the 5' portion and flanking regions of the apo(a) gene. Images PMID:1454851

  3. Sp-miR396a-5p acts as a stress-responsive genes regulator by conferring tolerance to abiotic stresses and susceptibility to Phytophthora nicotianae infection in transgenic tobacco.

    PubMed

    Chen, Lei; Luan, Yushi; Zhai, Junmiao

    2015-12-01

    Overexpression of Sp-miR396a-5p in tobacco increased tolerance to salt, drought, cold stress and susceptibility to Phytophthora nicotianae infection. MicroRNA396 (miR396) is one of the conserved microRNA families in plants, and it targeted growth-regulating factors (GRFs) family. The GRF transcription factors are associated with growth and stress responses. However, the molecular mechanisms of miR396 responding to environmental stresses are elusive. The purpose of this study was to explore the function of tomato miR396a-5p (Sp-miR396a-5p) in Solanaceae responses to abiotic and biotic stresses. We showed that Sp-miR396a-5p transcript levels were up-regulated under salt and drought stresses and down-regulated after Phytophthora infestans (P. infestans) infection. Consistently, overexpression of Sp-miR396a-5p in tobacco enhanced its tolerance to salt, drought and cold stresses. Additionally, the expression of Sp-miR396a-5p was found to be down-regulated under pathogen-related biotic stress. Tobacco plants overexpressing Sp-miR396a-5p showed increased susceptibility to Phytophthora nicotianae (P. nicotianae) infection. Physiological analysis indicated that Sp-miR396a-5p overexpression enhanced osmoregulation and decreased production of reactive oxygen species (ROS). Furthermore, four Sp-miR396a-5p target genes, NtGRF1, NtGRF3, NtGRF7 and NtGRF8, were down-regulated in these plants. Our results suggested that Sp-miR396a-5p plays critical roles in both abiotic stresses through targeting NtGRF7-regulated expression of osmotic stress-responsive genes and pathogen infection via the regulatory networks of NtGRF1 and NtGRF3.

  4. Demonstration of a new pathogenic mutation in human complex I deficiency: a 5-bp duplication in the nuclear gene encoding the 18-kD (AQDQ) subunit.

    PubMed Central

    van den Heuvel, L; Ruitenbeek, W; Smeets, R; Gelman-Kohan, Z; Elpeleg, O; Loeffen, J; Trijbels, F; Mariman, E; de Bruijn, D; Smeitink, J

    1998-01-01

    We report the cDNA cloning, chromosomal localization, and a mutation in the human nuclear gene encoding the 18-kD (AQDQ) subunit of the mitochondrial respiratory chain complex I. The cDNA has an open reading frame of 175 amino acids and codes for a protein with a molecular mass of 23.2 kD. Its gene was mapped to chromosome 5. A homozygous 5-bp duplication, destroying a consensus phosphorylation site, in the 18-kD cDNA was found in a complex I-deficient patient. The patient showed normal muscle morphology and a remarkably nonspecific fatal progressive phenotype without increased lactate concentrations in body fluids. The child's parents were heterozygous for the mutation. In 19 other complex I-deficient patients, no mutations were found in the 18-kD gene. PMID:9463323

  5. Translational enhancement of recombinant protein synthesis in transgenic silkworms by a 5'-untranslated region of polyhedrin gene of Bombyx mori Nucleopolyhedrovirus.

    PubMed

    Iizuka, Masashi; Tomita, Masahiro; Shimizu, Katsuhiko; Kikuchi, Yutaka; Yoshizato, Katsutoshi

    2008-06-01

    Previously, we established a method to produce recombinant proteins (r-proteins) in cocoons of germline transgenic silkworms, and showed that a step(s) in post-transcription processes was rate-limiting in obtaining a high yield of r-proteins. In this study, we examined whether the 5'-untranslated region (5'-UTR) of the polyhedrin gene (pol) of nucleopolyhedrovirus (NPV) has a translational enhancer activity in the r-protein expression by middle silk gland (MSG) cells of silkworm Bombyx mori (Bm). Sericin 1 gene (ser1) promoter-driven transformation vectors were constructed in which pol5'-UTRs of NPVs isolated from four different species, Bm, Spodoptera frugiperda, Ectropis oblique, and Malacosoma neustria, were each placed upstream of a reporter gene. Transient expression assays in MSGs showed that these pol5'-UTRs all enhanced the protein expression of reporter genes, and the pol5'-UTR of Bm NPV (pol5'-UTR/Bm) was the most effective among them. Thus, transgenic silkworms were generated, which bore the ser1 promoter-driven His-tagged secretory EGFP (sEGFP-His) gene under the control of pol5'-UTR/Bm. The synthesis of sEGFP-His proteins in MSGs of the transgenic worms was approximately 1.5-fold higher than that in those bearing null vectors. However, its mRNA expression levels were 67% of the control worms, indicating that the pol5'-UTR/Bm specifically enhanced the translational level. In conclusion, pol5'-UTR/Bm increased the yield of r-protein production in transgenic silkworms by enhancing the translational activity and this 5'-UTR could be useful for the mass production of r-proteins in germline transgenic silkworms.

  6. Effects of Genetic Polymorphism in CYP3A4 and CYP3A5 Genes on Tacrolimus Dose Among Kidney Transplant Recipients.

    PubMed

    Yousef, Al-Motassem; Qosa, Hisham; Bulatova, Nailya; Abuhaliema, Ali; Almadhoun, Hussein; Khayyat, Ghada; Olemat, Muhammad

    2016-05-01

    This study aimed to evaluate the effects of single nucleotide polymorphisms CYP3A4*1B and CYP3A5*3 on tacrolimus dose requirement among kidney transplant recipients. Blood levels of tacrolimus were measured using microparticle enzyme immunoassay. Genotyping analysis utilized specific polymerase chain reaction-restriction fragment length polymorphism methods for 137 kidney transplant recipients. The median tacrolimus dose was significantly lower in the CYP3A4*1/*1 carriers (0.06 mg/kg/d; range, 0.007 mg/kg/d to 0.17 mg/kg/d) as compared to the CYP3A4*1B/*1B carriers (0.1 mg/kg/d; range, 0.03 mg/kg/d to 0.22 mg/kg/d; P = .001). Patients with at least 1 CYP3A5*1 wild-type allele required higher median doses of tacrolimus (median, 0.08 mg/kg/d; range, 0.03 mg/kg/d to 0.22 mg/kg/d) as compared to the CYP3A5*3 carriers (median, 0.05 mg/kg/d; range, 0.007 mg/kg/d  to 0.17 mg/kg/d; P = .002). This study showed that tacrolimus dose requirement is lower in Jordanian kidney transplant recipients compared to other populations. Moreover, we found a correlation between genetic variations in CYP3A4 and CYP3A5 enzymes and tacrolimus blood levels among our kidney transplant recipients.

  7. 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.

  8. 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. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. 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. © 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

  10. 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.

  11. A 5′ Nuclease PCR (TaqMan) High-Throughput Assay for Detection of the mecA Gene in Staphylococci

    PubMed Central

    Killgore, George E.; Holloway, Brian; Tenover, Fred C.

    2000-01-01

    In an effort to find a rapid, efficient, and reliable method of screening large numbers of bacterial isolates for specific antimicrobial resistance genes, we compared conventional PCR results to the results generated using the TaqMan 5′ nuclease PCR kit in conjunction with an ABI Prism 7700 Sequence Detector for detecting the mecA gene in various species of staphylococci. DNA was extracted using two techniques. The first used a high-salt extraction method suitable for conventional PCR but resulted in a 7.2% rate of PCR inhibition with the TaqMan technique. PCR inhibition could be overcome by diluting samples 1:5 prior to testing. The second method used the Qiagen QIAamp Tissue Kit; no instances of PCR inhibition were encountered with this method. A total of 197 (96%) of the 206 samples with no inhibition showed agreement between the two methods. Eight of the nine disagreements were likely the result of low-level DNA cross contamination caused by frequent specimen handling. Target DNA in all eight of these samples was first detected in the initial tests only after >30 PCR cycles, and all were negative upon repeat testing even after 40 PCR cycles using freshly extracted DNA. Among those positive samples in agreement, target DNA was invariably detected before 30 PCR cycles. The TaqMan assay eliminated the need to load, run, stain, and read agarose gels and provided the advantage of instant detection of PCR product by laser-activated fluorescence. Thus, final results were obtained 2 h after PCR was initiated, as opposed to a requirement of 2 days to examine 96 samples by agarose gel electrophoresis. PMID:10878035

  12. A 5' nuclease PCR (TaqMan) high-throughput assay for detection of the mecA gene in staphylococci.

    PubMed

    Killgore, G E; Holloway, B; Tenover, F C

    2000-07-01

    In an effort to find a rapid, efficient, and reliable method of screening large numbers of bacterial isolates for specific antimicrobial resistance genes, we compared conventional PCR results to the results generated using the TaqMan 5' nuclease PCR kit in conjunction with an ABI Prism 7700 Sequence Detector for detecting the mecA gene in various species of staphylococci. DNA was extracted using two techniques. The first used a high-salt extraction method suitable for conventional PCR but resulted in a 7.2% rate of PCR inhibition with the TaqMan technique. PCR inhibition could be overcome by diluting samples 1:5 prior to testing. The second method used the Qiagen QIAamp Tissue Kit; no instances of PCR inhibition were encountered with this method. A total of 197 (96%) of the 206 samples with no inhibition showed agreement between the two methods. Eight of the nine disagreements were likely the result of low-level DNA cross contamination caused by frequent specimen handling. Target DNA in all eight of these samples was first detected in the initial tests only after >30 PCR cycles, and all were negative upon repeat testing even after 40 PCR cycles using freshly extracted DNA. Among those positive samples in agreement, target DNA was invariably detected before 30 PCR cycles. The TaqMan assay eliminated the need to load, run, stain, and read agarose gels and provided the advantage of instant detection of PCR product by laser-activated fluorescence. Thus, final results were obtained 2 h after PCR was initiated, as opposed to a requirement of 2 days to examine 96 samples by agarose gel electrophoresis.

  13. Cultural consonance, a 5HT2A receptor polymorphism, and depressive symptoms: a longitudinal study of gene x culture interaction in urban Brazil.

    PubMed

    Dressler, William W; Balieiro, Mauro C; Ribeiro, Rosane P; Dos Santos, José Ernesto

    2009-01-01

    In this study in urban Brazil we examine, as a predictor of depressive symptoms, the interaction between a single nucleotide polymorphism in the 2A receptor in the serotonin system (-1438G/A) and cultural consonance in family life, a measure of the degree to which an individual perceives her family as corresponding to a widely shared cultural model of the prototypical family. A community sample of 144 adults was followed over a 2-year-period. Cultural consonance in family life was assessed by linking individuals' perceptions of their own families with a shared cultural model of the family derived from cultural consensus analysis. The -1438G/A polymorphism in the 2A serotonin receptor was genotyped using a standard protocol for DNA extracted from leukocytes. Covariates included age, sex, socioeconomic status, and stressful life events. Cultural consonance in family life was prospectively associated with depressive symptoms. In addition, the interaction between genotype and cultural consonance in family life was significant. For individuals with the A/A variant of the -1438G/A polymorphism of the 2A receptor gene, the effect of cultural consonance in family life on depressive symptoms over a 2-year-period was larger (beta = -0.533, P < 0.01) than those effects for individuals with either the G/A (beta = -0.280, P < 0.10) or G/G (beta = -0.272, P < 0.05) variants. These results are consistent with a process in which genotype moderates the effects of culturally meaningful social experience on depressive symptoms. (c) 2008 Wiley-Liss, Inc.

  14. Genomic Landscape of Experimental Bladder Cancer in Rodents and Its Application to Human Bladder Cancer: Gene Amplification and Potential Overexpression of Cyp2a5/CYP2A6 Are Associated with the Invasive Phenotype

    PubMed Central

    Kanemoto, Kazuhiro; Fukuta, Katsuhiro; Kawai, Noriyasu; Tozawa, Keiichi; Ochiai, Masako; Okamoto, Koji; Ohnami, Sumiko; Sakamoto, Hiromi; Yoshida, Teruhiko; Kanai, Yae; Katoh, Masaru; Yasui, Takahiro; Kohri, Kenjiro; Kakizoe, Tadao; Nakagama, Hitoshi

    2016-01-01

    Non-muscle invasive (superficial) bladder cancer is a low-grade malignancy with good prognosis, while muscle invasive (invasive) bladder cancer is a high-grade malignancy with poor prognosis. N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) induces superficial bladder cancers with papillary morphology in rats and invasive bladder cancers with infiltrating phenotype in mice. In this study, we analyzed genomic landscapes of rodent BBN-induced bladder cancers using array-based comparative genomic hybridization (array CGH). While no significant copy number alterations were detected in superficial bladder tumors in rats, copy number gains in chromosomal regions 2D-E1, 7qA3, 9F2, and 11C-D were detected in invasive bladder tumors in mice. Amplification of representative genes located on 2D-E1 and 7qA3 chromosomal regions was confirmed by quantitative PCR. Cyp2a22 and Cyp2a5 genes but not Cyp2g1, Cyp2a12, and Rab4b genes on mouse chromosome 7qA3 were amplified in invasive bladder cancers. Although the human ortholog gene of Cyp2a22 has not been confirmed, the mouse Cyp2a5 gene is the ortholog of the human CYP2A6 gene located in chromosomal region 19q13.2, and CYP2A6 was identified by database search as one of the closest human homolog to mouse Cyp2a22. Considering a possibility that this region may be related to mouse 7qA3, we analyzed CYP2A6 copy number and expression in human bladder cancer using cell lines and resected tumor specimens. Although only one of eight cell lines showed more than one copy increase of the CYP2A6 gene, CYP2A6 amplification was detected in six out of 18 primary bladder tumors where it was associated with the invasive phenotype. Immunohistochemical analyses of 118 primary bladder tumors revealed that CYP2A6 protein expression was also higher in invasive tumors, especially in those of the scattered type. Together, these findings indicate that the amplification and overexpression of the CYP2A6 gene are characteristic of human bladder cancers with

  15. Genomic Landscape of Experimental Bladder Cancer in Rodents and Its Application to Human Bladder Cancer: Gene Amplification and Potential Overexpression of Cyp2a5/CYP2A6 Are Associated with the Invasive Phenotype.

    PubMed

    Kanemoto, Kazuhiro; Fukuta, Katsuhiro; Kawai, Noriyasu; Tozawa, Keiichi; Ochiai, Masako; Okamoto, Koji; Ohnami, Sumiko; Sakamoto, Hiromi; Yoshida, Teruhiko; Kanai, Yae; Katoh, Masaru; Yasui, Takahiro; Kohri, Kenjiro; Kakizoe, Tadao; Nakagama, Hitoshi

    2016-01-01

    Non-muscle invasive (superficial) bladder cancer is a low-grade malignancy with good prognosis, while muscle invasive (invasive) bladder cancer is a high-grade malignancy with poor prognosis. N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) induces superficial bladder cancers with papillary morphology in rats and invasive bladder cancers with infiltrating phenotype in mice. In this study, we analyzed genomic landscapes of rodent BBN-induced bladder cancers using array-based comparative genomic hybridization (array CGH). While no significant copy number alterations were detected in superficial bladder tumors in rats, copy number gains in chromosomal regions 2D-E1, 7qA3, 9F2, and 11C-D were detected in invasive bladder tumors in mice. Amplification of representative genes located on 2D-E1 and 7qA3 chromosomal regions was confirmed by quantitative PCR. Cyp2a22 and Cyp2a5 genes but not Cyp2g1, Cyp2a12, and Rab4b genes on mouse chromosome 7qA3 were amplified in invasive bladder cancers. Although the human ortholog gene of Cyp2a22 has not been confirmed, the mouse Cyp2a5 gene is the ortholog of the human CYP2A6 gene located in chromosomal region 19q13.2, and CYP2A6 was identified by database search as one of the closest human homolog to mouse Cyp2a22. Considering a possibility that this region may be related to mouse 7qA3, we analyzed CYP2A6 copy number and expression in human bladder cancer using cell lines and resected tumor specimens. Although only one of eight cell lines showed more than one copy increase of the CYP2A6 gene, CYP2A6 amplification was detected in six out of 18 primary bladder tumors where it was associated with the invasive phenotype. Immunohistochemical analyses of 118 primary bladder tumors revealed that CYP2A6 protein expression was also higher in invasive tumors, especially in those of the scattered type. Together, these findings indicate that the amplification and overexpression of the CYP2A6 gene are characteristic of human bladder cancers with

  16. Association of immune recovery with hyperlipidaemia and apolipoprotein gene polymorphisms following highly active antiretroviral therapy in a cohort of Chinese HIV patients

    PubMed Central

    Chan, Denise Pui-Chung; Lee, Man-Po; Wong, Ngai-Sze; Leung, Ross Ka-Kit; Naftalin, Claire Melinda; Lee, Shui-Shan

    2016-01-01

    Objective To examine the associations between CD4 recovery, dyslipidaemia and apolipoprotein (APO) gene single nucleotide polymorphisms (SNPs) following highly active antiretroviral therapy (HAART). Design Retrospective observational cohort study. Setting A major HIV care clinic in Hong Kong. Participants 197 Chinese treatment-naïve HIV patients. Outcome measures Maximum CD4 count and its rise 2–3 years after HAART initiation and their association with abnormal total cholesterol (TC), triglyceride (TG) and 8 selected APO SNP at multiple time points. Results Before HAART, abnormal levels of TC, TG, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol were detected in 13%, 26%, 59% and 19% of the recruited patients, respectively. APOA5 −1131T>C and c.553G>T were significantly associated with high pre-HAART TG while APOE 2198C>T was correlated with high TG at baseline and/or a rise 2–3 years following HAART initiation. Poor CD4 achievement, defined as the highest CD4 count <350/μL and a net gain of <100/μL, was associated with a low CD4 count ≤200/μL at baseline and a rise of TC beyond 5.17 mmol/L following HAART with or without the use of antilipid agents. Conversely, satisfactory CD4 achievement was associated with APOC3 3238GG genotype. Applying a linear generalised estimating equation, APOA5 −1131T>C was shown to be a predictor of a weaker temporal trend for CD4 response in the presence of a low baseline CD4≤200/μL. Conclusions Dyslipidaemia plays a predictive role in impacting immunological recovery following HAART, which could be partly explained by the APO gene SNP. PMID:27067897

  17. 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

    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 dystrophinmore » 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.« less

  18. Molecular Characterization of QX-Like and Variant Infectious Bronchitis Virus Strains in Malaysia Based on Partial Genomic Sequences Comprising the S-3a/3b-E-M-Intergenic Region-5a/5b-N Gene Order.

    PubMed

    Khanh, N P; Tan, S W; Yeap, S K; Satharasinghe, D A; Hair-Bejo, M; Bich, T N; Omar, A R

    2017-12-01

    Infectious bronchitis virus (IBV) is one of the major poultry pathogens of global importance. However, the prevalence of IBV strains in Malaysia is poorly characterized. The partial genomic sequences (6.8 kb) comprising the S-3a/3b-E-M-intergenic region-5a/5b-N gene order of 11 Malaysian IBVs isolated in 2014 and 2015 were sequenced using next-generation sequencing technology. Phylogenetic and pairwise sequence comparison analysis showed that the isolated IBVs are divided into two groups. Group 1 (IBS124/2015, IBS125/2015, IBS126/2015, IBS130/2015, IBS131/2015, IBS138/2015, and IBS142/2015) shared 90%-95% nucleotide and deduced amino acid similarities to the QX-like strain. Among these isolates, IBS142/2015 is the first IBV detected in Sarawak state located in East Malaysia (Borneo Island). Meanwhile, IBV isolates in Group 2 (IBS037A/2015, IBS037B/2015, IBS051/2015, and IBS180/2015) were 91.62% and 89.09% identical to Malaysian variant strain MH5365/95 (EU086600) at nucleotide and amino acid levels, respectively. In addition, all studied IBVs were distinctly separate from Massachusetts (70%-72% amino acid similarity) and European strains including 793/B, Italy-02, and D274 (68%-73% amino acid similarity). Viruses in Group 1 have the insertion of three amino acids at positions 23, 121, and 122 of the S1 protein and recombinant events detected at nucleotide position 4354-5864, with major parental sequence derived from QX-like (CK-CH-IBYZ-2011) and a minor parental sequence derived from Massachusetts vaccine strain (H120). This study demonstrated coexistence of the IBV Malaysian variant strain along with the QX-like strain in Malaysia.

  19. Genes

    MedlinePlus

    ... Together, they make up the blueprint for the human body and how it works. A person's genetic makeup is called a genotype. Information Genes are made of DNA. Strands of DNA make up part of your chromosomes . Chromosomes have matching pairs of 1 copy of ...

  20. Correlations of CYP2C9*3/CYP2D6*10/CYP3A5*3 gene polymorphisms with efficacy of etanercept treatment for patients with ankylosing spondylitis: A case-control study.

    PubMed

    Chen, Yuan-Yuan

    2017-03-01

    The tumor necrosis factor alpha (TNF-α) inhibitor etanercept has been proven to be effective in the treatment of ankylosing spondylitis (AS), while genetic polymorphism may affect drug metabolism or drug receptor, resulting in interindividual variability in drug disposition and efficacy. The purpose of this study is to investigate the correlations between CYP2C9*3/CYP2D6*10/CYP3A5*3 gene polymorphisms and the efficacy of etanercept treatment for patients with AS. From March 2012 to June 2015, 312 AS patients (174 males and 138 females, mean age: 35.2 ± 5.83 years) from 18 to 56 years old were enrolled in this study. Polymerase chain reaction-restriction fragment length polymorphism was applied to detect the allele and genotype frequencies of CYP2C93, CYP2D610, and CYP3A53 gene polymorphisms. The joint swelling score, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) level of AS patients were compared before and after 24-week etanercept treatment. Assessment in Ankylosing Spondylitis (ASAS) and bath ankylosing spondylitis disease activity index (BASDAI) scores were recorded to assess the efficacy of etanercept treatment. The AS patients with wild-type 1/1 and heterozygous 1/3 genotypes of CYP2C93 polymorphism accounted for 93.59% and 6.41%, respectively, without 3/3 genotype. The AS patients with wild-type CC, heterozygous CT, and mutation homozygous TT genotypes of CYP2D610 polymorphism accounted for 19.23%, 39.10%, and 41.67%, respectively. The AS patients with wild-type 1/1, heterozygous 1/3, and mutation homozygous 3/3 genotypes of CYP3A53 polymorphism accounted for 7.69%, 36.22%, and 56.09%, respectively. After 24-week treatment, AS patients with wild-type 1/1 genotype of CYP2C93, CC genotype of CYP2D610, and 3/3 genotype of CYP3A53 polymorphisms had lower joint swelling score, ESR, and CRP level. The joint swelling score, ESR, and CRP levels were significantly lower in the patients with CC genotype of CYP2D610 polymorphism than in CT and

  1. A gene-centric association scan for Coagulation Factor VII levels in European and African Americans: the Candidate Gene Association Resource (CARe) Consortium

    PubMed Central

    Taylor, Kira C.; Lange, Leslie A.; Zabaneh, Delilah; Lange, Ethan; Keating, Brendan J.; Tang, Weihong; Smith, Nicholas L.; Delaney, Joseph A.; Kumari, Meena; Hingorani, Aroon; North, Kari E.; Kivimaki, Mika; Tracy, Russell P.; O'Donnell, Christopher J.; Folsom, Aaron R.; Green, David; Humphries, Steve E.; Reiner, Alexander P.

    2011-01-01

    Polymorphisms in several distinct genomic regions, including the F7 gene, were recently associated with factor VII (FVII) levels in European Americans (EAs). The genetic determinants of FVII in African Americans (AAs) are unknown. We used a 50 000 single nucleotide polymorphism (SNP) gene-centric array having dense coverage of over 2 000 candidate genes for cardiovascular disease (CVD) pathways in a community-based sample of 16 324 EA and 3898 AA participants from the Candidate Gene Association Resource (CARe) consortium. Our aim was the discovery of new genomic loci and more detailed characterization of existing loci associated with FVII levels. In EAs, we identified three new loci associated with FVII, of which APOA5 on chromosome 11q23 and HNF4A on chromosome 20q12–13 were replicated in a sample of 4289 participants from the Whitehall II study. We confirmed four previously reported FVII-associated loci (GCKR, MS4A6A, F7 and PROCR) in CARe EA samples. In AAs, the F7 and PROCR regions were significantly associated with FVII. Several of the FVII-associated regions are known to be associated with lipids and other cardiovascular-related traits. At the F7 locus, there was evidence of at least five independently associated SNPs in EAs and three independent signals in AAs. Though the variance in FVII explained by the existing loci is substantial (20% in EA and 10% in AA), larger sample sizes and investigation of lower frequency variants may be required to identify additional FVII-associated loci in EAs and AAs and further clarify the relationship between FVII and other CVD risk factors. PMID:21676895

  2. Two Novel Missense Mutations and a 5bp Deletion in the Erythroid-Specific Promoter of the PKLR Gene in Two Unrelated Patients With Pyruvate Kinase Deficient Transfusion-Dependent Chronic Nonspherocytic Hemolytic Anemia.

    PubMed

    Kager, Leo; Minkov, Milen; Zeitlhofer, Petra; Fahrner, Bernhard; Ratzinger, Franz; Boztug, Kaan; Dossenbach-Glaninger, Astrid; Haas, Oskar A

    2016-05-01

    We report two children with severe chronic hemolytic anemia, the cause of which was difficult to establish because of transfusion dependency. Reduced erythrocyte pyruvate kinase activity in their asymptomatic parents provided the diagnostic clues for mutation screening of the PKLR gene and revealed that one child was a compound heterozygote of a novel paternally derived 5-bp deletion in the promoter region (c.-88_-84delTCTCT) and a maternally derived missense mutation in exon nine (c.1174G>A; p.Ala392Thr). The second child was a compound heterozygote of two novel missense mutations, namely a paternally derived exon ten c.1381G>A (p.Glu461Lys) and a maternally derived exon seven c.907-908delCC (p.Pro303GlyfsX12) variant. © 2016 Wiley Periodicals, Inc.

  3. Candidate Gene Association Resource (CARe): Design, Methods, and Proof of Concept

    PubMed Central

    Musunuru, Kiran; Lettre, Guillaume; Young, Taylor; Farlow, Deborah N.; Pirruccello, James P.; Ejebe, Kenechi G.; Keating, Brendan J.; Yang, Qiong; Chen, Ming-Huei; Lapchyk, Nina; Crenshaw, Andrew; Ziaugra, Liuda; Rachupka, Anthony; Benjamin, Emelia J.; Cupples, L. Adrienne; Fornage, Myriam; Fox, Ervin R.; Heckbert, Susan R.; Hirschhorn, Joel N.; Newton-Cheh, Christopher H.; Nizzari, Marcia M.; Paltoo, Dina N.; Papanicolaou, George J.; Patel, Sanjay R.; Psaty, Bruce M.; Rader, Daniel J.; Redline, Susan; Rich, Stephen S.; Rotter, Jerome I.; Taylor, Herman A.; Tracy, Russell P.; Vasan, Ramachandran S.; Wilson, James G.; Kathiresan, Sekar; Fabsitz, Richard R.; Boerwinkle, Eric; Gabriel, Stacey B.

    2011-01-01

    Background . The National Heart, Lung, and Blood Institute’s Candidate Gene Association Resource (CARe), a planned cross-cohort analysis of genetic variation in cardiovascular, pulmonary, hematological, and sleep-related traits, comprises more than 40,000 participants representing four ethnic groups in nine community-based cohorts. The goals of CARe include the discovery of new variants associated with traits using a candidate gene approach and the discovery of new variants using the genome-wide association mapping approach specifically in African Americans. Methods and Results . CARe has assembled DNA samples for more than 40,000 individuals self-identified as European-American, African-American, Hispanic, or Chinese-American, with accompanying data on hundreds of phenotypes that have been standardized and deposited in the CARe Phenotype Database. All participants were genotyped for seven single-nucleotide polymorphisms (SNPs) selected based on prior association evidence. We performed association analyses relating each of these SNPs to lipid traits, stratified by gender and ethnicity and adjusted for age and age2. In at least two of the ethnic groups, SNPs near CETP, LIPC, and LPL strongly replicated for association with high-density lipoprotein cholesterol concentrations, PCSK9 with low-density lipoprotein cholesterol levels, and LPL and APOA5 with serum triglycerides. Notably, some SNPs showed varying effect sizes and significance of association in different ethnic groups. Conclusions . The CARe Pilot Study validates the operational framework for phenotype collection, SNP genotyping, and analytical pipeline of the CARe project and validates the planned candidate gene study of ~2,000 biologic candidate loci in all participants and genome-wide association study in ~8,000 African-American participants. CARe will serve as a valuable resource for the scientific community. PMID:20400780

  4. Genetic Variants Associated with Gestational Hypertriglyceridemia and Pancreatitis

    PubMed Central

    Huang, Xie-Lin; Chen, Chao; Jin, Rong; Huang, Zhi-Ming; Zhou, Meng-Tao

    2015-01-01

    Severe hypertriglyceridemia is a well-known cause of pancreatitis. Usually, there is a moderate increase in plasma triglyceride level during pregnancy. Additionally, certain pre-existing genetic traits may render a pregnant woman susceptible to development of severe hypertriglyceridemia and pancreatitis, especially in the third trimester. To elucidate the underlying mechanism of gestational hypertriglyceridemic pancreatitis, we undertook DNA mutation analysis of the lipoprotein lipase (LPL), apolipoprotein C2 (APOC2), apolipoprotein A5 (APOA5), lipase maturation factor 1 (LMF1), and glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) genes in five unrelated pregnant Chinese women with severe hypertriglyceridemia and pancreatitis. DNA sequencing showed that three out of five patients had the same homozygous variation, p.G185C, in APOA5 gene. One patient had a compound heterozygous mutation, p.A98T and p.L279V, in LPL gene. Another patient had a compound heterozygous mutation, p.A98T & p.C14F in LPL and GPIHBP1 gene, respectively. No mutations were seen in APOC2 or LMF1 genes. All patients were diagnosed with partial LPL deficiency in non-pregnant state. As revealed in our study, genetic variants appear to play an important role in the development of severe gestational hypertriglyceridemia, and, p.G185C mutation in APOA5 gene appears to be the most common variant implicated in the Chinese population. Antenatal screening for mutations in susceptible women, combined with subsequent interventions may be invaluable in the prevention of potentially life threatening gestational hypertriglyceridemia-induced pancreatitis. PMID:26079787

  5. Genetic Variants Associated with Gestational Hypertriglyceridemia and Pancreatitis.

    PubMed

    Xie, Sai-Li; Chen, Tan-Zhou; Huang, Xie-Lin; Chen, Chao; Jin, Rong; Huang, Zhi-Ming; Zhou, Meng-Tao

    2015-01-01

    Severe hypertriglyceridemia is a well-known cause of pancreatitis. Usually, there is a moderate increase in plasma triglyceride level during pregnancy. Additionally, certain pre-existing genetic traits may render a pregnant woman susceptible to development of severe hypertriglyceridemia and pancreatitis, especially in the third trimester. To elucidate the underlying mechanism of gestational hypertriglyceridemic pancreatitis, we undertook DNA mutation analysis of the lipoprotein lipase (LPL), apolipoprotein C2 (APOC2), apolipoprotein A5 (APOA5), lipase maturation factor 1 (LMF1), and glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) genes in five unrelated pregnant Chinese women with severe hypertriglyceridemia and pancreatitis. DNA sequencing showed that three out of five patients had the same homozygous variation, p.G185C, in APOA5 gene. One patient had a compound heterozygous mutation, p.A98T and p.L279V, in LPL gene. Another patient had a compound heterozygous mutation, p.A98T & p.C14F in LPL and GPIHBP1 gene, respectively. No mutations were seen in APOC2 or LMF1 genes. All patients were diagnosed with partial LPL deficiency in non-pregnant state. As revealed in our study, genetic variants appear to play an important role in the development of severe gestational hypertriglyceridemia, and, p.G185C mutation in APOA5 gene appears to be the most common variant implicated in the Chinese population. Antenatal screening for mutations in susceptible women, combined with subsequent interventions may be invaluable in the prevention of potentially life threatening gestational hypertriglyceridemia-induced pancreatitis.

  6. Transcriptional Profiling of Human Liver Identifies Sex-Biased Genes Associated with Polygenic Dyslipidemia and Coronary Artery Disease

    PubMed Central

    Zhang, Yijing; Klein, Kathrin; Sugathan, Aarathi; Nassery, Najlla; Dombkowski, Alan; Zanger, Ulrich M.; Waxman, David J.

    2011-01-01

    Sex-differences in human liver gene expression were characterized on a genome-wide scale using a large liver sample collection, allowing for detection of small expression differences with high statistical power. 1,249 sex-biased genes were identified, 70% showing higher expression in females. Chromosomal bias was apparent, with female-biased genes enriched on chrX and male-biased genes enriched on chrY and chr19, where 11 male-biased zinc-finger KRAB-repressor domain genes are distributed in six clusters. Top biological functions and diseases significantly enriched in sex-biased genes include transcription, chromatin organization and modification, sexual reproduction, lipid metabolism and cardiovascular disease. Notably, sex-biased genes are enriched at loci associated with polygenic dyslipidemia and coronary artery disease in genome-wide association studies. Moreover, of the 8 sex-biased genes at these loci, 4 have been directly linked to monogenic disorders of lipid metabolism and show an expression profile in females (elevated expression of ABCA1, APOA5 and LDLR; reduced expression of LIPC) that is consistent with the lower female risk of coronary artery disease. Female-biased expression was also observed for CYP7A1, which is activated by drugs used to treat hypercholesterolemia. Several sex-biased drug-metabolizing enzyme genes were identified, including members of the CYP, UGT, GPX and ALDH families. Half of 879 mouse orthologs, including many genes of lipid metabolism and homeostasis, show growth hormone-regulated sex-biased expression in mouse liver, suggesting growth hormone might play a similar regulatory role in human liver. Finally, the evolutionary rate of protein coding regions for human-mouse orthologs, revealed by dN/dS ratio, is significantly higher for genes showing the same sex-bias in both species than for non-sex-biased genes. These findings establish that human hepatic sex differences are widespread and affect diverse cell metabolic processes

  7. Common variants in genes related to lipid and energy metabolism are associated with weight loss after an intervention in overweight/obese adolescents.

    PubMed

    Moleres, Adriana; Milagro, Fermín I; Marcos, Ascensión; González Zorzano, Eduardo; Campoy, Cristina; Garagorri, Jesús M; Azcona-Sanjulian, M Cristina; Martínez, J Alfredo; Marti, Amelia

    2014-07-01

    Some SNPs related to lipid and energy metabolism may be implicated not only in the development of obesity and associated comorbidities, but also in the weight loss response after a nutritional intervention. In this context, the present study analyzed four SNPs located within four genes known to be associated with obesity and other obesity-related complications, and their putative role in a weight-loss intervention in overweight/obese adolescents. The study population consisted of 199 overweight/obese adolescents (13-16 yr old) undergoing 10 weeks of a weight loss multidisciplinary intervention: the EVASYON programme (www.estudioevasyon.org). Adolescents were genotyped for 4 SNPs, and anthropometric measurements and biochemical markers were analyzed at the beginning and after the intervention. Interestingly, APOA5(rs662799) was associated with the baseline anthropometric and biochemical outcomes, whereas FTO (rs9939609) seemed to be related with the change of these values after the 10-week intervention. The other two SNPs, located in the CETP (rs1800777) and the APOA1 (rs670) genes, showed important relationships with adiposity markers. Specifically, a combined model including both SNPs turned up to explain up to 24% of BMI-SDS change after 10 weeks of the multidisciplinary intervention, which may contribute to under - stand the weight loss response. Common variants in genes related to lipid and energy metabolism may influence not only biochemical outcomes but also weight loss response after a multidisciplinary intervention carried out in obese/overweight adolescents.. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

  8. 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

  9. Common variation in the beta-carotene 15,15'-monooxygenase 1 gene affects circulating levels of carotenoids: a genome-wide association study.

    PubMed

    Ferrucci, Luigi; Perry, John R B; Matteini, Amy; Perola, Markus; Tanaka, Toshiko; Silander, Kaisa; Rice, Neil; Melzer, David; Murray, Anna; Cluett, Christie; Fried, Linda P; Albanes, Demetrius; Corsi, Anna-Maria; Cherubini, Antonio; Guralnik, Jack; Bandinelli, Stefania; Singleton, Andrew; Virtamo, Jarmo; Walston, Jeremy; Semba, Richard D; Frayling, Timothy M

    2009-02-01

    Low plasma levels of carotenoids and tocopherols are associated with increased risk of chronic disease and disability. Because dietary intake of these lipid-soluble antioxidant vitamins is only poorly correlated with plasma levels, we hypothesized that circulating carotenoids (vitamin A-related compounds) and tocopherols (vitamin E-related compounds) are affected by common genetic variation. By conducting a genome-wide association study in a sample of Italians (n = 1190), we identified novel common variants associated with circulating carotenoid levels and known lipid variants associated with alpha-tocopherol levels. Effects were replicated in the Women's Health and Aging Study (n = 615) and in the alpha-Tocopherol, beta-Carotene Cancer Prevention (ATBC) study (n = 2136). In meta-analyses including all three studies, the G allele at rs6564851, near the beta-carotene 15,15'-monooxygenase 1 (BCMO1) gene, was associated with higher beta-carotene (p = 1.6 x 10(-24)) and alpha-carotene (p = 0.0001) levels and lower lycopene (0.003), zeaxanthin (p = 1.3 x 10(-5)), and lutein (p = 7.3 x 10(-15)) levels, with effect sizes ranging from 0.10-0.28 SDs per allele. Interestingly, this genetic variant had no significant effect on plasma retinol (p > 0.05). The SNP rs12272004, in linkage disequilibrium with the S19W variant in the APOA5 gene, was associated with alpha-tocopherol (meta-analysis p = 7.8 x 10(-10)) levels, and this association was substantially weaker when we adjusted for triglyceride levels (p = 0.002). Our findings might shed light on the controversial relationship between lipid-soluble anti-oxidant nutrients and human health.

  10. 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, Defense...

  11. 32 CFR 168a.5 - Responsibilities.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 1 2014-07-01 2014-07-01 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, Defense...

  12. 32 CFR 168a.5 - Responsibilities.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 1 2012-07-01 2012-07-01 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, Defense...

  13. 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 of...

  14. 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 of...

  15. 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 of...

  16. 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 of...

  17. 32 CFR 352a.5 - Relationships.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 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 of...

  18. Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction.

    PubMed

    Jørgensen, Anders Berg; Frikke-Schmidt, Ruth; West, Anders Sode; Grande, Peer; Nordestgaard, Børge G; Tybjærg-Hansen, Anne

    2013-06-01

    Elevated non-fasting triglycerides mark elevated levels of remnant cholesterol. Using a Mendelian randomization approach, we tested whether genetically increased remnant cholesterol in hypertriglyceridaemia due to genetic variation in the apolipoprotein A5 gene (APOA5) associates with an increased risk of myocardial infarction (MI). We resequenced the core promoter and coding regions of APOA5 in individuals with the lowest 1% (n = 95) and highest 2% (n = 190) triglyceride levels in the Copenhagen City Heart Study (CCHS, n = 10 391). Genetic variants which differed in frequency between the two extreme triglyceride groups (c.-1131T > C, S19W, and c.*31C > T; P-value: 0.06 to <0.001), thus suggesting an effect on triglyceride levels, were genotyped in the Copenhagen General Population Study (CGPS), the CCHS, and the Copenhagen Ischemic Heart Disease Study (CIHDS), comprising a total of 5705 MI cases and 54 408 controls. Genotype combinations of these common variants associated with increases in non-fasting triglycerides and calculated remnant cholesterol of, respectively, up to 68% (1.10 mmol/L) and 56% (0.40 mmol/L) (P < 0.001), and with a corresponding odds ratio for MI of 1.87 (95% confidence interval: 1.25-2.81). Using APOA5 genotypes in instrumental variable analysis, the observational hazard ratio for a doubling in non-fasting triglycerides was 1.57 (1.32-2.68) compared with a causal genetic odds ratio of 1.94 (1.40-1.85) (P for comparison = 0.28). For calculated remnant cholesterol, the corresponding values were 1.67(1.38-2.02) observational and 2.23(1.48-3.35) causal (P for comparison = 0.21). These data are consistent with a causal association between elevated levels of remnant cholesterol in hypertriglyceridaemia and an increased risk of MI. Limitations include that remnants were not measured directly, and that APOA5 genetic variants may influence other lipoprotein parameters.

  19. 44 CFR Appendix A(5) to Part 61 - Appendix A(5) to Part 61

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 44 Emergency Management and Assistance 1 2013-10-01 2013-10-01 false Appendix A(5) to Part 61 A(5) Appendix A(5) to Part 61 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY... COVERAGE AND RATES Pt. 61, App. A(5) Appendix A(5) to Part 61 Federal Emergency Management Agency, Federal...

  20. 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... COVERAGE AND RATES Pt. 61, App. A(5) Appendix A(5) to Part 61 Federal Emergency Management Agency, Federal...

  1. 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 ...

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

    SciTech Connect

    Merkel, Martin; Loeffler, Britta; Kluger, Malte

    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 hAPOA5trmore » 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.« less

  3. Differential expression of CYP6A5 and CYP6A5v2 in pyrethroid-resistant house flies, Musca domestica.

    PubMed

    Zhu, Fang; Liu, Nannan

    2008-03-01

    Two cytochrome P450 alleles, CYP6A5 and CYP6A5v2, were isolated from a pyrethroid-resistant house fly stain, ALHF. The two alleles shared 98% similarity in amino acid sequence. To understand the importance of these two alleles in resistance and examine the expression profile of the two alleles between resistant and susceptible strains, quantitative real-time PCR (qRT-PCR) was performed and compared with the Northern blot analysis. We found that qRT-PCR was an efficient method to characterize the expression profiles between these two sequence-closely-related P450 genes between resistant and susceptible houses flies. One of them, CYP6A5v2, was constitutively overexpressed in ALHF house flies compared with susceptible house fly strains. Moreover, this gene was predominantly expressed in the abdominal tissues of ALHF, in which the primary detoxification organs of insects are located. However, there was no significant difference in the expression of CYP6A5 between ALHF and susceptible house flies. The genetic linkage analysis was conducted to determine the possible link between the constitutively overexpressed CYP6A5v2 and insecticide resistance. CYP6A5v2 was mapped on autosome 5, which is correlated with the linkage of resistance in ALHF. Taken together, the study suggests the importance of CYP6A5v2 in increasing metabolic detoxification of insecticides in ALHF. The distinct expression of CYP6A5 and CYP6A5v2 in resistant and susceptible house flies implies the functional difference of theses two genes in house flies and suggests that they are two recently diverged P450 genes presented in a single organism. (c) 2007 Wiley-Liss, Inc.

  4. 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) [DDDR&E(R&AT)], shall: (1) Administer this part... coordination with a representative of the Deputy Director, Defense Research and Engineering (Research and...

  5. 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) [DDDR&E(R&AT)], shall: (1) Administer this part... coordination with a representative of the Deputy Director, Defense Research and Engineering (Research and...

  6. 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

  7. TaCYP78A5 regulates seed size in wheat (Triticum aestivum).

    PubMed

    Ma, Meng; Zhao, Huixian; Li, Zhaojie; Hu, Shengwu; Song, Weining; Liu, Xiangli

    2016-03-01

    Seed size is an important agronomic trait and a major component of seed yield in wheat. However, little is known about the genes and mechanisms that determine the final seed size in wheat. Here, we isolated TaCYP78A5, the orthologous gene of Arabidopsis CYP78A5/KLUH in wheat, from wheat cv. Shaan 512 and demonstrated that the expression of TaCYP78A5 affects seed size. TaCYP78A5 encodes the cytochrome P450 (CYP) 78A5 protein in wheat and rescued the phenotype of the Arabidopsis deletion mutant cyp78a5. By affecting the extent of integument cell proliferation in the developing ovule and seed, TaCYP78A5 influenced the growth of the seed coat, which appears to limit seed growth. TaCYP78A5 silencing caused a 10% reduction in cell numbers in the seed coat, resulting in a 10% reduction in seed size in wheat cv. Shaan 512. By contrast, the overexpression of TaCYP78A5 increased the number of cells in the seed coat, resulting in seed enlargement of ~11-35% in Arabidopsis. TaCYP78A5 activity was positively correlated with the final seed size. However, TaCYP78A5 overexpression significantly reduced seed set in Arabidopsis, possibly due to an ovule development defect. TaCYP78A5 also influenced embryo development by promoting embryo integument cell proliferation during seed development. Accordingly, a working model of the influence of TaCYP7A5 on seed size was proposed. This study provides direct evidence that TaCYP78A5 affects seed size and is a potential target for crop improvement. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  8. Studying Genes

    MedlinePlus

    ... Sheets What are genes? Genes are segments of DNA that contain instructions for building the molecules that ... proteins. Parents pass their genes to their offspring. DNA is shaped like a corkscrew-twisted ladder, called ...

  9. Gene Therapy

    MedlinePlus

    ... vector. The most common gene therapy vectors are viruses because they can recognize certain cells and carry ... remove the original disease-causing genes from the viruses, replacing them with the genes needed to stop ...

  10. 22 CFR 9a.5 - Declassification and downgrading.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Declassification and downgrading. 9a.5 Section 9a.5 Foreign Relations DEPARTMENT OF STATE GENERAL SECURITY INFORMATION REGULATIONS APPLICABLE TO... of such information or material. ...

  11. 22 CFR 9a.5 - Declassification and downgrading.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Declassification and downgrading. 9a.5 Section 9a.5 Foreign Relations DEPARTMENT OF STATE GENERAL SECURITY INFORMATION REGULATIONS APPLICABLE TO... of such information or material. ...

  12. Methylation of miR-145a-5p promoter mediates adipocytes differentiation

    SciTech Connect

    Du, Jingjing; Cheng, Xiao; Shen, Linyuan

    2016-06-17

    MicroRNAs (miRNAs, miR) play important roles in adipocyte development. Recent studies showed that the expression of several miRNAs is closely related with promoter methylation. However, it is not known whether miRNA mediates adipocytes differentiation by means of DNA methylation. Here, we showed that miR-145a-5p was poorly expressed in adipose tissue from mice fed a high fat diet (HFD). Overexpression or inhibition of miR-145a-5p was unfavorable or beneficial, respectively, for adipogenesis, and these effects were achieved by regulating adipocyte-specific genes involved in lipogenic transcription, fatty acid synthesis, and fatty acid transportation. Particularly, we first suggested that miR-145a-5p mimics or inhibitors promotedmore » or repressed adipocytes proliferation by regulating p53 and p21, which act as cell cycle regulating factors. Surprisingly, the miR-145a-5p-repressed adipocyte differentiation was enhanced or rescued when cells treated with 5-Aza-dC were transfected with miR-145a-5p mimics or inhibitors, respectively. These data indicated that, as a new mean to positively regulate adipocyte proliferation, the process of miR-145a-5p-inhibited adipogenesis may be regulated by DNA methylation. -- Highlights: •MiR-145a-5p promotes adipocytes proliferation. •MiR-145a-5p is negatively correlated with obesity. •MiR-145a-5p mediates adipocytes differentiation via regulating pathway related adipocytes differentiation. MiR-145a-5p mediating adipocytes differentiation was regulated by DNA methylation.« less

  13. 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 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 the...

  14. 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 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 the...

  15. 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 the...

  16. 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 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 the...

  17. 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... THE HEALTH SCIENCES § 242a.5 Procedure for announcing meetings. (a) Except to the extent such...

  18. 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... THE HEALTH SCIENCES § 242a.5 Procedure for announcing meetings. (a) Except to the extent such...

  19. 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... THE HEALTH SCIENCES § 242a.5 Procedure for announcing meetings. (a) Except to the extent such...

  20. 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... THE HEALTH SCIENCES § 242a.5 Procedure for announcing meetings. (a) Except to the extent such...

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

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 false Procedure for announcing meetings. 242a.5 Section 242a.5 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE... THE HEALTH SCIENCES § 242a.5 Procedure for announcing meetings. (a) Except to the extent such...

  2. 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, electrotin...

  3. 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, electrotin...

  4. 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, electrotin...

  5. 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, electrotin...

  6. 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 the...

  7. 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. [Reserved] 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. [Reserved] ...

  8. 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. [Reserved] 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. [Reserved] ...

  9. 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. [Reserved] 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. [Reserved] ...

  10. 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. [Reserved] 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. [Reserved] ...

  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. [Reserved] 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. [Reserved] ...

  12. 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 general...

  13. 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 and...

  14. CYP3A5 Genotype and Time to Reach Tacrolimus Therapeutic Levels in Renal Transplant Children.

    PubMed

    Alvarez-Elías, A C; García-Roca, P; Velásquez-Jones, L; Valverde, S; Varela-Fascinetto, G; Medeiros, M

    2016-03-01

    CYP3A5 gene polymorphism rs776746 has been associated with lower tacrolimus dose requirements and bioavailability in both adults and children. This variant causes a loss of CYP3A5 activity owing to a splice site variant leading to a truncated inactive enzyme. The aim of this study was to determine if the rs776746 gene polymorphism is related to the time to reach tacrolimus therapeutic levels in renal transplant children. A prospective study was performed in renal transplant children receiving tacrolimus as part of their immunosuppressive regime. CYP3A5 genotype was determined by direct sequencing. Tacrolimus trough levels and serum creatinine at 1 week and 1 month after renal transplantation was obtained from clinical chart. A total of 42 patients were included; 19 (45.2%) were female, 23 (54.8%) received living-donor transplants, and 21 patients expressed CYP3A5*1/*1 or CYP3A5*1/*3. Tacrolimus dose was higher in expressers at week 1 (0.13 vs 0.10 mg/kg/d; P = .011), and week 4 after transplantation (0.17 vs 0.09 mg/kg/d; P < .0001). At 4 weeks after renal transplantation, only 9 patients from the expressers group (42.8%) had levels ≥7 ng/mL, in contrast to 18 in the nonexpressers group (85.7%; Fisher exact P = .008). Tacrolimus dose was significant higher in functional CYP3A5 expressers. Only 42.8% of such expressers had tacrolimus trough levels ≥7 ng/mL at 1 month after transplantation despite dose adjustments. Long-term follow up is needed to address the consequences of early post-transplantation bioavailability differences due to CYP3A5 genotype. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. 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

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

    SciTech Connect

    Genetos, Damian C.; Wong, Alice; Weber, Thomas J.

    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-more » 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.« less

  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. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  18. 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 from...

  19. 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 PACKAGINGS...

  20. 15 CFR 4a.5 - Duration of classification.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 15 Commerce and Foreign Trade 1 2014-01-01 2014-01-01 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 from...

  1. 15 CFR 4a.5 - Duration of classification.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 15 Commerce and Foreign Trade 1 2011-01-01 2011-01-01 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 from...

  2. 15 CFR 4a.5 - Duration of classification.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 15 Commerce and Foreign Trade 1 2013-01-01 2013-01-01 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 from...

  3. 26 CFR 1.1402(a)-5 - Dividends and interest.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... (CONTINUED) INCOME TAXES Tax on Self-Employment Income § 1.1402(a)-5 Dividends and interest. (a) All..., interest with respect to which a credit against tax is allowable as provided in section 35, that is... 26 Internal Revenue 12 2010-04-01 2010-04-01 false Dividends and interest. 1.1402(a)-5 Section 1...

  4. 26 CFR 1.1402(a)-5 - Dividends and interest.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... (CONTINUED) INCOME TAXES (CONTINUED) Tax on Self-Employment Income § 1.1402(a)-5 Dividends and interest. (a... securities. However, interest with respect to which a credit against tax is allowable as provided in section... 26 Internal Revenue 12 2011-04-01 2011-04-01 false Dividends and interest. 1.1402(a)-5 Section 1...

  5. 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 GRANTS...

  6. 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 GRANTS...

  7. 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 service...

  8. 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 GRANTS...

  9. 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 GRANTS...

  10. 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 GRANTS...

  11. Gene Therapy

    PubMed Central

    Scheller, E.L.; Krebsbach, P.H.

    2009-01-01

    Gene therapy is defined as the treatment of disease by transfer of genetic material into cells. This review will explore methods available for gene transfer as well as current and potential applications for craniofacial regeneration, with emphasis on future development and design. Though non-viral gene delivery methods are limited by low gene transfer efficiency, they benefit from relative safety, low immunogenicity, ease of manufacture, and lack of DNA insert size limitation. In contrast, viral vectors are nature’s gene delivery machines that can be optimized to allow for tissue-specific targeting, site-specific chromosomal integration, and efficient long-term infection of dividing and non-dividing cells. In contrast to traditional replacement gene therapy, craniofacial regeneration seeks to use genetic vectors as supplemental building blocks for tissue growth and repair. Synergistic combination of viral gene therapy with craniofacial tissue engineering will significantly enhance our ability to repair and replace tissues in vivo. PMID:19641145

  12. A5-miseq: an updated pipeline to assemble microbial genomes from Illumina MiSeq data.

    PubMed

    Coil, David; Jospin, Guillaume; Darling, Aaron E

    2015-02-15

    Open-source bacterial genome assembly remains inaccessible to many biologists because of its complexity. Few software solutions exist that are capable of automating all steps in the process of de novo genome assembly from Illumina data. A5-miseq can produce high-quality microbial genome assemblies on a laptop computer without any parameter tuning. A5-miseq does this by automating the process of adapter trimming, quality filtering, error correction, contig and scaffold generation and detection of misassemblies. Unlike the original A5 pipeline, A5-miseq can use long reads from the Illumina MiSeq, use read pairing information during contig generation and includes several improvements to read trimming. Together, these changes result in substantially improved assemblies that recover a more complete set of reference genes than previous methods. A5-miseq is licensed under the GPL open-source license. Source code and precompiled binaries for Mac OS X 10.6+ and Linux 2.6.15+ are available from http://sourceforge.net/projects/ngopt aaron.darling@uts.edu.au Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  13. CYP3A5*3 and *6 single nucleotide polymorphisms in three distinct Asian populations.

    PubMed

    Balram, C; Zhou, Qingyu; Cheung, Yin Bun; Lee, Edmund J D

    2003-06-01

    To determine the frequencies of two functional single nucleotide polymorphisms, CYP3A5*3 and CYP3A5*6, in the CYP3A5 gene in three distinct Asian ethnic groups, namely, the Chinese, Malays and Indians. Single nucleotide polymorphism analyses of CYP3A5*1, *3 and *6 were performed in 296 healthy subjects (108 Chinese, 98 Malays and 90 Indians) using the polymerase chain reaction-restriction fragment length polymorphism method. The *1 allele frequency was 25% in Chinese compared with 40% in Malays and Indians ( P=0.001). The *3 allele frequency was also higher in the Chinese population, being 76% versus 60% in the Malays and Indians ( P=0.001). The Malays and Indians also had allele frequencies significantly different from Caucasian, Japanese and African-American populations (each PA5 in Asians, in particular Malays and Indians but also Chinese although to a lesser extent, may be an important genetic contributor to interindividual as well as interethnic differences in clearance of CYP3A substrates.

  14. Enhancement of A5/1 encryption algorithm

    NASA Astrophysics Data System (ADS)

    Thomas, Ria Elin; Chandhiny, G.; Sharma, Katyayani; Santhi, H.; Gayathri, P.

    2017-11-01

    Mobiles have become an integral part of today’s world. Various standards have been proposed for the mobile communication, one of them being GSM. With the rising increase of mobile-based crimes, it is necessary to improve the security of the information passed in the form of voice or data. GSM uses A5/1 for its encryption. It is known that various attacks have been implemented, exploiting the vulnerabilities present within the A5/1 algorithm. Thus, in this paper, we proceed to look at what these vulnerabilities are, and propose the enhanced A5/1 (E-A5/1) where, we try to improve the security provided by the A5/1 algorithm by XORing the key stream generated with a pseudo random number, without increasing the time complexity. We need to study what the vulnerabilities of the base algorithm (A5/1) is, and try to improve upon its security. This will help in the future releases of the A5 family of algorithms.

  15. 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 religious...

  16. 42 CFR 54a.5 - Religious character and independence.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 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 religious...

  17. 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 religious...

  18. 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 religious...

  19. 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 religious...

  20. 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

  1. Effect of polymorphic CYP3A5 genotype on the single-dose simvastatin pharmacokinetics in healthy subjects.

    PubMed

    Kim, Kyoung-Ah; Park, Pil-Whan; Lee, Ock-Je; Kang, Dong-Kyun; Park, Ji-Young

    2007-01-01

    Simvastatin, a cholesterol-lowering agent, is mainly metabolized by CYP3A4/5. The objective of this study was to investigate the effect of CYP3A5*3 genotype on the pharmacokinetics of simvastatin in humans. Twenty-two men with CYP3A5*1/*1 (n = 4), CYP3A5*1/*3 (n = 8), or CYP3A5*3/*3 (n = 10) genotypes were enrolled. Each subject ingested a 20-mg dose of simvastatin, and plasma simvastatin concentrations were measured for 12 hours after dosing. The mean (+/-SD) area under the plasma concentration-time curve for simvastatin in the CYP3A5*1/*1 carriers (4.94 +/- 2.25 ng x h/mL) was significantly lower than CYP3A5*3/*3 carriers (16.35 +/- 6.37 ng x h/mL; P = .013, Bonferroni test). The mean (+/-SD) oral clearance was also significantly different between CYP3A5*1/*1 carriers (4.80 +/- 2.35 L/h) and CYP3A5*3/*3 carriers (1.35 +/- 0.61 L/h; P < .05, Dunn's test). However, other pharmacokinetic parameters including peak plasma concentrations and half-life did not show any difference between genotype groups. These findings suggest that the polymorphic CYP3A5 gene affects the disposition of simvastatin and provides a plausible explanation for interindividual variability of simvastatin disposition.

  2. 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

    ... Engines V2500-A1, V2522-A5, V2524-A5, V2525-D5, V2527-A5, V2527E-A5, V2527M-A5, V2528-D5, V2530-A5, and V2533-A5 Turbofan Engines AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Notice of proposed... Aero Engines (IAE) V2500-A1, V2522-A5, V2524-A5, V2525-D5, V2527-A5, V2527E-A5, V2527M-A5, V2528-D5...

  3. Exosomal miR-21a-5p mediates cardioprotection by mesenchymal stem cells.

    PubMed

    Luther, Kristin M; Haar, Lauren; McGuinness, Myc; Wang, Yang; Lynch, Tom; Phan, Anh; Song, Yang; Shen, Zilong; Gardner, George; Kuffel, Gina; Ren, Xiaoping; Zilliox, Michael J; Keith Jones, W

    2018-04-23

    Though experimental, stem cell transplantation has the potential to improve the condition of the heart after myocardial infarction. It does so by reducing infarct size and inducing repair of heart muscle and its blood supply. Mesenchymal stem cells (MSC) have been found to be effective in pre-clinical animal models and clinical trials, but the mechanisms by which they induce cardioprotection and repair are still not fully understood. Small extracellular vesicles known as exosomes are now recognized to be key mediators of beneficial MSC paracrine effects, and the concept that they transfer miRNA to change gene expression in recipient cells is of current therapeutic interest. We present complete deep miRNA sequencing of MSC exosome cargo, and found that of several cardioprotective miRNAs, miR-21a-5p was the most abundant. Because miR-21a-5p is a well-known cardioprotective miRNA, we investigated the hypothesis that MSC exosomes can cardioprotect the heart by increasing the level of miR-21a-5p in recipient cardiac cells, thereby downregulating expression of the pro-apoptotic gene products PDCD4, PTEN, Peli1 and FasL in the myocardium. Using miR-21 mimic transfection and treatment with wild type and miR-21a knockout MSC exosomes, we confirmed that exosomal miR-21a-5p is transferred into myocardium and is a major cardioprotective paracrine factor produced by MSCs acting via synergistic activity on multiple pathways. The data supports that residual cardioprotective effect may be due to other ncRNA or protein cargo. In silico analyses support that MSC exosomes may also contribute to angiogenesis, cell proliferation and other aspects of cardiac repair. Copyright © 2018. Published by Elsevier Ltd.

  4. Nutrient Intake, Apolipoprotein A5 -1131T>C Polymorphism and Its Relationship with Obesity

    NASA Astrophysics Data System (ADS)

    Sari, M. I.; Sari, D. I.

    2017-03-01

    Obesity is associated with the development of some of the most prevalent diseases of modern society. The World Health Organization estimates that at least 2.8 million adult die each year as result of being obesity. Nutrient intake is a key environmental factor that may interact with genotype to affect risk of obesity. The aim of study was assess the relation between nutrient intake and apolipoprotein A5 -1131T>C polimorphism with obesity. A cross sectional study has been carried out on 139 subjects. Nutrient intake data was collected by using a 24 hour dietary recall and analyzed by nutrisurvey software. Anthropometric variables were measured and body mass index (BMI). Apolipoprotein A5 -1131T>C polymorphism was visualized with 5% agarose gel after restriction length fragment polymorphism (RFLP) digested with MseI. Results : Subjects in this study were 55 male and 84 female, with average age 19.20 ± 1.08, 75 had obese and 64 non obese. Based on the chi square test is found a relationship between total energy intake and protein intake in obese group compared to the non-obese group (p = 0.029, p = 0.006) and no relationship was found in Apolipoprotein A5 -1131T> C polymorphism with obesity. These findings indicate that nutrient intake no depending with apolipoprotein A5 gene variant to modulate obesity

  5. Trichoderma genes

    DOEpatents

    Foreman, Pamela [Los Altos, CA; Goedegebuur, Frits [Vlaardingen, NL; Van Solingen, Pieter [Naaldwijk, NL; Ward, Michael [San Francisco, CA

    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.

  6. 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

    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 mRNAsmore » 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.« less

  7. Ovarian remnant syndrome in a 5-year-old bitch

    PubMed Central

    2005-01-01

    Abstract A 5-year-old German shepherd bitch was presented with a 3-week history of vaginal bleeding. Ovarian remnant syndrome was diagnosed on vaginoscopy, vaginal cytology, serum progesterone levels, ultrasonography, and exploratory laparotomy. The condition resolved following surgical excision of the remaining ovarian tissue. PMID:15759831

  8. Ovarian remnant syndrome in a 5-year-old bitch.

    PubMed

    Sangster, Cheryl

    2005-01-01

    A 5-year-old German shepherd bitch was presented with a 3-week history of vaginal bleeding. Ovarian remnant syndrome was diagnosed on vaginoscopy, vaginal cytology, serum progesterone levels, ultrasonography, and exploratory laparotomy. The condition resolved following surgical excision of the remaining ovarian tissue.

  9. 12 CFR 261a.5 - Request for access to record.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 261a.5 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM RULES REGARDING ACCESS TO PERSONAL INFORMATION UNDER THE PRIVACY ACT OF 1974 Procedures for... Information Office, Board of Governors of the Federal Reserve System, 20th and Constitution Avenue NW...

  10. 12 CFR 261a.5 - Request for access to records.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 261a.5 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) RULES REGARDING ACCESS TO PERSONAL INFORMATION UNDER THE PRIVACY ACT 1974 Procedures... information contained in a system of records maintained by the Board's OIG, you may submit the request in...

  11. 12 CFR 261a.5 - Request for access to records.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 261a.5 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) RULES REGARDING ACCESS TO PERSONAL INFORMATION UNDER THE PRIVACY ACT 1974 Procedures... information contained in a system of records maintained by the Board's OIG, you may submit the request in...

  12. 12 CFR 261a.5 - Request for access to records.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 261a.5 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) RULES REGARDING ACCESS TO PERSONAL INFORMATION UNDER THE PRIVACY ACT 1974 Procedures... information contained in a system of records maintained by the Board's OIG, you may submit the request in...

  13. 12 CFR 261a.5 - Request for access to records.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 261a.5 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM RULES REGARDING ACCESS TO PERSONAL INFORMATION UNDER THE PRIVACY ACT 1974 Procedures for Requests... information contained in a system of records maintained by the Board's OIG, you may submit the request in...

  14. MiR-10a-5p targets TFAP2C to promote gemcitabine resistance in pancreatic ductal adenocarcinoma.

    PubMed

    Xiong, Guangbing; Huang, Hua; Feng, Mengyu; Yang, Gang; Zheng, Suli; You, Lei; Zheng, Lianfang; Hu, Ya; Zhang, Taiping; Zhao, Yupei

    2018-04-03

    By regulating target genes, microRNAs play essential roles in carcinogenesis and drug resistance in human pancreatic ductal adenocarcinoma (PDAC). Previous studies have shown that microRNA-10a-5p (miR-10a-5p) is overexpressed in PDAC and acts as an oncogene to promote the metastatic behavior of PDAC cells. However, the role of miR-10a-5p in PDAC chemoresistance remains unclear. The effects of miR-10a-5p on biological behaviors were analyzed. MiR-10a-5p and TFAP2C levels in tissues were detected, and the clinical value was evaluated. We found that miR-10a-5p is up-regulated in gemcitabine-resistant PDAC cells and enhances PDAC cell gemcitabine resistance in vitro and vivo. Meanwhile, we also determined that miR-10a-5p promotes the migratory and invasive ability of PDAC cells. Next, we confirmed that transcription factor activating protein 2 gamma (TFAP2C) is a target of miR-10a-5p, and TFAP2C overexpression resensitizes PDAC cells to gemcitabine, which is initiated by miR-10a-5p. Further studies revealed that TFAP2C also decreased PDAC cell migration and invasion capability. Finally, survival analysis demonstrated that high miR-10a-5p expression levels and low TFAP2C expression levels were both independent adverse prognostic factors in patients with PDAC. Together, these results indicate that miR-10a-5p/TFAP2C may be new therapeutic target and prognostic marker in PDAC.

  15. A 5MV Tandetron to Universidad Autonoma de Madrid

    SciTech Connect

    Tengblad, Olof

    1999-11-16

    A 5MV Tandetron accelerator is being projected for the Center of Material Analysis of the Universidad Autonoma de Madrid. The accelerator will be dedicated to Material Science but it meant to be open to all fields of science and industry that can profit from this kind of installations. Estimated construction time and delivery of the accelerator implies that the first experiments can be performed in the spring 2001.

  16. GeneEd -- A Genetics Educational Resource

    MedlinePlus

    ... on. Feature: Genetics 101 GeneEd — A Genetics Educational Resource Past Issues / Summer 2013 Table of Contents Science ... in 2012. GeneEd is a safe and useful resource for students and teachers in grades 9-12 ...

  17. Association between CYP3A5 genotypes with hypertension in Chinese Han population: A case-control study.

    PubMed

    Li, Zhanzhan; Chen, Peng; Zhou, Tao; Chen, Xiaofang; Chen, Lizhang

    2017-01-01

    The association of CYP3A5 gene polymorphisms with hypertension in the Chinese population is unknown. We explored the association between the CYP3A5 (rs776746) gene and hypertension in the Chinese Han population. Using a case-control design, 340 cases and 254 controls were enrolled from the Third Affiliated Hospital of South Medical University between July and December of 2015. We used a standardized questionnaire to collect data regarding age, sex, smoking, drinking, family history of hypertension, and physical exercise. Height and weight were measured, and the body mass index (BMI) was calculated by weight/height 2 . Blood pressure was measured three times after 5 min of rest with at least 15 s between measurements, and the mean was considered the final BP. A Clinical examination was conducted. A total of 594 participants, including 340 cases and 254 controls, were entered into the analyses. The genotype frequencies of the CYP3A5 G>A polymorphism did not deviate from the Hardy-Weinberg equilibrium. The genotype frequencies among the cases were 38.8% (GA, 132 individuals), 42.9% (GG, 146 individuals), and 18.2% (AA, 62 individuals). The differences in genotype between the cases and the controls were statistically significant. The AA genotype was associated with an elevated risk of hypertension after adjusting for potential confounders in Model 2. There was no interaction between smoking and the CYP3A5 genotype, while the interaction between drinking and the CYP3A5 genotype was significant. The CYP3A5 gene may be associated with the risk of hypertension in the Chinese Han population, and this effect may be exacerbated by drinking.

  18. Novel Streptomycin and Spectinomycin Resistance Gene as a Gene Cassette within a Class 1 Integron Isolated from Escherichia coli

    PubMed Central

    Sandvang, Dorthe

    1999-01-01

    The aadA genes, encoding resistance to streptomycin and spectinomycin, have been found as gene cassettes in different gram-negative and gram-positive bacterial species. The present study has revealed the sequence of a new gene, aadA5, integrated as a gene cassette together with the trimethoprim resistance gene dfr7 in a class 1 integron. The integron was located on a plasmid and was identified in a pathogenic porcine Escherichia coli isolate. PMID:10582907

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

    SciTech Connect

    Yuan, Jian; Xiao, Gelei; The Institute of Skull Base Surgery & Neuro-oncology at Hunan, Changsha, Hunan 410008

    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, includingmore » 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.« less

  20. 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.

  1. MiR-20a-5p promotes radio-resistance by targeting Rab27B in nasopharyngeal cancer cells.

    PubMed

    Huang, Dabing; Bian, Geng; Pan, Yueyin; Han, Xinghua; Sun, Yubei; Wang, Yong; Shen, Guodong; Cheng, Min; Fang, Xiang; Hu, Shilian

    2017-01-01

    MicroRNAs (miRNAs) was reported to be involved in cancer radio-resistance, which remains a major obstacle for effective cancer therapy. The differently expressed miRNAs were detected by RNA-seq experiment in nasopharyngeal cancer (NPC) cells. MiR-20a-5p was selected as our target, which was subject to finding its target gene Rab27B via bioinformatics analysis. The qRT-PCR, western blot and the luciferase reporter assays were performed to confirm Rab27B as the target of miR-20a-5p. In addition, the roles of miR-20a-5p in NPC radio-resistance were detected by transfection of either miR-20a-5p-mimic or miR-20a-5p-antagomiR. The involvement of Rab27B with NPC radio-resistance was also detected by the experiments with siRNA-mediated repression of Rab27B or over-expression of GFP-Rab27B. Wound healing and invasion assays were performed to detect the roles of both miR-20a-5p and Rab27B. MiR-20a-5p promotes NPC radio-resistance. We identified that its target gene Rab27B negatively correlates with miR-20a-5p-mediated NPC radio-resistance by systematic studies of a radio-sensitive (CNE-2) and resistant (CNE-1) NPC cell lines. Repression of Rab27B by siRNA suppresses cell apoptosis and passivates CNE-2 cells, whereas over-expression of Rab27B triggered cell apoptosis and sensitizes CNE-1 cells. MiR-20a-5p and its target gene Rab27B might be involved in the NPC radio-resistance. Thus the key players and regulators involved in this pathway might be the potential targets for developing effective therapeutic strategies against NPC.

  2. miR-200a-5p regulates myocardial necroptosis induced by Se deficiency via targeting RNF11.

    PubMed

    Yang, Tianshu; Cao, Changyu; Yang, Jie; Liu, Tianqi; Lei, Xin Gen; Zhang, Ziwei; Xu, Shiwen

    2018-05-01

    Necroptosis has been discovered as a new paradigm of cell death and may play a key role in heart disease and selenium (Se) deficiency. Hence, we detected the specific microRNA (miRNA) in response to Se-deficient heart using microRNAome analysis. For high-throughput sequencing using Se-deficient chicken cardiac tissue, we selected miR-200a-5p and its target gene ring finger protein 11 (RNF11) based on differential expression in cardiac tissue and confirmed the relationship between miR-200a-5p and RNF11 by dual luciferase reporter assay and real-time quantitative PCR (qRT-PCR) in cardiomyocytes. We further explored the function of miR-200a-5p and observed that overexpression of miR-200a-5p spark the receptor interacting serine/threonine kinase 3 (RIP3)-dependent necroptosis in vivo and in vitro. To understand whether miR-200a-5p and RNF11 are involved in the RIP3-dependent necroptosis pathway, we presumed that oxidative stress, inflammation response and the mitogen-activated protein kinase (MAPK) pathway might trigger necroptosis. Interestingly, necroptosis trigger, z-VAD-fmk, failed to induce necroptosis but enhanced cell survival against necrosis in cardiomyocytes with knockdown of miR-200a-5p. Our present study provides a new insight that the modulation of miR-200a-5p and its target gene might block necroptosis in the heart, revealing a novel myocardial necrosis regulation model in heart disease. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  3. [Non-compaction cardiomyopathy in a 5-generation Chinese family].

    PubMed

    Ding, Zhong-ru; Huang, Guo-ming; Wang, Hong-ru; Tu, Xiao-wen; Liu, Chuan-yin

    2012-04-01

    Familial left ventricular noncompaction(LVNC) is quite rare. We screened for the presence of LVNC and related clinical characteristics in a 5-generation Chinese family. Comprehensive medical history was obtained from 40 members in a 5-generation Chinese family. Systemic clinical investigations including echocardiography (UCG), routine and ambulatory electrocardiogram (ECG), X-rays were performed in 33 family members. Cardiovascular magnetic resonance image (MRI) was carried out in 2 family members. Sudden cardiac death (including 1 occurred while following-up) was reported in 7 family members (17.5%, 7/40). LVNC was diagnosed in 10 out of the 33 family members (30.3%) and heart enlargement was evidenced in 3, heart failure in 2, complete left branch conductive block in 3, serious sick sinus syndrome (SSS) treated with permanent pacemaker implantation in 1 and paroxysmal supraventricular tachycardia treated with radiofrequency ablation procedure in 1 out of these 10 LVNC patients. Primary pedigree analysis revealed that offspring from female patients were at the highest risk to be affected by LVNC (15/18, 83.3%) while LVNC was absent in offspring of male LVNC patients (0/8). Moreover, clinical heart failure symptoms and arrhythmias were more severe in female LVNC patients than in male LVNC patients. Primary familial investigation reveals the matrilineal inheritance of familial LVNC in this 5-generation Chinese family, further investigations are warranted to explore the potential mutations in the mitochondrial genome responsible for LVNC in this family.

  4. 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…

  5. miR-26a-5p Regulates TNRC6A Expression and Facilitates Theca Cell Proliferation in Chicken Ovarian Follicles.

    PubMed

    Kang, Li; Yang, Chunhong; Wu, Haizhen; Chen, Qiuyue; Huang, Libo; Li, Xianyao; Tang, Hui; Jiang, Yunliang

    2017-11-01

    Ovarian theca cells play an indispensable role in ovarian follicular development and hormone secretion. miR-26a-5p was reported to be differentially expressed in mature and immature chicken ovaries in our previous study; however, the role of miR-26a-5p in regulating ovarian follicle function is still unclear. In this study, we demonstrated that the expression dynamics of TNRC6A mRNA in either chicken ovaries or follicles showed an opposite trend compared with that of chicken miR-26a-5p expression. miR-26a-5p inhibited TNRC6A mRNA expression by directly targeting its 3'-untranslated region in cultured chicken theca cells. Overexpression of miR-26a-5p promoted chicken follicular theca cell proliferation in vitro. Furthermore, overexpression of miR-26a-5p and knockdown of TNRC6A significantly upregulated the antiapoptotic BCL-2 gene. Taken together, this study revealed the expression dynamics of miR-26a-5p and TNRC6A in chicken ovaries and ovarian follicles and the relationship between the expression of miR-26a-5p and TNRC6A in chicken ovarian theca cells. These results suggest that miR-26a-5p facilitates chicken ovarian theca cell proliferation by targeting the TNRC6A gene.

  6. Molecular typing of Treponema pallidum: a 5-year surveillance in Shanghai, China.

    PubMed

    Dai, Ting; Li, Kang; Lu, Haikong; Gu, Xin; Wang, Qianqiu; Zhou, Pingyu

    2012-11-01

    Previously, a small study showed that 14f was the predominant subtype of Treponema pallidum in Shanghai, China. The result was quite different from the genotype distribution in other areas of China. This study aimed to identify the strain types of Treponema pallidum in samples collected over a 5-year period in Shanghai. From 2007 to 2011, genital swabs were collected from patients with syphilis from the Shanghai Skin Disease Hospital. Positive specimens were typed by the enhanced typing method by adding a tp0548 gene to the existing arp and tpr genotype system. In total, 304 of the 372 enrolled patients yielded fully typeable DNA. Ten arp types (4, 6, 8, 9, 11, 12, 13, 14, 15, and 19), 3 tpr types (a, d, and o), and 5 tp0548 types (a, c, f, g, and i) were identified. In total, 12 subtypes were identified with a combination of the arp and tpr genes. Subtype 14d was found in 270 samples (88.8%). When the combination included the tp0548 gene, the 12 CDC subtypes identified were divided into 14 strain types. The predominant type was 14d/f (88.8%), followed by 15d/f (3.6%), 13d/f (1.3%), and 19d/c (1.3%). Two of the 44 14d/f-infected patients and both of the 19d/c-infected patients who underwent a lumbar puncture were diagnosed with neurosyphilis. This study showed that the predominant type in Shanghai was 14d/f. While this is in keeping with data from other areas in China, it is different from an earlier report showing that 14f is the most common genotype in Shanghai. Further studies are needed to better understand the association between strain types and neurosyphilis.

  7. Novel DREB A-5 subgroup transcription factors from desert moss (Syntrichia caninervis) confers multiple abiotic stress tolerance to yeast.

    PubMed

    Li, Haiyan; Zhang, Daoyuan; Li, Xiaoshuang; Guan, Kaiyun; Yang, Honglan

    2016-05-01

    Syntrichia caninervis Mitt. is a typical desiccation tolerant moss from a temperate desert which has been a good resource for stress tolerant gene isolation. Dehydration responsive element binding proteins (DREBs) was proven to play an important role in responding to abiotic stress, which has been identified in many plants, and were rarely reported in moss. In this study, we cloned ten DREB genes from S. caninervis, and investigated their abiotic stress response and stress tolerance. The results showed that ten ScDREB proteins belonged to the A-5 sub-group of the DREB sub-family. Six genes, ScDREB1, ScDREB2, ScDREB4, ScDREB6, ScDREB7, and ScDREB8 were involved in the ABA-dependent signal pathway and the desiccation, salt, and cold stress response. ScDREB3 also responded to desiccation, salt, and cold stresses, but was insensitive to ABA treatment. Another gene, ScDREB5, was involved in an ABA-independent cold stress-responsive signal pathway. Two genes, ScDREB9 and ScDREB10, responded slightly or had no response to neither stress factor or ABA treatment. We transformed four typical genes into yeast cells and the stress tolerance ability of transgenic yeast was evaluated. The results showed that ScDREB3 and ScDREB5 enhanced the yeast's cold and salt tolerance. ScDREB8 and ScDREB10 conferred the osmotic, salt, cold, and high temperature stresses tolerance, especially for osmotic and salt stresses. Our results indicated that A-5 sub-group DREB genes in S. caninervis played important roles in abiotic stresses response and enhanced stress tolerance to transgenic yeast. To our knowledge, this is the first report on DREB genes characterization from desiccation tolerant moss, and this study will not only provide insight into the molecular mechanisms of S. caninervis adaptation to environmental stresses, but also provides valuable gene candidates for plant molecular breeding. Copyright © 2016 Elsevier GmbH. All rights reserved.

  8. 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

  9. Mandatory influenza vaccination of healthcare workers: a 5-year study.

    PubMed

    Rakita, Robert M; Hagar, Beverly A; Crome, Patricia; Lammert, Joyce K

    2010-09-01

    The rate of influenza vaccination among healthcare workers (HCWs) is low, despite a good rationale and strong recommendations for vaccination from many health organizations. To increase influenza vaccination rates by instituting the first mandatory influenza vaccination program for HCWs. A 5-year study (from 2005 to 2010) at Virginia Mason Medical Center, a tertiary care, multispecialty medical center in Seattle, Washington, with approximately 5,000 employees. All HCWs of the medical center were required to receive influenza vaccination. HCWs who were granted an accommodation for medical or religious reasons were required to wear a mask at work during influenza season. The main outcome measure was rate of influenza vaccination among HCWs. In the first year of the program, there were a total of 4,703 HCWs, of whom 4,588 (97.6%) were vaccinated, and influenza vaccination rates of more than 98% were sustained over the subsequent 4 years of our study. Less than 0.7% of HCWs were granted an accommodation for medical or religious reasons and were required to wear a mask at work during influenza season, and less than 0.2% of HCWs refused vaccination and left Virginia Mason Medical Center. A mandatory influenza vaccination program for HCWs is feasible, results in extremely high vaccination rates, and can be sustained over the course of several years.

  10. X-Linked Glomerulopathy Due to COL4A5 Founder Variant.

    PubMed

    Barua, Moumita; John, Rohan; Stella, Lorenzo; Li, Weili; Roslin, Nicole M; Sharif, Bedra; Hack, Saidah; Lajoie-Starkell, Ginette; Schwaderer, Andrew L; Becknell, Brian; Wuttke, Matthias; Köttgen, Anna; Cattran, Daniel; Paterson, Andrew D; Pei, York

    2018-03-01

    Alport syndrome is a rare hereditary disorder caused by rare variants in 1 of 3 genes encoding for type IV collagen. Rare variants in COL4A5 on chromosome Xq22 cause X-linked Alport syndrome, which accounts for ∼80% of the cases. Alport syndrome has a variable clinical presentation, including progressive kidney failure, hearing loss, and ocular defects. Exome sequencing performed in 2 affected related males with an undefined X-linked glomerulopathy characterized by global and segmental glomerulosclerosis, mesangial hypercellularity, and vague basement membrane immune complex deposition revealed a COL4A5 sequence variant, a substitution of a thymine by a guanine at nucleotide 665 (c.T665G; rs281874761) of the coding DNA predicted to lead to a cysteine to phenylalanine substitution at amino acid 222, which was not seen in databases cataloguing natural human genetic variation, including dbSNP138, 1000 Genomes Project release version 01-11-2004, Exome Sequencing Project 21-06-2014, or ExAC 01-11-2014. Review of the literature identified 2 additional families with the same COL4A5 variant leading to similar atypical histopathologic features, suggesting a unique pathologic mechanism initiated by this specific rare variant. Homology modeling suggests that the substitution alters the structural and dynamic properties of the type IV collagen trimer. Genetic analysis comparing members of the 3 families indicated a distant relationship with a shared haplotype, implying a founder effect. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  11. Impact of cytochrome p450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients.

    PubMed

    Thervet, Eric; Anglicheau, Dany; King, Barry; Schlageter, Marie-Hélène; Cassinat, Bruno; Beaune, Philippe; Legendre, Christophe; Daly, Ann K

    2003-10-27

    Tacrolimus pharmacokinetic characteristics vary greatly among individuals. Tacrolimus is a substrate of cytochrome p450 (CYP), of subfamily CYP3A. CYP3A activity is the sum of the activities of the family of CYP3A genes, including CYP3A5. Subjects with the CYP3A5*1/*1 genotype express large amounts of CYP3A5. Heterozygotes (genotype CYP3A5*1/*3) also express the enzyme. We postulated that CYP3A5 polymorphism is associated with tacrolimus pharmacokinetic variations. CYP3A5 genotype was evaluated in 80 renal transplant recipients and correlated with the daily tacrolimus dose and concentration-to-dose ratio. The frequency of the homozygous CYP3A5*1 genotype (CYP3A5*1/*1) was 5%, and 11% of subjects were heterozygous (CYP3A5*1/*3). The mean doses required to obtain the targeted concentration-to-dose ratio were significantly lower in patients with the CYP3A5*1/*1 genotype. Determination of CYP3A5 genotype is predictive of the dose of tacrolimus in renal transplant recipients and may help to determine the initial daily dose needed by individual patients for adequate immunosuppression without excess nephrotoxicity.

  12. A5-Positive Primary Sensory Neurons Are Nonpermissive for Productive Infection with Herpes Simplex Virus 1 In Vitro▿

    PubMed Central

    Bertke, Andrea S.; Swanson, Sophia M.; Chen, Jenny; Imai, Yumi; Kinchington, Paul R.; Margolis, Todd P.

    2011-01-01

    Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) establish latency and express the latency-associated transcript (LAT) preferentially in different murine sensory neuron populations, with most HSV-1 LAT expression in A5+ neurons and most HSV-2 LAT expression in KH10+ neurons. To study the mechanisms regulating the establishment of HSV latency in specific subtypes of neurons, cultured dissociated adult murine trigeminal ganglion (TG) neurons were assessed for relative permissiveness for productive infection. In contrast to that for neonatal TG, the relative distribution of A5+ and KH10+ neurons in cultured adult TG was similar to that seen in vivo. Productive infection with HSV was restricted, and only 45% of cultured neurons could be productively infected with either HSV-1 or HSV-2. A5+ neurons supported productive infection with HSV-2 but were selectively nonpermissive for productive infection with HSV-1, a phenomenon that was not due to restricted viral entry or DNA uncoating, since HSV-1 expressing β-galactosidase under the control of the neurofilament promoter was detected in ∼90% of cultured neurons, with no preference for any neuronal subtype. Infection with HSV-1 reporter viruses expressing enhanced green fluorescent protein (EGFP) from immediate early (IE), early, and late gene promoters indicated that the block to productive infection occurred before IE gene expression. Trichostatin A treatment of quiescently infected neurons induced productive infection preferentially from non-A5+ neurons, demonstrating that the nonpermissive neuronal subtype is also nonpermissive for reactivation. Thus, HSV-1 is capable of entering the majority of sensory neurons in vitro; productive infection occurs within a subset of these neurons; and this differential distribution of productive infection is determined at or before the expression of the viral IE genes. PMID:21507969

  13. Long non-coding RNA XIST exerts oncogenic functions in pancreatic cancer via miR-34a-5p.

    PubMed

    Sun, Zhixia; Zhang, Baogang; Cui, Tingting

    2018-04-01

    Long non-coding RNAs (lncRNAs) have been implicated in the occurrence and progression of multiple cancers. In the present study, we investigated the role of lncRNA X inactive-specific transcript (XIST) in the development and progression of pancreatic cancer (PC). Firstly, we found that lncRNA XIST was markedly upregulated in PC tissues and PC cell lines, respectively. Overexpression of XIST significantly promoted the proliferation, migration and invasion, and suppressed cell apoptosis of BxPC-3 cells; knockdown of XIST significantly inhibited the proliferation, migration and invasion, and accelerated cell apoptosis of PANC-1 cells. Furthermore, BxPC-3 and PANC-1 cells transfected with different vectors were injected subcutaneously into nude mice to explore tumor formation. We found that XIST promoted tumor formation in vivo. Subsequently, we found that microRNA-34a-5p (miR‑34a-5p) was downregulated in PC tissues, and predicted a poor prognosis in PC patients. In addition, the results indicated that miR-34a-5p is a target gene of XIST and was significantly negatively correlated with XIST. More importantly, we found that miR-34a-5p rescued the facilitation of malignant behavior mediated by XIST. These results indicated that XIST and miR-34a-5p may be potential effective therapeutic targets for PC.

  14. A 5-cm dipole for the SSC-DE-1

    SciTech Connect

    Caspi, S.

    1990-04-30

    A 5cm SSC superconducting dipole that develops 6.6 tesla at 5790 A is proposed. The two layer magnet has 12% more transfer function than the present design as a result of using thin collars and close in'' iron. The thin collars provide precise positioning of the coils; they also provide minimum prestress (perhaps 2000 psi) as aid for magnet assembly. A welded skin around the iron provides the final prestress and shapes and the coil geometry. A prestressed aluminum bar placed between the vertically split iron yokes provides precise control of the gap between yokes halves and is designed tomore » allow gap to close tightly during cooldown so that there is no decrease of prestress. In order to reduce the effect of iron saturation on the field multipoles the iron ID has been optimized to an elliptical shape. The coil inner layer is a 30 strand cable with 1.3:1 cu/sc. The outer layer is a 36 strand cable wit 1.8:1 cu/sc. At the operating field of 6.6 tesla the current density in the copper is 666 A/mm{sup 2} and 760 A/mm{sup 2} in the inner and outer layers respectively. The magnet short sample performance is limited by the inner layer. Operating at 4.35 K the maximum current and central field are 6896 A and 7.95 tesla. The calculated operating short sample temperature at 6.6 tesla and 5798 A is 5.17 K (0.82 K temperature margin). The magnet stored energy is 100.0 (KJ/m) at the 5790 A operating current. A mechanically similar 5cm bore two layer dipole for the cable test facility (D-16B-1) has been recently built and tested. The magnet had no collars and the iron was placed directly on the coil OD. The magnet's first quench was at 7 tesla with 6000 A and it reached 7.6 tesla at 6600 A. This paper contains tables and figures associated with the design.« less

  15. 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

  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. Rare genetic variants with large effect on triglycerides in subjects with a clinical diagnosis of familial vs nonfamilial hypertriglyceridemia.

    PubMed

    De Castro-Orós, Isabel; Civeira, Fernando; Pueyo, María Jesús; Mateo-Gallego, Rocío; Bolado-Carrancio, Alfonso; Lamíquiz-Moneo, Itziar; Álvarez-Sala, Luis; Fabiani, Fernando; Cofán, Montserrat; Cenarro, Ana; Rodríguez-Rey, José Carlos; Ros, Emilio; Pocoví, Miguel

    2016-01-01

    Most primary severe hypertriglyceridemias (HTGs) are diagnosed in adults, but their molecular foundations have not been completely elucidated. We aimed to identify rare dysfunctional mutations in genes encoding regulators of lipoprotein lipase (LPL) function in patients with familial and non-familial primary HTG. We sequenced promoters, exons, and exon-intron boundaries of LPL, APOA5, LMF1, and GPIHBP1 in 118 patients with severe primary HTG (triglycerides >500 mg/dL) and 53 normolipidemic controls. Variant functionality was analyzed using predictive software and functional assays for mutations in regulatory regions. We identified 29 rare variants, 10 of which had not been previously described: c.(-16A>G), c.(1018+2G>A), and p.(His80Arg) in LPL; p.(Arg143Alafs*57) in APOA5; p.(Val140Ile), p.(Leu235Ile), p.(Lys520*), and p.(Leu552Arg) in LMF1; and c.(-83G>A) and c.(-192A>G) in GPIHBP1. The c.(1018+2G>A) variant led to deletion of exon 6 in LPL cDNA, whereas the c.(-16A>G) analysis showed differences in the affinity for nuclear proteins. Overall, 20 (17.0%) of the patients carried at least one allele with a rare pathogenic variant in LPL, APOA5, LMF1, or GPIHBP1. The presence of a rare pathogenic variant was not associated with lipid values, family history of HTG, clinical diagnosis, or previous pancreatitis. Less than one in five subjects with triglycerides >500 mg/dL and no major secondary cause for HTG may carry a rare pathogenic mutation in LPL, APOA5, LMF1, or GPIHBP1. The presence of a rare pathogenic variant is not associated with a differential phenotype. Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.

  18. A 5'-regulatory region and two coding region polymorphisms modulate promoter activity and gene expression of the growth suppressor gene ZBED6 in cattle

    USDA-ARS?s Scientific Manuscript database

    Zinc finger, BED-type containing 6 (ZBED6) is an important transcription factor in placental mammals, affecting development, cell proliferation, and growth. Polymorphisms in its promoter and coding regions are likely to impact ZBED6 transcription and growth traits. In this study, a total of three no...

  19. 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

    ... could result in an uncontained failure of the high-pressure (HP) compressor stage 3-8 drum and... cracks, and replacing the reducer and HP compressor stage 3-8 drum if the reducer is cracked. Examining..., V2527M-A5, V2528-D5, V2530-A5, and V2533-A5 turbofan engines with high-pressure (HP) compressor stage 3-8...

  20. Inhibition of MiR-199a-5p reduced cell proliferation in autosomal dominant polycystic kidney disease through targeting CDKN1C.

    PubMed

    Sun, Lijun; Zhu, Jiaqi; Wu, Ming; Sun, Haipeng; Zhou, Chenchen; Fu, Lili; Xu, Chenggang; Mei, Changlin

    2015-01-15

    With a prevalence of about 1:500 to 1:1,000, autosomal dominant polycystic kidney disease (ADPKD) often causes renal failure, with many serious complications. However, there is no Food and Drug Administration (FDA) approved therapy available. MiR-199a-5p level in ADPKD patient samples, rat model, and cell lines were determined with Realtime PCR assay. After miR-199a-5p inhibitor was transfected, we detected the cell proliferation and apoptosis using an MTT assay and an Annexin V-FITC staining kit, respectively. Finally, TargetScan version 5.1 was used to predict the miRNA target and the target gene of miR-199a-5p was proved by a Luciferase assay. We identified a dramatically up-regulated microRNA, miR-199a-5p, in ADPKD tissues and cell lines. Our data show that inhibition of miR-199a-5p suppressed cyst cells proliferation and induced cell apoptosis. We found that miR-199a-5p might exert this effect through targeting CDKN1C/p57. Up-regulation of miR-199a-5p in ADPKD tissues might promote cell proliferation through suppressing CDKN1C, suggesting miR-199a-5p as a novel target for ADPKD treatment.

  1. Induction of apoptosis in nasal polyp-derived fibroblasts by bleomycin A5 in vitro.

    PubMed

    Wu, Fan; Tian, Peng; Ma, Yun; Wang, Jingyi; Ou, Huashuang; Zou, Hua

    2018-04-01

    The present study aimed to evaluate the pro-apoptotic effects of bleomycin A5 on nasal polyp‑derived fibroblasts (NPDFs) and the underlying molecular mechanisms. Nasal polyp tissue was acquired from 10 patients during surgery and NPDFs were isolated from surgical tissues. Fibroblasts were identified using immunohistochemistry. Bleomycin A5 was used to treat NPDFs along a concentration gradient. Cell viability was evaluated using a Cell Counting Kit‑8 assay. A flow cytometric Annexin V‑fluorescein isothiocyanate/propidium iodide assay was used to determine the percentage of apoptotic NPDFs. The mRNA expression levels of apoptotic genes were determined by reverse transcription‑quantitative polymerase chain reaction and levels of proteins associated with apoptosis were determined by western blotting. The results indicated that bleomycin A5 was able to induce apoptosis in NPDFs in a dose‑dependent manner. NPDFs treated with bleomycin A5 were identified to contain significantly high amounts of the active forms of caspase‑3 and showed considerable cleavage of poly(ADP‑ribose) polymerase. The mRNA and protein expression levels of the pro‑apoptotic molecule Bcl‑2‑associated X protein were significantly higher in treated NPDFs than in untreated NPDFs. In contrast, the mRNA and protein expression of the anti‑apoptotic molecule B‑cell lymphoma 2 (Bcl‑2) was significantly lower in treated NPDFs. These results indicated that bleomycin A5 could induce apoptosis in primary NPDFs through activation of the Bcl‑2 family and caspase cascades in a time-, and concentration-dependent manner.

  2. 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

  3. Gene cluster statistics with gene families.

    PubMed

    Raghupathy, Narayanan; Durand, Dannie

    2009-05-01

    Identifying genomic regions that descended from a common ancestor is important for understanding the function and evolution of genomes. In distantly related genomes, clusters of homologous gene pairs are evidence of candidate homologous regions. Demonstrating the statistical significance of such "gene clusters" is an essential component of comparative genomic analyses. However, currently there are no practical statistical tests for gene clusters that model the influence of the number of homologs in each gene family on cluster significance. In this work, we demonstrate empirically that failure to incorporate gene family size in gene cluster statistics results in overestimation of significance, leading to incorrect conclusions. We further present novel analytical methods for estimating gene cluster significance that take gene family size into account. Our methods do not require complete genome data and are suitable for testing individual clusters found in local regions, such as contigs in an unfinished assembly. We consider pairs of regions drawn from the same genome (paralogous clusters), as well as regions drawn from two different genomes (orthologous clusters). Determining cluster significance under general models of gene family size is computationally intractable. By assuming that all gene families are of equal size, we obtain analytical expressions that allow fast approximation of cluster probabilities. We evaluate the accuracy of this approximation by comparing the resulting gene cluster probabilities with cluster probabilities obtained by simulating a realistic, power-law distributed model of gene family size, with parameters inferred from genomic data. Surprisingly, despite the simplicity of the underlying assumption, our method accurately approximates the true cluster probabilities. It slightly overestimates these probabilities, yielding a conservative test. We present additional simulation results indicating the best choice of parameter values for data

  4. Compare Gene Calls

    SciTech Connect

    Ecale Zhou, Carol L.

    2016-07-05

    Compare Gene Calls (CGC) is a Python code used for combining and comparing gene calls from any number of gene callers. A gene caller is a computer program that predicts the extends of open reading frames within genomes of biological organisms.

  5. 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…

  6. Polymorphism in transmembrane region of MICA gene and cholelithiasis

    PubMed Central

    Shih, Shou-Chuan; Lee, Yann-Jinn; Liu, Hsin-Fu; Dang, Ching-Wen; Chang, Shih-Chuan; Lin, Shee-Chan; Kao, Chin-Roa

    2003-01-01

    AIM: To study the significance of polymorphism of MHC class I chain-related gene A (MICA) gene in patients with cholelithiasis. METHODS: Subjects included 170 unrelated adults (83 males) with cholelithiasis and 245 randomly selected unrelated adults (130 males) as controls. DNA was extracted from peripheral leukocytes and analyzed for polymorphism of 5 alleles (A4, A5, A5.1, A6 and A9) of the MICA gene. RESULTS: There was no significant difference in phenotype, allele, and genotype frequencies of any of the 5 alleles between cholelithiasis patients and controls. CONCLUSION: This study demonstrates that MICA alleles studied bear no relation to cholelithiasis. PMID:12854159

  7. The functional implications of common genetic variation in CYP3A5 and ABCB1 in human proximal tubule cells.

    PubMed

    Knops, Noël; van den Heuvel, Lambertus P; Masereeuw, Rosalinde; Bongaers, Inge; de Loor, Henriëtte; Levtchenko, Elena; Kuypers, Dirk

    2015-03-02

    Calcineurin inhibitors (CNIs) are the primary immunosuppressive drugs used in solid organ transplantation but are associated with the development of histological lesions leading to kidney failure. CNIs are metabolized by CYP3A and excreted by not only P-glycoprotein (P-gp) (ABCB1) in the gut and liver, but also by proximal tubule cells (PTCs) in the kidney. Multiple studies have demonstrated the importance of genetic variation in CYP3A5 and ABCB1 for CNI disposition and nephrotoxicity. The present study was designed to study the functional implication of variation in these two genes in human PTCs. A technique was developed to culture cells from renal tissue obtained from renal graft recipients by routine kidney biopsy. Primary cells were immortalized, subcloned, and then characterized for specific PTC markers (AQP1, CD13, brush border morphology) and donor CYP3A5(rs776746)/ABCB1(rs1045642) genotype. We then selected specific sets of confirmed conditionally immortalized PTCs (ciPTC) according to different combinations of the aforementioned genetic variants. Quantitative real-time polymerase chain reaction, Western blot, and immunohistochemistry were performed for studying CYP3A5 and ABCB1 expression. CYP3A5 activity was assessed by differential midazolam (MDZ) hydroxylation and P-gp (ABCB1 product) activity by a calcein efflux assay. Differential drug metabolism between cell lines was assessed by tacrolimus disappearance over 24 h. Cell lines were generated from 27 out of 38 tissue samples. On the basis of genotype and PTC biomarkers, 11 subclones were selected. In vitro PTC morphology with brush border microvilli was confirmed. CYP3A5*1 carriers had increased 1-OH/4-OH MDZ formation versus homozygous *3 carriers (mean: 2.36 (95% CI:1.11-3.40) vs 0.88 (95% CI:0.48-1.27); p < 0.05). P-gp activity was confirmed by calcein accumulation (mean 38.6%; 95% CI:32.8-44.4%), which was higher in cell lines with the ABCB1 3435TT than the 3435CC/CT genotype (46.2% vs 35.5%; 95

  8. 42 CFR 2a.5 - Contents of application; research projects in which drugs will be administered.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 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 AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.5 Contents of...

  9. 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 AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.5 Contents of...

  10. 42 CFR 2a.5 - Contents of application; research projects in which drugs will be administered.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 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 AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.5 Contents of...

  11. 42 CFR 2a.5 - Contents of application; research projects in which drugs will be administered.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 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 AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.5 Contents of...

  12. 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 grant...

  13. 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 grant...

  14. 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 grant...

  15. 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 grant...

  16. 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 grant...

  17. Homology search for genes.

    PubMed

    Cui, Xuefeng; Vinar, Tomás; Brejová, Brona; Shasha, Dennis; Li, Ming

    2007-07-01

    Life science researchers often require an exhaustive list of protein coding genes similar to a given query gene. To find such genes, homology search tools, such as BLAST or PatternHunter, return a set of high-scoring pairs (HSPs). These HSPs then need to be correlated with existing sequence annotations, or assembled manually into putative gene structures. This process is error-prone and labor-intensive, especially in genomes without reliable gene annotation. We have developed a homology search solution that automates this process, and instead of HSPs returns complete gene structures. We achieve better sensitivity and specificity by adapting a hidden Markov model for gene finding to reflect features of the query gene. Compared to traditional homology search, our novel approach identifies splice sites much more reliably and can even locate exons that were lost in the query gene. On a testing set of 400 mouse query genes, we report 79% exon sensitivity and 80% exon specificity in the human genome based on orthologous genes annotated in NCBI HomoloGene. In the same set, we also found 50 (12%) gene structures with better protein alignment scores than the ones identified in HomoloGene. The Java implementation is available for download from http://www.bioinformatics.uwaterloo.ca/software.

  18. Impact of the CYP3A5*1 Allele on the Pharmacokinetics of Tacrolimus in Japanese Heart Transplant Patients.

    PubMed

    Uno, Takaya; Wada, Kyoichi; Matsuda, Sachi; Terada, Yuka; Oita, Akira; Kawase, Atsushi; Takada, Mitsutaka

    2018-04-24

    Tacrolimus, a major immunosuppressant used after transplantation, is associated with large interindividual variation involving genetic polymorphisms in metabolic processes. A common variant of the cytochrome P450 (CYP) 3A5 gene, CYP3A5*3, affects blood concentrations of tacrolimus. However, tacrolimus pharmacokinetics at the early stage of transplantation have not been adequately studied in heart transplantation. We retrospectively examined the impact of the CYP3A5 genotype on tacrolimus pharmacokinetics at the early stage of heart transplantation. The tacrolimus pharmacokinetic profile was obtained from 65 patients during the first 5 weeks after heart transplantation. Differences in the patients' characteristics and tacrolimus pharmacokinetic parameters between the CYP3A5 expresser (*1/*1 or *1/*3 genotypes) and non-expresser (*3/*3 genotype) groups were assessed by the Chi-square test, Student's t test, or Mann-Whitney U test. The CYP3A5 *1/*1, *1/*3, and *3/*3 genotypes were detected in 5, 22, and 38 patients, respectively. All patients started clotrimazole therapy approximately 1 week after starting tacrolimus. Apparent clearance and dose/weight to reach the target trough concentration (C 0 ) were significantly higher in the expresser group than in the non-expresser group (0.32 vs. 0.19 L/h/kg, p = 0.0003; 0.052 vs. 0.034 mg/kg/day, p = 0.0002); there were no significant differences in the area under the concentration-time curve from 0 to 12 h (AUC 0-12 ) and concentrations at any sampling time point between the two groups. Similar concentration-time curves for tacrolimus were obtained in the expresser and non-expresser groups by dose adjustment based on therapeutic drug monitoring. These results demonstrate the importance of the CYP3A5 genotype in tacrolimus dose optimization based on therapeutic drug monitoring after heart transplantation.

  19. 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…

  20. A 5′-terminal phosphate is required for stable ternary complex formation and translation of leaderless mRNA in Escherichia coli

    PubMed Central

    Giliberti, Jacqueline; O'Donnell, Sean; Van Etten, William J.; Janssen, Gary R.

    2012-01-01

    The bacteriophage λ's cI mRNA was utilized to examine the importance of the 5′-terminal phosphate on expression of leadered and leaderless mRNA in Escherichia coli. A hammerhead ribozyme was used to produce leadered and leaderless mRNAs, in vivo and in vitro, that contain a 5′-hydroxyl. Although these mRNAs may not occur naturally in the bacterial cell, they allow for the study of the importance of the 5′-phosphorylation state in ribosome binding and translation of leadered and leaderless mRNAs. Analyses with mRNAs containing either a 5′-phosphate or a 5′-hydroxyl indicate that leaderless cI mRNA requires a 5′-phosphate for stable ribosome binding in vitro as well as expression in vivo. Ribosome-binding assays show that 30S subunits and 70S ribosomes do not bind as strongly to 5′-hydroxyl as they do to 5′-phosphate containing leaderless mRNA and the tRNA-dependent ternary complex is less stable. Additionally, filter-binding assays revealed that the 70S ternary complex formed with a leaderless mRNA containing a 5′-hydroxyl has a dissociation rate (koff) that is 4.5-fold higher compared with the complex formed with a 5′-phosphate leaderless mRNA. Fusion to a lacZ reporter gene revealed that leaderless cI mRNA expression with a 5′-hydroxyl was >100-fold lower than the equivalent mRNA with a 5′-phosphate. These data indicate that a 5′-phosphate is an important feature of leaderless mRNA for stable ribosome binding and expression. PMID:22291205

  1. MiR-181a-5p is downregulated in hepatocellular carcinoma and suppresses motility, invasion and branching-morphogenesis by directly targeting c-Met.

    PubMed

    Korhan, Peyda; Erdal, Esra; Atabey, Neşe

    2014-08-08

    c-Met receptor tyrosine kinase has been regarded as a promising therapeutic target for hepatocellular carcinoma (HCC). Recently, microRNAs (miRNAs) have been shown as a novel mechanism to control c-Met expression in cancer. In this study, we investigate the potential contribution of miR-181a-5p dysregulation to the biology of c-Met overexpression in HCC. Herein, we found an inverse expression pattern between miR-181a-5p and c-Met expression in normal, cirrhotic and HCC liver tissues. Luciferase assay confirmed that miR-181a-5p binding to the 3'-UTR of c-Met downregulated the expression of c-Met in HCC cells. Overexpression of miR-181a-5p suppressed both HGF-independent and -dependent activation of c-Met and consequently diminished branching-morphogenesis and invasion. Combined treatment with miR-181a-5p and c-Met inhibitor led to a further inhibition of c-Met-driven cellular activities. Knockdown of miR-181a-5p promoted HGF-independent/-dependent signaling of c-Met and accelerated migration, invasion and branching-morphogenesis. In conclusion, our results demonstrated for the first time that c-Met is a functional target gene of miR-181a-5p and the loss of miR-181a-5p expression led to the activation of c-Met-mediated oncogenic signaling in hepatocarcinogenesis. These findings display a novel molecular mechanism of c-Met regulation in HCC and strategies to increase miR-181a5p level might be an alternative approach for the enhancement of the inhibitory effects of c-Met inhibitors. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Sustained Endothelial Expression of HoxA5 In Vivo Impairs Pathological Angiogenesis And Tumor Progression

    PubMed Central

    Cuevas, Ileana; Layman, Hans; Coussens, Lisa; Boudreau, Nancy

    2015-01-01

    HoxA5 is expressed in quiescent endothelial cells (EC), but absent in activated angiogenic EC. To examine the efficacy of targeting HoxA5 therapeutically to quell pathologic or tumor angiogenesis, we generated an inducible, transgenic mouse model of sustained HoxA5 expression in ECs. During pathologic angiogenesis, sustained HoxA5 regulates expression several angiogenic effector molecules, notably increased expression of TSP-2 and reduced expression of VEGF, thus leading to inhibition of pathological angiogenesis in tissues. To evaluate if this impressive reduction of vascularization could also impact tumor angiogenesis, HoxA5 mice were bred with a mouse model of de novo squamous carcinogenesis, e.g., K14-HPV16 mice. Activation of EC-HoxA5 significantly reduced infiltration by mast cells into neoplastic skin, an early hallmark of progression to dysplasia, reduced angiogenic vasculature, and blunted characteristics of tumor progression. To evaluate HoxA5 as a therapeutic, topical application of a HoxA5 transgene onto early neoplastic skin of K14-HPV16 mice similarly resulted in a significant impairment of angiogenic vasculature and progression to dysplasia to a similar extent as observed with genetic delivery of HoxA5. Together these data indicate that HoxA5 represents a novel molecule for restricting pathological and tumorigenic angiogenesis. PMID:25821967

  3. 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 -1585more » 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.« less

  4. The Light Skin Allele of SLC24A5 in South Asians and Europeans Shares Identity by Descent

    PubMed Central

    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

    2013-01-01

    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

  5. Gene therapy for blindness.

    PubMed

    Sahel, José-Alain; Roska, Botond

    2013-07-08

    Sight-restoring therapy for the visually impaired and blind is a major unmet medical need. Ocular gene therapy is a rational choice for restoring vision or preventing the loss of vision because most blinding diseases originate in cellular components of the eye, a compartment that is optimally suited for the delivery of genes, and many of these diseases have a genetic origin or genetic component. In recent years we have witnessed major advances in the field of ocular gene therapy, and proof-of-concept studies are under way to evaluate the safety and efficacy of human gene therapies. Here we discuss the concepts and recent advances in gene therapy in the retina. Our review discusses traditional approaches such as gene replacement and neuroprotection and also new avenues such as optogenetic therapies. We conjecture that advances in gene therapy in the retina will pave the way for gene therapies in other parts of the brain.

  6. Variation in oral clearance of saquinavir is predicted by CYP3A5*1 genotype but not by enterocyte content of cytochrome P450 3A5.

    PubMed

    Mouly, Stéphane J; Matheny, Chris; Paine, Mary F; Smith, Glenn; Lamba, Jatinder; Lamba, Vishal; Pusek, Susan N; Schuetz, Erin G; Stewart, Paul W; Watkins, Paul B

    2005-12-01

    Saquinavir, a widely prescribed human immunodeficiency virus 1 protease inhibitor, has a low and variable oral bioavailability that has been attributed to extensive first-pass extraction mediated by hepatic or intestinal cytochrome P450 (CYP) 3A4 and intestinal P-glycoprotein (P-gp). The polymorphic CYP3A5 has also been shown to influence the saquinavir metabolite/parent urinary ratio, suggesting a role for CYP3A5. Twenty healthy subjects received a single oral dose of saquinavir (600 mg) with water (control) and, on a separate occasion, with Seville orange juice (a selective intestinal CYP3A4/5 inhibitor). Hepatic CYP3A4 activity was evaluated by use of the erythromycin breath test. Duodenal biopsy specimens were used to assess relative intestinal CYP3A4 and CYP3A5 protein contents. Relative P-gp content was also assessed in the biopsy specimens and in lymphocytes. Genetic polymorphisms in MDR1 (in exon 21 and 26), CYP3A5 (*1 and *3), and CYP3A4*1B were identified by direct sequencing. Saquinavir plasma concentrations were measured by tandem liquid chromatography-mass spectrometry. Pharmacokinetic parameter estimates (maximum concentration, time to reach maximum concentration, area under the concentration-time curve, apparent oral clearance [CL/F]) were computed by standard noncompartmental methods. Stepwise multiple regression analysis was used to identify the hepatic or intestinal variables that predicted variation in saquinavir pharmacokinetic measures. Baseline saquinavir CL/F was not correlated with liver CYP3A4 activity (the erythromycin breath test result), intestinal CYP3A4 content, or intestinal P-gp content (r(2) = 0.08, 0.08, and 0.007, respectively; P > .2). MDR1 genotype and lymphocyte P-gp content were also not predictive. Among the 6 subjects expressing intestinal CYP3A5, the mean saquinavir CL/F was almost twice as high as for the 14 nonexpressors (36.7 L/h [95% confidence interval (CI), 18.7-54.6 L/h] and 19.3 L/h [95% CI, 11.2-27.4 L

  7. Evolution of gene expression after gene amplification.

    PubMed

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

    2015-04-24

    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. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  8. 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

  9. 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

  10. 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.

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

    SciTech Connect

    Xu, Ning; Zhang, Jianjun; Shen, Conghuan

    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-basedmore » 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.« less

  12. 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.

  13. High glucose up-regulates microRNA-34a-5p to aggravate fibrosis by targeting SIRT1 in HK-2 cells.

    PubMed

    Xue, Meng; Li, Yang; Hu, Fang; Jia, Yi-Jie; Zheng, Zong-Ji; Wang, Ling; Xue, Yao-Ming

    2018-03-25

    Tubulointerstitial fibrosis (TIF) is crucial in the development of renal fibrosis in diabetic nephropathy(DN). Previous data shows that SIRT1 plays an important role on fibrosis, but the effect on TIF in DN and underlying mechanisms remains uncertain. In this study, we evaluated the vital role of SIRT1 and identified SIRT1 as a downstream target gene of microRNA-34a-5p (miR-34a-5p) in TIF of DN. The result revealed that expression of miR-34a-5p, fibronectin(FN),collagen type I (COL1) and transforming growth factor β1 (TGF-β1) were up-regulated accompanied by the corresponding down-regulation of SIRT1 in renal tissues of high fat diet and streptozotocin(HFD/STZ)induced diabetic mice with DN, and that the SIRT1 mRNA level was negatively correlated with miR-34a-5p expression in high glucose stimulated human proximal tubule cell line(HK-2) cells. We then demonstrated that overexpression of SIRT1 reduced, whereas small interfering RNA targeting SIRT1 enhanced the expressions of TGF-β1 and fibrosis-related genes including FN and COL1 in HK-2 cells. Furthermore, we identified that miR-34a-5p directly suppressed SIRT1 to increase the profibrogenic effects of TGFβ1 through targeting the 3'untranslated region of SIRT1. The functional correlation of miR-34a-5p induced SIRT1 decrease was supported by overexpression and inhibition of miR-34a-5p in HK-2 cells. All the results reveal that SIRT1 which is vital in the evolution of renal TIF in DN can be directly suppressed by miR-34a-5p, and suggest that miR-34a-5p is a new target for DN treatment. Copyright © 2018 Elsevier Inc. All rights reserved.

  14. 26 CFR 20.2056A-5 - Imposition of section 2056A estate tax.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 14 2012-04-01 2012-04-01 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 Estate...

  15. 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 Estate...

  16. 26 CFR 1.411(a)-5 - Service included in determination of nonforfeitable percentage.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... employee has nonforfeitable rights under the predecessor plan, are determined under section 411(a) (5) and... Plans, Etc. § 1.411(a)-5 Service included in determination of nonforfeitable percentage. (a) In general... right to his employer-derived accrued benefit under section 411(a)(2) and § 1.411(a)-3, all of an...

  17. 45 CFR 12a.5 - Real property reported excess to GSA.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... REAL PROPERTY TO ASSIST THE HOMELESS § 12a.5 Real property reported excess to GSA. (a) Each landholding... property. (b) If a landholding agency reports a property to GSA which has been reviewed by HUD for homeless... § 12a.5(g) and will advise HUD of the availability of the property for use by the homeless as provided...

  18. 26 CFR 1.410(a)-5 - Year of service; break in service.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 5 2013-04-01 2013-04-01 false Year of service; break in service. 1.410(a)-5...(a)-5 Year of service; break in service. (a) Year of service. For the rules relating to years of.... (c) Breaks in service—(1) General rule. This paragraph provides rules with respect to breaks in...

  19. 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 customer...

  20. 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

  1. CYP3A5 regulates prostate cancer cell growth by facilitating nuclear translocation of AR.

    PubMed

    Mitra, Ranjana; Goodman, Oscar B

    2015-04-01

    The central role of androgen receptor (AR) signaling is established in prostate cancer growth and progression. We propose CYP3A5 is part of a feedback loop that modulates the sensitivity of AR to androgen exposure. The purpose of this study is to elucidate the mechanism of regulation of AR expression by CYP3A5. To identify the role of CYP3A5 in regulating AR signaling, CYP3A5 protein expression was inhibited using CYP3A5 siRNA and azamulin. Both cell fractionation and immunocytochemical approaches in combination with dihydrotestosterone (DHT) and R1881 treatment were used to evaluate changes in AR nuclear translocation. CYP3A5 siRNA blocked growth of LNCaP and C4-2 cells by 30-60% (P ≤ 0.005). Azamulin, a CYP3A pharmacologic inhibitor, reduced the growth of LNCaP, C4-2 and 22RV1 lines by ∼ 40% (P ≤ 0.005). CYP3A5 siRNA inhibited growth in response to DHT and R1881 treatment in LNCaP and C4-2 by decreasing nuclear AR localization and resulting in diminished PSA and TMPRSS2 expression. Decreased AR nuclear localization resulting from CYP3A5 inhibition resulted in growth inhibition comparable to IC60 and IC40 of bicalutamide in LNCaP and C4-2 cell lines. Conversely, the CYP3A inducer rifampicin enhanced AR nuclear localization. As CYP3A5 regulates the nuclear translocation of AR; co-targeting CYP3A5 may provide a novel strategy for enhancing the efficacy of androgen deprivation therapy. Consequentially, these data suggest that concomitant medications may impact androgen deprivation therapy's efficacy. © 2015 Wiley Periodicals, Inc.

  2. Primetime for Learning Genes.

    PubMed

    Keifer, Joyce

    2017-02-11

    Learning genes in mature neurons are uniquely suited to respond rapidly to specific environmental stimuli. Expression of individual learning genes, therefore, requires regulatory mechanisms that have the flexibility to respond with transcriptional activation or repression to select appropriate physiological and behavioral responses. Among the mechanisms that equip genes to respond adaptively are bivalent domains. These are specific histone modifications localized to gene promoters that are characteristic of both gene activation and repression, and have been studied primarily for developmental genes in embryonic stem cells. In this review, studies of the epigenetic regulation of learning genes in neurons, particularly the brain-derived neurotrophic factor gene ( BDNF ), by methylation/demethylation and chromatin modifications in the context of learning and memory will be highlighted. Because of the unique function of learning genes in the mature brain, it is proposed that bivalent domains are a characteristic feature of the chromatin landscape surrounding their promoters. This allows them to be "poised" for rapid response to activate or repress gene expression depending on environmental stimuli.

  3. 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

  4. The long noncoding RNA CASC2 inhibits tumorigenesis through modulating the expression of PTEN by targeting miR-18a-5p in esophageal carcinoma.

    PubMed

    Zhang, Wenjing; He, Wei; Gao, Jianfeng; Wang, Yuanyuan; Zang, Wenqiao; Dong, Ziming; Zhao, Guoqiang

    2017-12-01

    Abundant evidence indicates that long noncoding RNAs (lncRNAs) play an important role in various cellular processes, tumorigenesis, and the development of cancer. An increasing number studies are exploring this lncRNA-mediated mechanism. CASC2 is a novel gene in lncRNAs, located at chromosome 10q26. The present study aimed to examine the expression of lncRNA CASC2 in esophageal carcinoma (EC) tissue and to explore the effect of the upregulation of CASC2 on EC cell lines and specific regulatory mechanisms. We found the expression of CASC2 to be significantly downregulated in EC tissues and EC cell lines; moreover, low expression of CACS2 was associated with advanced TNM stage and lymph node metastases. Furthermore, upregulation of CASC2 significantly inhibited the proliferation of EC cells both in vitro and in vivo as well as their invasion in vitro; it also induced the apoptosis of EC9706 and EC1 cells. Additional experiments indicated that CASC2 interacted directly with miR-18a-5p, and there was a negative correlation between miR-18a-5p and CASC2 in EC tissues. We also found that miR-18a-5p directly targeted PTEN, a tumor suppressor gene, and could downregulate the protein expression of PTEN. Our experiments suggest that CASC2, acting as a competing endogenous RNAs (ceRNAs) of miR-18a-5p, exerts its biological effects by modulating the expression of PTEN. These findings indicate that the CASC2-miR-18a-5p-PTEN axis may be a novel target for further studies aimed at the prevention and treatment of EC. Copyright © 2017. Published by Elsevier Inc.

  5. Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia.

    PubMed

    Hardies, Katia; de Kovel, Carolien G F; Weckhuysen, Sarah; Asselbergh, Bob; Geuens, Thomas; Deconinck, Tine; Azmi, Abdelkrim; May, Patrick; Brilstra, Eva; Becker, Felicitas; Barisic, Nina; Craiu, Dana; Braun, Kees P J; Lal, Dennis; Thiele, Holger; Schubert, Julian; Weber, Yvonne; van 't Slot, Ruben; Nürnberg, Peter; Balling, Rudi; Timmerman, Vincent; Lerche, Holger; Maudsley, Stuart; Helbig, Ingo; Suls, Arvid; Koeleman, Bobby P C; De Jonghe, Peter

    2015-11-01

    The epileptic encephalopathies are a clinically and aetiologically heterogeneous subgroup of epilepsy syndromes. Most epileptic encephalopathies have a genetic cause and patients are often found to carry a heterozygous de novo mutation in one of the genes associated with the disease entity. Occasionally recessive mutations are identified: a recent publication described a distinct neonatal epileptic encephalopathy (MIM 615905) caused by autosomal recessive mutations in the SLC13A5 gene. Here, we report eight additional patients belonging to four different families with autosomal recessive mutations in SLC13A5. SLC13A5 encodes a high affinity sodium-dependent citrate transporter, which is expressed in the brain. Neurons are considered incapable of de novo synthesis of tricarboxylic acid cycle intermediates; therefore they rely on the uptake of intermediates, such as citrate, to maintain their energy status and neurotransmitter production. The effect of all seven identified mutations (two premature stops and five amino acid substitutions) was studied in vitro, using immunocytochemistry, selective western blot and mass spectrometry. We hereby demonstrate that cells expressing mutant sodium-dependent citrate transporter have a complete loss of citrate uptake due to various cellular loss-of-function mechanisms. In addition, we provide independent proof of the involvement of autosomal recessive SLC13A5 mutations in the development of neonatal epileptic encephalopathies, and highlight teeth hypoplasia as a possible indicator for SLC13A5 screening. All three patients who tried the ketogenic diet responded well to this treatment, and future studies will allow us to ascertain whether this is a recurrent feature in this severe disorder. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  6. 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

  7. History of gene therapy.

    PubMed

    Wirth, Thomas; Parker, Nigel; Ylä-Herttuala, Seppo

    2013-08-10

    Two decades after the initial gene therapy trials and more than 1700 approved clinical trials worldwide we not only have gained much new information and knowledge regarding gene therapy in general, but also learned to understand the concern that has persisted in society. Despite the setbacks gene therapy has faced, success stories have increasingly emerged. Examples for these are the positive recommendation for a gene therapy product (Glybera) by the EMA for approval in the European Union and the positive trials for the treatment of ADA deficiency, SCID-X1 and adrenoleukodystrophy. Nevertheless, our knowledge continues to grow and during the course of time more safety data has become available that helps us to develop better gene therapy approaches. Also, with the increased understanding of molecular medicine, we have been able to develop more specific and efficient gene transfer vectors which are now producing clinical results. In this review, we will take a historical view and highlight some of the milestones that had an important impact on the development of gene therapy. We will also discuss briefly the safety and ethical aspects of gene therapy and address some concerns that have been connected with gene therapy as an important therapeutic modality. Copyright © 2013 Elsevier B.V. All rights reserved.

  8. 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

  9. 26 CFR 1.691(a)-5 - Installment obligations acquired from decedent.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Income in Respect of Decedents § 1.691(a)-5 Installment... inheritance from the decedent or by reason of the decedent's death) shall include in its gross income when...

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

    DOE PAGES

    Staquicini, Fernanda I.; Qian, Ming D.; Salameh, Ahmad; ...

    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

  11. 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.

  12. 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 4221...

  13. 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 4221...

  14. 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 4221...

  15. 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 4221...

  16. 17 CFR 240.16a-5 - Odd-lot dealers.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Odd-lot dealers. 240.16a-5....16a-5 Odd-lot dealers. Transactions by an odd-lot dealer (a) in odd-lots as reasonably necessary to carry on odd-lot transactions, or (b) in round lots to offset odd-lot transactions previously or...

  17. 17 CFR 240.16a-5 - Odd-lot dealers.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 3 2013-04-01 2013-04-01 false Odd-lot dealers. 240.16a-5....16a-5 Odd-lot dealers. Transactions by an odd-lot dealer (a) in odd-lots as reasonably necessary to carry on odd-lot transactions, or (b) in round lots to offset odd-lot transactions previously or...

  18. 17 CFR 240.16a-5 - Odd-lot dealers.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 3 2012-04-01 2012-04-01 false Odd-lot dealers. 240.16a-5....16a-5 Odd-lot dealers. Transactions by an odd-lot dealer (a) in odd-lots as reasonably necessary to carry on odd-lot transactions, or (b) in round lots to offset odd-lot transactions previously or...

  19. 17 CFR 240.16a-5 - Odd-lot dealers.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 4 2014-04-01 2014-04-01 false Odd-lot dealers. 240.16a-5....16a-5 Odd-lot dealers. Transactions by an odd-lot dealer (a) in odd-lots as reasonably necessary to carry on odd-lot transactions, or (b) in round lots to offset odd-lot transactions previously or...

  20. 17 CFR 240.16a-5 - Odd-lot dealers.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Odd-lot dealers. 240.16a-5....16a-5 Odd-lot dealers. Transactions by an odd-lot dealer (a) in odd-lots as reasonably necessary to carry on odd-lot transactions, or (b) in round lots to offset odd-lot transactions previously or...

  1. 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. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. EPHRIN-A5 REGULATES INTER-MALE AGGRESSION IN MICE

    PubMed Central

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

    2015-01-01

    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. PMID:25746458

  3. [Antiphospholipid antibodies and recurrent abortions: possible pathogenetic role of annexin A5 investigated by confocal microscopy].

    PubMed

    Peluso, G; Morrone, G

    2007-06-01

    It has been established that antiphospholipid antibodies (aPL) are associated with recurrent abortions, but the pathophysiologic mechanisms that characterize thrombosis and recurrent pregnancy losses are still not clear.However, it is known that they are associated with the presence of antibodies directed against anionic phospholipids and putative cofactors. In this study the pathogenetic role of annexin A5, a potent anticoagulant cofactor protein for its anticoagulant property in recurrent abortions, was investigated. Endothelial cells of human umbilical veins ''EAHY2936 Line'' in culture were used, incubated with antiphospholipid anticardiolipin (ACA) antibodies purified from plasma of patients with recurrent abortions. The expression of annexin A5 on the cells with ACA was investigated by immunofluorescence and by confocal microscope. The negative control was also carried out: EAHY cells in cultivation medium without ACA. Confocal analysis revealed a uniform distribution of annexin A5 on the cellular membranes in the negative control. Instead, in EAHY cells with ACA, the annexin A5 appears distributed in irregular manners on the cellular membranes (cytoplasmic and nuclear). The results of an irregular ''cluster'' distribution of annexin A5 on the EAHY cells in presence of aPL, and in agreement with the literature, demonstrated that aPL, inhibiting annexin A5 ability to protect anionic phospholipid, promote the coagulation factors to diffuse laterally against phospholipids.

  4. A 5′ Nuclease Genotyping Assay for Identification of Macrolide-Resistant Mycoplasma genitalium in Clinical Specimens

    PubMed Central

    Kristiansen, Gitte Qvist; Lisby, Jan Gorm

    2016-01-01

    Rapid and sensitive detection of macrolide resistance in Mycoplasma genitalium is required for the guidance of adequate antimicrobial treatment. Previous studies have confirmed that single-base mutations at position 2058 or 2059 in domain V of the 23S rRNA gene of M. genitalium result in high-level macrolide resistance. Sequencing of PCR products remains the gold standard for the identification of mutations conferring resistance to macrolides but is laborious and time-consuming. The aim of the present study was to develop a 5′ nuclease genotyping assay to detect single nucleotide polymorphisms in the 23S rRNA gene of Mycoplasma genitalium that are associated with macrolide resistance by combining PCR with hydrolysis probes and subsequent endpoint genotyping analysis. The 5′ nuclease genotyping assay was used as a referral test to be used on M. genitalium-positive samples and was validated on 259 positive samples, of which 253 (97.7%) were successfully sequenced. With the newly developed assay, 237/259 (91.5%) investigated M. genitalium-positive samples were genotyped. The positive and the negative predictive values were 100% when evaluated on successfully genotyped samples. The newly developed assay discriminated macrolide-resistant M. genitalium in clinical specimens possessing A2058G, A2058C, A2058T, and A2059G mutations with a sensitivity of 94.4% (95% confidence interval [CI], 90.7% to 98.2%) and a specificity of 92.7% (95% CI, 87.8% to 97.6%) when evaluated on successfully sequenced samples. The assay can correctly guide antimicrobial treatment of M. genitalium infections. PMID:27053672

  5. Smart Genes, Stupid Science.

    ERIC Educational Resources Information Center

    Randerson, Sherman; Mahadeva, Madhu N.

    1983-01-01

    Because many people still believe that specific, identifiable genes dictate the level of human intelligence and that the number/quality of these genes can be evaluated, presents evidence from human genetics (related to nervous system development) to counter this view. Also disputes erroneous assumptions made in "heritability studies" of human…

  6. Human housekeeping genes, revisited.

    PubMed

    Eisenberg, Eli; Levanon, Erez Y

    2013-10-01

    Housekeeping genes are involved in basic cell maintenance and, therefore, are expected to maintain constant expression levels in all cells and conditions. Identification of these genes facilitates exposure of the underlying cellular infrastructure and increases understanding of various structural genomic features. In addition, housekeeping genes are instrumental for calibration in many biotechnological applications and genomic studies. Advances in our ability to measure RNA expression have resulted in a gradual increase in the number of identified housekeeping genes. Here, we describe housekeeping gene detection in the era of massive parallel sequencing and RNA-seq. We emphasize the importance of expression at a constant level and provide a list of 3804 human genes that are expressed uniformly across a panel of tissues. Several exceptionally uniform genes are singled out for future experimental use, such as RT-PCR control genes. Finally, we discuss both ways in which current technology can meet some of past obstacles encountered, and several as yet unmet challenges. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. GENE EXPRESSION NETWORKS

    EPA Science Inventory

    "Gene expression network" is the term used to describe the interplay, simple or complex, between two or more gene products in performing a specific cellular function. Although the delineation of such networks is complicated by the existence of multiple and subtle types of intera...

  8. Anomalous unrooted gene trees.

    PubMed

    Degnan, James H

    2013-07-01

    The coalescent and multispecies coalescent model rooted genealogies backward through time. Often, the direction of time is unknown in trees estimated from molecular sequences due to reversible mutation models, absence of an appropriate outgroup, and the absence of the molecular clock. In this article, probabilities of unrooted gene-tree topologies under the multispecies coalescent are considered. The main result is that for any species-tree topology with seven or more taxa, there exist branch lengths such that there are unrooted gene-tree topologies that are more likely than the one that has the same unrooted topology as the species tree. Species trees with such anomalous unrooted gene trees (AUGTs) are characterized for trees with five and six taxa, and patterns of branch lengths leading to AUGTs and rooted anomalous gene trees are explored. The results could be useful for understanding gene tree discordance and designing simulations studies for inferring challenging species trees.

  9. Genes, genome and Gestalt.

    PubMed

    Grisolia, Cesar Koppe

    2005-03-31

    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.

  10. Enhanced Fructose Utilization Mediated by SLC2A5 Is a Unique Metabolic Feature of Acute Myeloid Leukemia with Therapeutic Potential.

    PubMed

    Chen, Wen-Lian; Wang, Yue-Ying; Zhao, Aihua; Xia, Li; Xie, Guoxiang; Su, Mingming; Zhao, Linjing; Liu, Jiajian; Qu, Chun; Wei, Runmin; Rajani, Cynthia; Ni, Yan; Cheng, Zhen; Chen, Zhu; Chen, Sai-Juan; Jia, Wei

    2016-11-14

    Rapidly proliferating leukemic progenitor cells consume substantial glucose, which may lead to glucose insufficiency in bone marrow. We show that acute myeloid leukemia (AML) cells are prone to fructose utilization with an upregulated fructose transporter GLUT5, which compensates for glucose deficiency. Notably, AML patients with upregulated transcription of the GLUT5-encoding gene SLC2A5 or increased fructose utilization have poor outcomes. Pharmacological blockage of fructose uptake ameliorates leukemic phenotypes and potentiates the cytotoxicity of the antileukemic agent, Ara-C. In conclusion, this study highlights enhanced fructose utilization as a metabolic feature of AML and a potential therapeutic target. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Formation of Persistent Hyperplastic Primary Vitreous in Ephrin-A5−/− Mice

    PubMed Central

    Son, Alexander I.; Sheleg, Michal; Cooper, Margaret A.; Sun, Yuhai; Kleiman, Norman J.; Zhou, Renping

    2014-01-01

    Purpose. Primary vitreous regression is a critical event in mammalian eye development required for proper ocular maturity and unhindered vision. Failure of this event results in the eye disease persistent hyperplastic primary vitreous (PHPV), also identified as persistent fetal vasculature (PFV), a condition characterized by the presence of a fibrovascular mass adjacent to the lens and retina, and associated with visual disability and blindness. Here, we identify ephrin-A5 to be a critical regulator for primary vitreous regression. Methods. Wild-type and ephrin-A5−/− eyes were examined at various developmental stages to determine the progression of PHPV. Eye tissue was sectioned and examined by H&E staining. Protein expression and localization was determined through immunohistochemistry. Relative levels of Eph receptors were determined by RT-PCR. Results. Ephrin-A5−/− animals develop ocular phenotypes representative of PHPV, most notably the presence of a large hyperplastic mass posterior to the lens that remains throughout the lifetime of the animal. The aberrant tissue in these mutant mice consists of residual hyaloid vessels surrounded by pigmented cells of neural crest origin. Labeling with bromodeoxyuridine (BrdU) and detection of proliferating cell nuclear antigen (PCNA) expression shows that the mass in ephrin-A5−/− animals is mitotically active in embryonic and postnatal stages. Conclusions. Ephrin-A5 is a critical factor that regulates primary vitreous regression. PMID:24550361

  12. After repeated division, bone marrow stromal cells express inhibitory factors with osteogenic capabilities, and EphA5 is a primary candidate.

    PubMed

    Yamada, Tsuyoshi; Yuasa, Masato; Masaoka, Tomokazu; Taniyama, Takashi; Maehara, Hidetsugu; Torigoe, Ichiro; Yoshii, Toshitaka; Shinomiya, Kenichi; Okawa, Atsushi; Sotome, Shinichi

    2013-12-01

    The differentiation capability of human bone marrow stromal cells (hBMSCs) is thought to deteriorate over multiple doubling processes. To clarify the deterioration mechanisms, the multilineage differentiation capabilities of short- and long-term passaged BMSCs were compared. Predictably, long-term passaged BMSCs showed reduced differentiation capacities compared to short-term passaged cells. Furthermore, a non-human primate heterotopic bone formation model demonstrated that long-term passaged BMSCs have bone formation capabilities but also exert inhibitory effects on bone formation. This finding indicated that long-term passaged BMSCs express higher levels of inhibitory factors than short-term passaged BMSCs do. Co-culture assays of short- and long-term passaged BMSCs suggested that the inhibitory signals required cell-cell contact and would therefore be expressed on the cell membrane. A microarray analysis of BMSCs identified ephrin type-A receptor 5 (EphA5) as an inhibitory factor candidate. Quantitative PCR revealed that among all members of the ephrin and Eph receptor families, only the expression of EphA5 was increased by BMSC proliferation. A gene knockdown analysis using siRNAs demonstrated that knockdown of EphA5 gene expression in long-term passaged BMSCs led to an increase in ALP mRNA expression. These results indicate that EphA5 may be a negative regulator of bone formation. A better understanding of the roles of the ephrin and Eph receptor families in hBMSCs may lead to alternative approaches for manipulating hBMSC fate. In addition, this avenue of discovery may provide new therapeutic targets and quality-control markers of the osteogenic differentiation capabilities of hBMSCs. © 2013.

  13. 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

  14. Differential expression of miR-672-5p and miR-146a-5p in osteoblasts in rats after steroid intervention.

    PubMed

    Li, Pengfei; Sun, Nan; Zeng, Jianchun; Zeng, Yirong; Fan, Yueguang; Feng, Wenjun; Li, Jie

    2016-10-10

    Apoptosis of osteoblasts and osteocytes is one cause of steroid-induced osteonecrosis of the femoral head; however, the molecular mechanism of steroid affecting osteoblasts at the genetic level is unclear. The aim of the present work is to examine differential expression of osteoblasts in rats after steroid intervention and to verify expression by real-time polymerase chain reaction (RT-PCR). Primary culture, passaging and identification of osteoblasts of SD neonatal rats were conducted; osteoblasts were divided into two groups, the control group, and the steroid group. Total RNA was extracted separately, and quality control was performed; by means of RNA labeling and microarray hybridization, data were collected and then standardized to ascertain differences in miRNA expression between the two groups. The gene expression spectrum was analyzed. Obvious differential expression of miR-672-5p and miR-146a-5p was verified by RT-PCR. Miranda, microcosm and mirdb bioinformatics software were used to predict target genes. Compared with the control group, morphologically, the osteoblasts in the steroid group were more irregular and showed various shapes. The number of miRNAs (fold change >2) in the steroid group was six. Four miRNAs were upregulated and two miRNAs were downregulated. In particular, upregulated miR-672-5p expression and downregulated miR-146a-5p expression were significant. RT-PCR results showed that the 2(-△△) CT value of miR-672-5p in the steroid group was 3.743-fold of that in the control group, and the 2(-△△) CT value of miR-146a-5p in the steroid group was 0.322-fold of that in the control group. Angptl4, Ccdc51, Ssbp3 and RGD1306991 were predicted as the target gene of miR-672-5p, while Hrp12 was that of miR-146a-5p. Expression profiles of miR-672-5p and miR-146a-5p had the most significant changes in the osteoblasts of rats with steroid intervention, which may provide a new viewpoint to pathogenesis of osteonecrosis of the femoral head

  15. 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

  16. The glutamine transporter ASCT2 (SLC1A5) promotes tumor growth independently of the amino acid transporter LAT1 (SLC7A5).

    PubMed

    Cormerais, Yann; Massard, Pierre André; Vucetic, Milica; Giuliano, Sandy; Tambutté, Eric; Durivault, Jerome; Vial, Valérie; Endou, Hitoshi; Wempe, Michael F; Parks, Scott K; Pouyssegur, Jacques

    2018-02-23

    The transporters for glutamine and essential amino acids, ASCT2 (solute carrier family 1 member 5, SLC1A5) and LAT1 (solute carrier family 7 member 5, SLC7A5), respectively, are overexpressed in aggressive cancers and have been identified as cancer-promoting targets. Moreover, previous work has suggested that glutamine influx via ASCT2 triggers essential amino acids entry via the LAT1 exchanger, thus activating mechanistic target of rapamycin complex 1 (mTORC1) and stimulating growth. Here, to further investigate whether these two transporters are functionally coupled, we compared the respective knockout (KO) of either LAT1 or ASCT2 in colon (LS174T) and lung (A549) adenocarcinoma cell lines. Although ASCT2 KO significantly reduced glutamine import (>60% reduction), no impact on leucine uptake was observed in both cell lines. Although an in vitro growth-reduction phenotype was observed in A549- ASCT2 KO cells only, we found that genetic disruption of ASCT2 strongly decreased tumor growth in both cell lines. However, in sharp contrast to LAT1 KO cells, ASCT2 KO cells displayed no amino acid (AA) stress response (GCN2/EIF2a/ATF4) or altered mTORC1 activity (S6K1/S6). We therefore conclude that ASCT2 KO reduces tumor growth by limiting AA import, but that this effect is independent of LAT1 activity. These data were further supported by in vitro cell proliferation experiments performed in the absence of glutamine. Together these results confirm and extend ASCT2's pro-tumoral role and indicate that the proposed functional coupling model of ASCT2 and LAT1 is not universal across different cancer types. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  17. A Bitslice Implementation of Anderson's Attack on A5/1

    NASA Astrophysics Data System (ADS)

    Bulavintsev, Vadim; Semenov, Alexander; Zaikin, Oleg; Kochemazov, Stepan

    2018-03-01

    The A5/1 keystream generator is a part of Global System for Mobile Communications (GSM) protocol, employed in cellular networks all over the world. Its cryptographic resistance was extensively analyzed in dozens of papers. However, almost all corresponding methods either employ a specific hardware or require an extensive preprocessing stage and significant amounts of memory. In the present study, a bitslice variant of Anderson's Attack on A5/1 is implemented. It requires very little computer memory and no preprocessing. Moreover, the attack can be made even more efficient by harnessing the computing power of modern Graphics Processing Units (GPUs). As a result, using commonly available GPUs this method can quite efficiently recover the secret key using only 64 bits of keystream. To test the performance of the implementation, a volunteer computing project was launched. 10 instances of A5/1 cryptanalysis have been successfully solved in this project in a single week.

  18. Analyses of SLC13A5-epilepsy patients reveal perturbations of TCA cycle.

    PubMed

    Bainbridge, Matthew N; Cooney, Erin; Miller, Marcus; Kennedy, Adam D; Wulff, Jacob E; Donti, Taraka; Jhangiani, Shalini N; Gibbs, Richard A; Elsea, Sarah H; Porter, Brenda E; Graham, Brett H

    2017-08-01

    To interrogate the metabolic profile of five subjects from three families with rare, nonsense and missense mutations in SLC13A5 and Early Infantile Epileptic Encephalopathies (EIEE) characterized by severe, neonatal onset seizures, psychomotor retardation and global developmental delay. Mass spectrometry of plasma, CSF and urine was used to identify consistently dysregulated analytes in our subjects. Distinctive elevations of citrate and dysregulation of citric acid cycle intermediates, supporting the hypothesis that loss of SLC13A5 function alters tricarboxylic acid cycle (TCA) metabolism and may disrupt metabolic compartmentation in the brain. Our results indicate that analysis of plasma citrate and other TCA analytes in SLC13A5 deficient patients define a diagnostic metabolic signature that can aid in diagnosing children with this disease. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Key role of the N-terminus of chicken annexin A5 in vesicle aggregation

    PubMed Central

    Turnay, Javier; Guzmán-Aránguez, Ana; Lecona, Emilio; Barrasa, Juan I; Olmo, Nieves; Lizarbe, Ma Antonia

    2009-01-01

    Annexins are calcium-dependent phospholipid-binding proteins involved in calcium signaling and intracellular membrane trafficking among other functions. Vesicle aggregation is a crucial event to make possible the membrane remodeling but this process is energetically unfavorable, and phospholipid membranes do not aggregate and fuse spontaneously. This issue can be circumvented by the presence of different agents such as divalent cations and/or proteins, among them some annexins. Although human annexin A5 lacks the ability to aggregate vesicles, here we demonstrate that its highly similar chicken ortholog induces aggregation of vesicles containing acidic phospholipids even at low protein and/or calcium concentration by establishment of protein dimers. Our experiments show that the ability to aggregate vesicles mainly resides in the N-terminus as truncation of the N-terminus of chicken annexin A5 significantly decreases this process and replacement of the N-terminus of human annexin A5 by that of chicken switches on aggregation; in both cases, there are no changes in the overall protein structure and only minor changes in phospholipid binding. Electrostatic repulsions between negatively charged residues in the concave face of the molecule, mainly in the N-terminus, seem to be responsible for the impairment of dimer formation in human annexin A5. Taking into account that chicken annexin A5 presents a high sequence and structural similarity with mammalian annexins absent in birds, as annexins A3 and A4, some of the physiological functions exerted by these proteins may be carried out by chicken annexin A5, even those that could require calcium-dependent membrane aggregation. PMID:19388055

  20. Differentially Coexpressed Disease Gene Identification Based on Gene Coexpression Network.

    PubMed

    Jiang, Xue; Zhang, Han; Quan, Xiongwen

    2016-01-01

    Screening disease-related genes by analyzing gene expression data has become a popular theme. Traditional disease-related gene selection methods always focus on identifying differentially expressed gene between case samples and a control group. These traditional methods may not fully consider the changes of interactions between genes at different cell states and the dynamic processes of gene expression levels during the disease progression. However, in order to understand the mechanism of disease, it is important to explore the dynamic changes of interactions between genes in biological networks at different cell states. In this study, we designed a novel framework to identify disease-related genes and developed a differentially coexpressed disease-related gene identification method based on gene coexpression network (DCGN) to screen differentially coexpressed genes. We firstly constructed phase-specific gene coexpression network using time-series gene expression data and defined the conception of differential coexpression of genes in coexpression network. Then, we designed two metrics to measure the value of gene differential coexpression according to the change of local topological structures between different phase-specific networks. Finally, we conducted meta-analysis of gene differential coexpression based on the rank-product method. Experimental results demonstrated the feasibility and effectiveness of DCGN and the superior performance of DCGN over other popular disease-related gene selection methods through real-world gene expression data sets.

  1. Nonintegrating Gene Therapy Vectors.

    PubMed

    Athanasopoulos, Takis; Munye, Mustafa M; Yáñez-Muñoz, Rafael J

    2017-10-01

    Gene delivery vectors that do not rely on host cell genome integration offer several advantages for gene transfer, chiefly the avoidance of insertional mutagenesis and position effect variegation. However, unless engineered for replication and segregation, nonintegrating vectors will dilute progressively in proliferating cells, and are not exempt of epigenetic effects. This article provides an overview of the main nonintegrating viral (adenoviral, adeno-associated viral, integration-deficient retro-lentiviral, poxviral), and nonviral (plasmid vectors, artificial chromosomes) vectors used for preclinical and clinical cell and gene therapy applications. Particular emphasis is placed on their use in hematologic disease. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. A Novel Phytophthora sojae Resistance Rps12 Gene Mapped to a Genomic Region That Contains Several Rps Genes.

    PubMed

    Sahoo, Dipak K; Abeysekara, Nilwala S; Cianzio, Silvia R; Robertson, Alison E; Bhattacharyya, Madan K

    2017-01-01

    Phytophthora sojae Kaufmann and Gerdemann, which causes Phytophthora root rot, is a widespread pathogen that limits soybean production worldwide. Development of Phytophthora resistant cultivars carrying Phytophthora resistance Rps genes is a cost-effective approach in controlling this disease. For this mapping study of a novel Rps gene, 290 recombinant inbred lines (RILs) (F7 families) were developed by crossing the P. sojae resistant cultivar PI399036 with the P. sojae susceptible AR2 line, and were phenotyped for responses to a mixture of three P. sojae isolates that overcome most of the known Rps genes. Of these 290 RILs, 130 were homozygous resistant, 12 heterzygous and segregating for Phytophthora resistance, and 148 were recessive homozygous and susceptible. From this population, 59 RILs homozygous for Phytophthora sojae resistance and 61 susceptible to a mixture of P. sojae isolates R17 and Val12-11 or P7074 that overcome resistance encoded by known Rps genes mapped to Chromosome 18 were selected for mapping novel Rps gene. A single gene accounted for the 1:1 segregation of resistance and susceptibility among the RILs. The gene encoding the Phytophthora resistance mapped to a 5.8 cM interval between the SSR markers BARCSOYSSR_18_1840 and Sat_064 located in the lower arm of Chromosome 18. The gene is mapped 2.2 cM proximal to the NBSRps4/6-like sequence that was reported to co-segregate with the Phytophthora resistance genes Rps4 and Rps6. The gene is mapped to a highly recombinogenic, gene-rich genomic region carrying several nucleotide binding site-leucine rich repeat (NBS-LRR)-like genes. We named this novel gene as Rps12, which is expected to be an invaluable resource in breeding soybeans for Phytophthora resistance.

  3. A Novel Phytophthora sojae Resistance Rps12 Gene Mapped to a Genomic Region That Contains Several Rps Genes

    PubMed Central

    Sahoo, Dipak K.; Abeysekara, Nilwala S.; Cianzio, Silvia R.; Robertson, Alison E.

    2017-01-01

    Phytophthora sojae Kaufmann and Gerdemann, which causes Phytophthora root rot, is a widespread pathogen that limits soybean production worldwide. Development of Phytophthora resistant cultivars carrying Phytophthora resistance Rps genes is a cost-effective approach in controlling this disease. For this mapping study of a novel Rps gene, 290 recombinant inbred lines (RILs) (F7 families) were developed by crossing the P. sojae resistant cultivar PI399036 with the P. sojae susceptible AR2 line, and were phenotyped for responses to a mixture of three P. sojae isolates that overcome most of the known Rps genes. Of these 290 RILs, 130 were homozygous resistant, 12 heterzygous and segregating for Phytophthora resistance, and 148 were recessive homozygous and susceptible. From this population, 59 RILs homozygous for Phytophthora sojae resistance and 61 susceptible to a mixture of P. sojae isolates R17 and Val12-11 or P7074 that overcome resistance encoded by known Rps genes mapped to Chromosome 18 were selected for mapping novel Rps gene. A single gene accounted for the 1:1 segregation of resistance and susceptibility among the RILs. The gene encoding the Phytophthora resistance mapped to a 5.8 cM interval between the SSR markers BARCSOYSSR_18_1840 and Sat_064 located in the lower arm of Chromosome 18. The gene is mapped 2.2 cM proximal to the NBSRps4/6-like sequence that was reported to co-segregate with the Phytophthora resistance genes Rps4 and Rps6. The gene is mapped to a highly recombinogenic, gene-rich genomic region carrying several nucleotide binding site-leucine rich repeat (NBS-LRR)-like genes. We named this novel gene as Rps12, which is expected to be an invaluable resource in breeding soybeans for Phytophthora resistance. PMID:28081566

  4. Extending gene ontology with gene association networks.

    PubMed

    Peng, Jiajie; Wang, Tao; Wang, Jixuan; Wang, Yadong; Chen, Jin

    2016-04-15

    Gene ontology (GO) is a widely used resource to describe the attributes for gene products. However, automatic GO maintenance remains to be difficult because of the complex logical reasoning and the need of biological knowledge that are not explicitly represented in the GO. The existing studies either construct whole GO based on network data or only infer the relations between existing GO terms. None is purposed to add new terms automatically to the existing GO. We proposed a new algorithm 'GOExtender' to efficiently identify all the connected gene pairs labeled by the same parent GO terms. GOExtender is used to predict new GO terms with biological network data, and connect them to the existing GO. Evaluation tests on biological process and cellular component categories of different GO releases showed that GOExtender can extend new GO terms automatically based on the biological network. Furthermore, we applied GOExtender to the recent release of GO and discovered new GO terms with strong support from literature. Software and supplementary document are available at www.msu.edu/%7Ejinchen/GOExtender jinchen@msu.edu or ydwang@hit.edu.cn Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  5. Therapeutic synthetic gene networks.

    PubMed

    Karlsson, Maria; Weber, Wilfried

    2012-10-01

    The field of synthetic biology is rapidly expanding and has over the past years evolved from the development of simple gene networks to complex treatment-oriented circuits. The reprogramming of cell fate with open-loop or closed-loop synthetic control circuits along with biologically implemented logical functions have fostered applications spanning over a wide range of disciplines, including artificial insemination, personalized medicine and the treatment of cancer and metabolic disorders. In this review we describe several applications of interactive gene networks, a synthetic biology-based approach for future gene therapy, as well as the utilization of synthetic gene circuits as blueprints for the design of stimuli-responsive biohybrid materials. The recent progress in synthetic biology, including the rewiring of biosensing devices with the body's endogenous network as well as novel therapeutic approaches originating from interdisciplinary work, generates numerous opportunities for future biomedical applications. Copyright © 2012 Elsevier Ltd. All rights reserved.

  6. Genes underlying altruism.

    PubMed

    Thompson, Graham J; Hurd, Peter L; Crespi, Bernard J

    2013-01-01

    William D. Hamilton postulated the existence of 'genes underlying altruism', under the rubric of inclusive fitness theory, a half-century ago. Such genes are now poised for discovery. In this article, we develop a set of intuitive criteria for the recognition and analysis of genes for altruism and describe the first candidate genes affecting altruism from social insects and humans. We also provide evidence from a human population for genetically based trade-offs, underlain by oxytocin-system polymorphisms, between alleles for altruism and alleles for non-social cognition. Such trade-offs between self-oriented and altruistic behaviour may influence the evolution of phenotypic diversity across all social animals.

  7. Genes underlying altruism

    PubMed Central

    Thompson, Graham J.; Hurd, Peter L.; Crespi, Bernard J.

    2013-01-01

    William D. Hamilton postulated the existence of ‘genes underlying altruism’, under the rubric of inclusive fitness theory, a half-century ago. Such genes are now poised for discovery. In this article, we develop a set of intuitive criteria for the recognition and analysis of genes for altruism and describe the first candidate genes affecting altruism from social insects and humans. We also provide evidence from a human population for genetically based trade-offs, underlain by oxytocin-system polymorphisms, between alleles for altruism and alleles for non-social cognition. Such trade-offs between self-oriented and altruistic behaviour may influence the evolution of phenotypic diversity across all social animals. PMID:24132092

  8. Clock genes and sleep.

    PubMed

    Landgraf, Dominic; Shostak, Anton; Oster, Henrik

    2012-01-01

    In most species--from cyanobacteria to humans--endogenous clocks have evolved that drive 24-h rhythms of behavior and physiology. In mammals, these circadian rhythms are regulated by a hierarchical network of cellular oscillators controlled by a set of clock genes organized in a system of interlocked transcriptional feedback loops. One of the most prominent outputs of the circadian system is the synchronization of the sleep-wake cycle with external (day-) time. Clock genes also have a strong impact on many other biological functions, such as memory formation, energy metabolism, and immunity. Remarkably, large overlaps exist between clock gene and sleep (loss) mediated effects on these processes. This review summarizes sleep clock gene interactions for these three phenomena, highlighting potential mediators linking sleep and/or clock function to physiological output in an attempt to better understand the complexity of diurnal adaptation and its consequences for health and disease.

  9. 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.

  10. 26 CFR 1.613A-5 - Election under section 613A(c)(4).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... TAX (CONTINUED) INCOME TAXES (CONTINUED) Natural Resources § 1.613A-5 Election under section 613A(c)(4... percentage depletion deductions for the taxable year based upon such election. The election may be made, on... claim for credit or refund. The election allows the taxpayer to treat as his depletable natural gas...

  11. 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…

  12. 42 CFR 85a.5 - Conduct of investigations of places of employment.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Conduct of investigations of places of employment... PLACES OF EMPLOYMENT § 85a.5 Conduct of investigations of places of employment. (a)(1) Prior to beginning..., operator or agent in charge at the place of employment, explain the nature, purpose and scope of the...

  13. 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 corporation...

  14. 17 CFR 260.10a-5 - Eligibility of Canadian Trustees.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... pursuant to the Trust Companies Act (Canada), R.S.C. 1985, or the Canada Deposit Insurance Corporation Act... (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 Rule Under Section 310 § 260.10a-5... trustee under an indenture qualified or to be qualified under the Act and filed in connection with...

  15. 26 CFR 1.382-3 - Definitions and rules relating to a 5-percent shareholder.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... friendly to management to convince them to acquire L's stock based on an understanding that L will assemble... retroactive application of the rules of this paragraph (j) affects the information reported on an information... and rules relating to a 5-percent shareholder. (a) Definitions—(1) Entity—(i) In general. An entity is...

  16. 26 CFR 1.382-3 - Definitions and rules relating to a 5-percent shareholder.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... friendly to management to convince them to acquire L's stock based on an understanding that L will assemble... retroactive application of the rules of this paragraph (j) affects the information reported on an information... and rules relating to a 5-percent shareholder. (a) Definitions—(1) Entity—(i) In general. An entity is...

  17. 26 CFR 1.382-3 - Definitions and rules relating to a 5-percent shareholder.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... management to convince them to acquire L's stock based on an understanding that L will assemble a group that... retroactive application of the rules of this paragraph (j) affects the information reported on an information... relating to a 5-percent shareholder. (a) Definitions—(1) Entity—(i) In general. An entity is any...

  18. The Reliability of a 5km Run Test on a Motorized Treadmill

    ERIC Educational Resources Information Center

    Driller, Matthew; Brophy-Williams, Ned; Walker, Anthony

    2017-01-01

    The purpose of the present study was to determine the reliability of a 5km run test on a motorized treadmill. Over three consecutive weeks, 12 well-trained runners completed three 5km time trials on a treadmill following a standardized warm-up. Runners were partially-blinded to their running speed and distance covered. Total time to complete the…

  19. HRCT features in a 5-year-old child with follicular bronchiolitis.

    PubMed

    Reittner, P; Fotter, R; Lindbichler, F; Tillich, M; Varga, E M; Zach, M; Popper, H

    1997-11-01

    High-resolution CT (HRCT) is the most sensitive radiographic method to image small airways disease. We discuss the HRCT features of follicular bronchiolitis in a 5-year-old boy and correlate them with the histopathological findings. The changes described include centrilobular nodules, bronchiectasis and bronchiolectasis, branching opacities and areas of reduced lung attenuation.

  20. 26 CFR 20.2056A-5 - Imposition of section 2056A estate tax.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 14 2010-04-01 2010-04-01 false Imposition of section 2056A estate tax. 20... (CONTINUED) ESTATE AND GIFT TAXES ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Taxable Estate § 20.2056A-5 Imposition of section 2056A estate tax. (a) In general. An estate tax is imposed under...

  1. 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 § 48.4061(a)-3(a...

  2. 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 § 48.4061(a)-3(a...

  3. 26 CFR 48.4061(a)-5 - Sale of automobile truck bodies and chassis.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 16 2010-04-01 2010-04-01 true 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 § 48.4061(a)-3(a...

  4. 26 CFR 48.4061(a)-5 - Sale of automobile truck bodies and chassis.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 16 2011-04-01 2011-04-01 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 § 48.4061(a)-3(a...

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

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Contents of application; research projects in which... AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.5 Contents of application; research projects in which drugs will be administered. (a) In addition to the information...

  6. 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…

  7. 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…

  8. 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…

  9. Endophytic fungus Purpureocillium sp. A5 protect mangrove plant Kandelia candel under copper stress.

    PubMed

    Gong, Bin; Liu, Guixiang; Liao, Rquan; Song, Jingjing; Zhang, Hong

    Mangrove is an important ecosystem in the world. Mangrove ecosystems have a large capacity in retaining heavy metals, and now they are usually considered as sinks for heavy metals. However, the mechanism of why the soil of mangrove ecosystems can retain heavy metal is not certain. In this research, endophytic fungus Purpureocillium sp. A5 was isolated and identified from the roots of Kandelia candel. When this fungus was added, it protected the growth of K. candel under Cu stress. This can be illustrated by analyzing chlorophyll A and B, RWC and WSD to leaves of K. candel. Purpureocillium sp. A5 reduces uptake of Cu in K. candel and changes the pH characterization of soil. Furthermore, A5 increase the concentration of Cu complexes in soil, and it enhanced the concentration of carbonate-bound Cu, Mn-Fe complexes Cu and organic-bound Cu in soil. Nevertheless, a significant reduction of the Cu ion was noted among A5-treated plants. This study is significant and illustrates a promising potential use for environmental remediation of endophytes, and also may partially explain the large capacity of mangrove ecosystems in retaining heavy metals. Copyright © 2017 Sociedade Brasileira de Microbiologia. Published by Elsevier Editora Ltda. All rights reserved.

  10. Traumatic diaphragmatic hernia in a 5-month-old boxer dog.

    PubMed

    Hoddinott, Katie

    2013-05-01

    A 5-month-old intact male boxer dog was presented to the Metro Animal Emergency Clinic, Dartmouth, Nova Scotia after being hit by a car. Radiography identified a diaphragmatic hernia with the stomach herniated into the thoracic cavity. Diaphragmatic herniorrhaphy and splenectomy were performed without complication. The patient returned to his regular active lifestyle.

  11. 26 CFR 1.410(a)-5 - Year of service; break in service.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Year of service; break in service. 1.410(a)-5... service; break in service. (a) Year of service. For the rules relating to years of service under... 29 CFR Part 2530, relating to minimum standards for employee pension benefits plans. (c) Breaks in...

  12. 26 CFR 1.613A-5 - Election under section 613A(c)(4).

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... TAX (CONTINUED) INCOME TAXES (CONTINUED) Natural Resources § 1.613A-5 Election under section 613A(c)(4... claim for credit or refund. The election allows the taxpayer to treat as his depletable natural gas... production, as well as primary production, but in determining the taxpayer's depletable natural gas quantity...

  13. Genital primary herpes simplex infection in a 5-month-old infant.

    PubMed

    Batalla, Ana; Flórez, Angeles; Dávila, Paula; Ojea, Vanesa; Abalde, Teresa; de la Torre, Carlos

    2011-08-15

    Genital primary herpes simplex infection is very uncommon in infants. Asymptomatic and oral primary infections are the most frequent presentations in this age group. We report a case of genital primary herpetic infection in a 5-month-old male, exclusively breastfed, whose mother suffered from active labial herpes.

  14. Gene therapy for achromatopsia.

    PubMed

    Michalakis, Stylianos; Schön, Christian; Becirovic, Elvir; Biel, Martin

    2017-03-01

    The present review summarizes the current status of achromatopsia (ACHM) gene therapy-related research activities and provides an outlook for their clinical application. ACHM is an inherited eye disease characterized by a congenital absence of cone photoreceptor function. As a consequence, ACHM is associated with strongly impaired daylight vision, photophobia, nystagmus and a lack of color discrimination. Currently, six genes have been linked to ACHM. Up to 80% of the patients carry mutations in the genes CNGA3 and CNGB3 encoding the two subunits of the cone cyclic nucleotide-gated channel. Various animal models of the disease have been established and their characterization has helped to increase our understanding of the pathophysiology associated with ACHM. With the advent of adeno-associated virus vectors as valuable gene delivery tools for retinal photoreceptors, a number of promising gene supplementation therapy programs have been initiated. In recent years, huge progress has been made towards bringing a curative treatment for ACHM into clinics. The first clinical trials are ongoing or will be launched soon and are expected to contribute important data on the safety and efficacy of ACHM gene supplementation therapy. Copyright © 2017 John Wiley & Sons, Ltd.

  15. 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 inmore » 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.« less

  16. 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

  17. Harnessing gene expression networks to prioritize candidate epileptic encephalopathy genes.

    PubMed

    Oliver, Karen L; Lukic, Vesna; Thorne, Natalie P; Berkovic, Samuel F; Scheffer, Ingrid E; Bahlo, Melanie

    2014-01-01

    We apply a novel gene expression network analysis to a cohort of 182 recently reported candidate Epileptic Encephalopathy genes to identify those most likely to be true Epileptic Encephalopathy genes. These candidate genes were identified as having single variants of likely pathogenic significance discovered in a large-scale massively parallel sequencing study. Candidate Epileptic Encephalopathy genes were prioritized according to their co-expression with 29 known Epileptic Encephalopathy genes. We utilized developing brain and adult brain gene expression data from the Allen Human Brain Atlas (AHBA) and compared this to data from Celsius: a large, heterogeneous gene expression data warehouse. We show replicable prioritization results using these three independent gene expression resources, two of which are brain-specific, with small sample size, and the third derived from a heterogeneous collection of tissues with large sample size. Of the nineteen genes that we predicted with the highest likelihood to be true Epileptic Encephalopathy genes, two (GNAO1 and GRIN2B) have recently been independently reported and confirmed. We compare our results to those produced by an established in silico prioritization approach called Endeavour, and finally present gene expression networks for the known and candidate Epileptic Encephalopathy genes. This highlights sub-networks of gene expression, particularly in the network derived from the adult AHBA gene expression dataset. These networks give clues to the likely biological interactions between Epileptic Encephalopathy genes, potentially highlighting underlying mechanisms and avenues for therapeutic targets.

  18. Harnessing Gene Expression Networks to Prioritize Candidate Epileptic Encephalopathy Genes

    PubMed Central

    Oliver, Karen L.; Lukic, Vesna; Thorne, Natalie P.; Berkovic, Samuel F.; Scheffer, Ingrid E.; Bahlo, Melanie

    2014-01-01

    We apply a novel gene expression network analysis to a cohort of 182 recently reported candidate Epileptic Encephalopathy genes to identify those most likely to be true Epileptic Encephalopathy genes. These candidate genes were identified as having single variants of likely pathogenic significance discovered in a large-scale massively parallel sequencing study. Candidate Epileptic Encephalopathy genes were prioritized according to their co-expression with 29 known Epileptic Encephalopathy genes. We utilized developing brain and adult brain gene expression data from the Allen Human Brain Atlas (AHBA) and compared this to data from Celsius: a large, heterogeneous gene expression data warehouse. We show replicable prioritization results using these three independent gene expression resources, two of which are brain-specific, with small sample size, and the third derived from a heterogeneous collection of tissues with large sample size. Of the nineteen genes that we predicted with the highest likelihood to be true Epileptic Encephalopathy genes, two (GNAO1 and GRIN2B) have recently been independently reported and confirmed. We compare our results to those produced by an established in silico prioritization approach called Endeavour, and finally present gene expression networks for the known and candidate Epileptic Encephalopathy genes. This highlights sub-networks of gene expression, particularly in the network derived from the adult AHBA gene expression dataset. These networks give clues to the likely biological interactions between Epileptic Encephalopathy genes, potentially highlighting underlying mechanisms and avenues for therapeutic targets. PMID:25014031

  19. Classification of genes based on gene expression analysis

    NASA Astrophysics Data System (ADS)

    Angelova, M.; Myers, C.; Faith, J.

    2008-05-01

    Systems biology and bioinformatics are now major fields for productive research. DNA microarrays and other array technologies and genome sequencing have advanced to the point that it is now possible to monitor gene expression on a genomic scale. Gene expression analysis is discussed and some important clustering techniques are considered. The patterns identified in the data suggest similarities in the gene behavior, which provides useful information for the gene functionalities. We discuss measures for investigating the homogeneity of gene expression data in order to optimize the clustering process. We contribute to the knowledge of functional roles and regulation of E. coli genes by proposing a classification of these genes based on consistently correlated genes in expression data and similarities of gene expression patterns. A new visualization tool for targeted projection pursuit and dimensionality reduction of gene expression data is demonstrated.

  20. Comparison of the biological effects of exogenous and endogenous 1,25-dihydroxyvitamin D3on the mature osteoblast cell line MLO-A5.

    PubMed

    Yang, Dongqing; Anderson, Paul H; Turner, Andrew G; Morris, Howard A; Atkins, Gerald J

    2016-11-01

    Clinical and animal data indicate that serum 25-hydroxyvitamin D 3 (25D) exerts an anabolic effect on bone while serum 1α,25-dihydroxyvitamin D 3 (1,25D) stimulates bone mineral loss, although the mechanism responsible for these divergent actions is unknown. Biological effects of 25D on bone cells are dependent on the local conversion to 1,25D by the 25-hydroxyvitamin D-1α-hydroxylase enzyme, CYP27B1. Therefore, identification of possible differential activities of locally produced and exogenously supplied 1,25D in bone is likely to be informative for guiding optimal administration of vitamin D supplements for bone health. The mature osteoblastic cell line MLO-A5 expresses both the vitamin D receptor (Vdr) and Cyp27b1, and therefore is a suitable model for comparing the activities of 1,25D arising from these sources. Biologically, exogenous and endogenous sources of 1,25D have similar effects on proliferation, mineralisation and induction of a range of genes by MLO-A5 osteoblasts under osteogenic conditions although endogenous 1,25D levels are markedly lower than exogenous levels. Significant differences of pharmacokinetics and pharmacodynamics of 1,25D are evident between these two sources particularly in terms of modulating gene expression for Cyp24a1 and other genes largely expressed by embedded osteoblasts/osteocytes suggesting that endogenously synthesised 1,25D is more efficiently utilised by the differentiating osteoblast. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. 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.

  2. 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

  3. 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

    2014-07-03

    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. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  4. Recovery of reliability by retest after a 5-minute interval in frequency doubling technology perimetry.

    PubMed

    Tsukamoto, Hidetoshi; Mukai, Satoshi; Iwase, Aiko; Mishima, Hiromu K

    2006-01-01

    In frequency doubling technology (FDT) perimetry, the incidence of tests classified as unreliable is higher in the second-tested left eye than in the first-tested right eye when perimetry is performed without a rest period. The purpose of this study was to determine whether the incidence of unreliable results was reduced when the retest began after a 5-min rest period. The subjects were 978 residents of Miyoshi City, Japan, who underwent FDT perimetry during a medical checkup. FDT perimetry was always performed first on the right eye and then on the left eye without a rest interval. When the results were determined to be unreliable, FDT perimetry was repeated after a 5-min rest interval. The perimetric results were determined to be unreliable in one eye of 119 subjects; the results of the first-tested right eye were unreliable in 24 (20.2%), and the results of the second-tested left eye were unreliable in 95 (79.8%) subjects. This difference in the incidence of reliability was significant (P<0.001). After a 5-min rest interval, the percentage of eyes with reliable results recovered to 92% of the right eyes and to 86% of the left eyes. The incidence of unreliable results in FDT perimetry of the second-tested left eye was higher than that of the first-tested right eye when tests were performed without a rest interval. However, the incidence of unreliability in the eye was decreased when the retest was performed after a 5-min rest interval. Copyright (c) Japanese Ophthalmological Society 2006.

  5. A 5TH GENERATION FIGHTER FOR BELGIUM:LUXURY OR NECESSITY

    DTIC Science & Technology

    2016-02-16

    AIR WAR COLLEGE AIR UNIVERSITY A 5TH GENERATION FIGHTER FOR BELGIUM: LUXURY OR NECESSITY? by Patrik De Groot, Lieutenant Colonel...completing the F-16 conversion program at Tucson (AZ), he started his operational career in 1997 at the 10th Fighter Bomber Wing in Kleine Brogel (BEL...correctly identify the technological requirements for a future fighter platform which has to deliver responsive and effective airpower in the

  6. Gene disruption and basic phenotypic analysis of nine novel yeast genes from chromosome XIV.

    PubMed

    Capozzo, C; Sartorello, F; Dal Pero, F; D'Angelo, M; Vezzi, A; Campanaro, S; Valle, G

    2000-09-15

    In this work, we describe the disruption of nine ORFs of S. cerevisiae (YNL123w, YNL119w, YNL115c, YNL108c, YNL110c, YNL124w, YNL233w, YNL232w and YNL231c) in two genetic backgrounds: FY1679 and CEN.PK2. For the construction of the deletant strains, we used the strategy of short flanking homology (SFH) PCR. The SFH-deletion cassette was made by PCR amplification of the KanMX4 module with primers containing a 5' region of 40 bases homologous to the target yeast gene and with a 3' region of 20 bases homologous to pFA6a-KanMX4 MCS. Sporulation and tetrad analysis of heterozygous deletants revealed that YNL110c, YNL124w and YNL232w are essential genes. The subcellular localization of the protein encoded by the essential gene YNL110c was investigated using the green fluorescent protein (GFP) approach, revealing a nuclear pattern. Basic phenotypic analysis of the non-essential genes revealed that the growth of ynl119w delta haploid cells was severely affected at 37 degrees C in N3 medium, indicating that this gene is required at high temperatures with glycerol as a non-fermentable substrate. The ynl233w delta haploid cells also showed a particular phenotype under light microscopy and were studied in detail in a separate work. Copyright 2000 John Wiley & Sons, Ltd.

  7. 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.

  8. Expression of brown-midrib in a spontaneous sorghum mutant is linked to a 5'-UTR deletion in lignin biosynthesis gene SbCAD2

    USDA-ARS?s Scientific Manuscript database

    Brown midrib (bmr) mutants in sorghum (Sorghum bicolor (L.) Moench) and several other C4 grasses are associated with reduced lignin concentration, altered lignin composition and improved cell wall digestibility, which are desirable properties in biomass development for the emerging lignocellulosic b...

  9. Characterization of the fan1 locus in soybean line A5 and development of molecular assays for high-throughput genotyping of FAD3 genes

    USDA-ARS?s Scientific Manuscript database

    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...

  10. Discriminative stimulus properties of indorenate, a 5-HT1A, 5-HT1B and 5-HT2C agonist: a study in rats.

    PubMed

    Sánchez, H; Velázquez-Martínez, D N

    2001-03-01

    Indorenate (INDO), initially described as an antihypertensive agent, also has some effects on behaviour, with anxiolytic and anorectic actions being reported. The aim of the present experiment was to examine the activity of INDO at the behavioural level at various serotonin (5-hydroxytryptamine, 5-HT) receptor sites by comparing its stimulus properties with those of other 5-HT receptor agonists and by examining its interactions with some 5-HT antagonists. Rats were trained to discriminate between 10.0 mg/kg INDO (administered intraperitoneally (90 min before the start of the session) from saline. A Fixed Ratio 10 (FR10) schedule of reinforcement was in effect in each drug condition. During generalization test sessions, the discrimination index (DI, responses to drug lever/responses to drug + saline lever) was calculated from the responses emitted before the first reinforcer of the session. DI was a function of the dose of INDO employed. Generalization to the discriminative stimulus properties of INDO was observed with the 5-HT1A receptor agonist 8-OH-DPAT (1.0 mg/kg produced 90% generalization) and the 5-HT(1B/2C) receptor agonist 1-(3-trifluoromethylphenyl) piperazine (TFMPP) (3.0 mg/kg produced up to 75% generalization). Yohimbine (5.6 mg/kg), buspirone (1.0 mg/kg), 6-chloro-2-(1-piperaziny)pyrazine (1.0 mg/kg) and m-chlorophenylpiperazine (mCPP) (1.0 mg/kg) induced a DI of 70%, 50% and 48% and 55%, respectively. In generalization tests, ritanserin (0.01-1.0 mg/kg) induced saline-like responding. NAN-190 (3.0 mg/kg), a 5-HT1A receptor antagonist, was able to reduce the DI of INDO to 50%. Although the 5-HT(2C/2A) receptor antagonists cinanserin (10.0 mg/kg) and metergoline (0.3 mg/kg) were able to reduce the stimulus properties of INDO to 60% and 30%, respectively, only ritanserin (1.0 mg/kg) reduced the stimulus properties of INDO to 25% with a clear dose-response relationship. The results suggest that INDO acts as an agonist at 5-HT1A receptor sites, but its

  11. 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

  12. 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.

  13. Molecular epidemiology of Acinetobacter baumannii and Acinetobacter nosocomialis in Germany over a 5-year period (2005-2009).

    PubMed

    Schleicher, X; Higgins, P G; Wisplinghoff, H; Körber-Irrgang, B; Kresken, M; Seifert, H

    2013-08-01

    To investigate the species distribution within the Acinetobacter calcoaceticus-Acinetobacter baumannii complex and the molecular epidemiology of A. baumannii and Acinetobacter nosocomialis, 376 Acinetobacter isolates were collected prospectively from hospitalized patients at 15 medical centres in Germany during three surveillance studies conducted over a 5-year period. Species identification was performed by molecular methods. Imipenem minimum inhibitory concentrations (MIC) were determined by broth microdilution. The prevalence of the most common carbapenemase-encoding genes was investigated by oxacillinase (OXA) -multiplex polymerase chain reaction (PCR). The molecular epidemiology was investigated by repetitive sequence-based PCR (rep-PCR; DiversiLab™). Acinetobacter pittii was the most prevalent Acinetobacter species (n = 193), followed by A. baumannii (n = 140), A. calcoaceticus (n = 10) and A. nosocomialis (n = 8). The majority of A. baumannii was represented by sporadic isolates (n = 70, 50%) that showed unique rep-PCR patterns, 25 isolates (18%) clustered with one or two other isolates, and only 45 isolates (32%) belonged to one of the previously described international clonal lineages. The most prevalent clonal lineage was international clone (IC) 2 (n = 34) and IC 1 (n = 6). According to CLSI, 25 A. baumannii isolates were non-susceptible to imipenem (MIC ≥ 8 mg/L), all of which produced an OXA-58-like or OXA-23-like carbapenemase. The rate of imipenem susceptibility among A. baumannii isolates decreased from 96% in 2005 to 76% in 2009. All other Acinetobacter isolates were susceptible to imipenem. The population structure of carbapenem-susceptible A. baumannii in Germany is highly diverse. Imipenem non-susceptibility was strongly associated with the clonal lineages IC 2 and IC 1. These data underscore the high clonality of carbapenem-resistant A. baumannii isolates. © 2012 The Authors. Clinical Microbiology and Infection © 2012 European Society of

  14. [Surgical treatment of a pheocromocytoma bilateral in a 5 year old patient with the von Hippel-Lindau disease].

    PubMed

    Blanco, J A; Blanco, D; Alastrue, A; Castellví, A; Isnard, R M; Pintos, G; Mangas, A; Roig, N; Casasa, J M

    2004-01-01

    The disease of Von Hippel Lindau (VHL) is hereditary and causes a predisposition to the development of tumours. Organs such as the cerebellum, the pancreas, the kidney, the suprarenal glands and the retina are more usually affected by this disease. We present the case of a 5-year-old patient who suffers from asiymptomatic high blood pressure. In the family antecedents, it is relevant the case of the father, with pheocromocytoma bilateral, which led us to carry out a genetic study of his two sons. Our patient, the younger; presented a mutation of the VHL gene in the short arm of the chromosome 3. In one of the periodic controls, it could be detected high blood pressure of 160/100 mm. Hg, clinically asymptomatic. The other child did not present a genetic mutation and has no disease. The presence of high catecholamines, the detection of a 3 cm left suprarenal mass through the ecography, the TAC that did not show a right suprarenal pathology and the MBIG scintigraphy confirmed the diagnostic of pheocromocytoma. The RNM showed another 0.8-cm mass which confirmed a pheocromocytoma bilateral. We started the treatment against high blood pressure with fenoxibenzamine and diltiazem, and we controlled this problem. We also prepared the pre-and-post operation anesthetic strategy, which is so important for the surgical success. The operation started by a laparoscopic, we made left adrenalectomy and we had to reconvert to laparotomy to make partial right adrenalectomy. Six months after the operation, the patient is free from symptomatology and follows a treatment with glucocorticoides with smaller and smaller doses. The case is exceptional because it embodies the following characteristics: early diagnostic age, family affectation and discovery of asymptomatic high blood pressure. It needed an appropriate preanesthetic and anesthetic preparation, which gave way to an operation without complications. The postoperation was also stable and presented no complications.

  15. 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

  16. Heterologous gene expression driven by carbonic anhydrase gene promoter in Dunaliella salina

    NASA Astrophysics Data System (ADS)

    Chai, Yurong; Lu, Yumin; Wang, Tianyun; Hou, Weihong; Xue, Lexun

    2006-12-01

    Dunaliella salina, a halotolerant unicellular green alga without a rigid cell wall, can live in salinities ranging from 0.05 to 5 mol/L NaCl. These features of D. salina make it an ideal host for the production of antibodies, oral vaccine, and commercially valuable polypeptides. To produce high level of heterologous proteins from D. salina, highly efficient promoters are required to drive expression of target genes under controlled condition. In the present study, we cloned a 5' franking region of 1.4 kb from the carbonic anhydrase ( CAH) gene of D. salina by genomic walking and PCR. The fragment was ligated to the pMD18-T vector and characterized. Sequence analysis indicated that this region contained conserved motifs, including a TATA- like box and CAAT-box. Tandem (GT)n repeats that had a potential role of transcriptional control, were also found in this region. The transcription start site (TSS) of the CAH gene was determined by 5' RACE and nested PCR method. Transformation assays showed that the 1.4 kb fragment was able to drive expression of the selectable bar (bialaphos resistance) gene when the fusion was transformed into D. salina by biolistics. Northern blotting hybridizations showed that the bar transcript was most abundant in cells grown in 2 mol/L NaCl, and less abundant in 0.5 mol/L NaCl, indicating that expression of the bar gene was induced at high salinity. These results suggest the potential use of the CAH gene promoter to induce the expression of heterologous genes in D. salina under varied salt condition.

  17. Genes In Space-5

    NASA Image and Video Library

    2018-04-13

    iss055e020319 (April 13, 2018) --- Flight Engineer Ricky Arnold processes of samples inside the Miniature Polymerase Chain Reaction (miniPCR) for the Genes In Space-5 experiment. The research gathered from Genes in Space-5 may be valuable in the development of procedures to maintain astronaut health and prevent an increased risk of cancer on deep space missions. The investigation also provides a deeper understanding of the human immune system, while giving student researchers a direct connection to the space program and offering hands-on educational experiences on Earth and promoting involvement in STEM fields.

  18. 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

  19. 17 CFR 270.3a-5 - Exemption for subsidiaries organized to finance the operations of domestic or foreign companies.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... organized to finance the operations of domestic or foreign companies. 270.3a-5 Section 270.3a-5 Commodity..., INVESTMENT COMPANY ACT OF 1940 § 270.3a-5 Exemption for subsidiaries organized to finance the operations of domestic or foreign companies. (a) A finance subsidiary will not be considered an investment company under...

  20. 17 CFR 270.3a-5 - Exemption for subsidiaries organized to finance the operations of domestic or foreign companies.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... organized to finance the operations of domestic or foreign companies. 270.3a-5 Section 270.3a-5 Commodity..., INVESTMENT COMPANY ACT OF 1940 § 270.3a-5 Exemption for subsidiaries organized to finance the operations of domestic or foreign companies. (a) A finance subsidiary will not be considered an investment company under...

  1. 17 CFR 270.3a-5 - Exemption for subsidiaries organized to finance the operations of domestic or foreign companies.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... organized to finance the operations of domestic or foreign companies. 270.3a-5 Section 270.3a-5 Commodity..., INVESTMENT COMPANY ACT OF 1940 § 270.3a-5 Exemption for subsidiaries organized to finance the operations of domestic or foreign companies. (a) A finance subsidiary will not be considered an investment company under...

  2. 17 CFR 270.3a-5 - Exemption for subsidiaries organized to finance the operations of domestic or foreign companies.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... organized to finance the operations of domestic or foreign companies. 270.3a-5 Section 270.3a-5 Commodity..., INVESTMENT COMPANY ACT OF 1940 § 270.3a-5 Exemption for subsidiaries organized to finance the operations of domestic or foreign companies. (a) A finance subsidiary will not be considered an investment company under...

  3. Enhancement of jump performance after a 5-RM squat is associated with postactivation potentiation.

    PubMed

    Mitchell, Cameron J; Sale, Digby G

    2011-08-01

    Weight lifting exercise may induce postactivation potentiation (PAP), thereby enhancing performance of a subsequent biomechanically similar "explosive" movement. However, it has not been shown that weight lifting induces PAP, indicated as potentiation of muscle twitch force. Therefore, the present study tested whether a five repetition maximum squat (5-RM squat) both induced PAP and increased the height of subsequently performed counter-movement jumps (CMJs). Eleven male athletes completed four laboratory sessions on separate days. Two sessions determined whether the 5-RM squat induced PAP: in one, a quadriceps maximal twitch was evoked immediately before and 8 min after a set of five CMJs (control); in the other, a twitch was evoked before a CMJ set, which was followed by a 4-min rest, a 5-RM squat, a 4-min rest, and a second twitch. Another two sessions tested the effect of the 5-RM squat on jump performance: in one session, two sets of five CMJs were performed with an 8-min rest between the sets (control); in the second, a 5-RM squat was performed 4 min after the first set of CMJs, and then after another 4 min the second set of CMJs was performed. Neither twitch torque nor CMJ height changed in the control sessions (P > 0.05). In contrast, interpolation of the 5-RM squat increased (P < 0.05) both twitch torque (49.5 ± 7.8 to 54.8 ± 11.9 N m; i.e., PAP = 10.7%) and CMJ height (48.1 ± 5.6 to 49.5 ± 5.9 cm; 2.9%). Since PAP was present at the time when CMJ height increased, it was concluded that PAP may have contributed to the increased CMJ height after a 5-RM squat.

  4. 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.

  5. MoBio: A 5 DOF trans-humeral robotic prosthesis.

    PubMed

    Abayasiri, R Achintha M; Madusanka, D G Kanishka; Arachchige, N M P; Silva, A T S; Gopura, R A R C

    2017-07-01

    In this paper, a 5 DOF trans-humeral robotic prosthesis: MoBio is proposed. MoBio includes 2 DOF at wrist which is rare in other trans-humeral prostheses. Through anthropometric features MoBio prosthetic arm can achieve elbow flexion/extension, forearm supination/pronation, wrist radial/ulnar deviation, wrist flexion/extension and compound motion of thumb and index finger. An EMG based control method which uses EMG signals of the biceps brachii and triceps brachii, is used with a motion switching mechanism to control the prosthesis. Experimental results have verified the usability and effectiveness of MoBio in performing Activities of Daily Living.

  6. 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.

  7. [Coffin-Siris syndrome in a 5-year-old girl].

    PubMed

    Meinecke, P; Engelbrecht, R; Schaefer, E

    1986-09-01

    A 5 1/2 year old female patient with Coffin-Siris syndrome is described. This syndrome is characterised by multiple congenital anomalies and mental retardation. The important clinical features include postnatal growth retardation, microcephaly, considerable psychomotor retardation, coarse facies with thick lips, sparse scalp hair with hypertrichosis of the face and body, as well as hypoplasia or even aplasia of distal phalanges of fingers and toes. Chromosomal aberrations, which could be considered as differential diagnosis are excluded by the finding of a normal karyotype. The aetiology or pathogenesis of this syndrome are not really known.

  8. "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. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Naming genes beyond Caenorhabditis

    USDA-ARS?s Scientific Manuscript database

    The nomenclature of genes in Caenorhabditis elegans is based on long-standing, successful guidelines established in the late 1970s. Over time these guidelines have matured into a comprehensive, systematic nomenclature that is easy to apply, descriptive and therefore highly informative. Recently, a f...

  10. Genes for magnesium transport.

    PubMed

    Gardner, Richard C

    2003-06-01

    We know very little about the regulation of magnesium uptake and the control of magnesium homeostasis. After years of relative neglect, however, rapid progress is now being made in understanding the molecular biology of magnesium transport in eukaryotes. Several new gene families have been implicated, and tools are in place for the dissection of the biochemical and biological roles played by the encoded proteins.

  11. Are there anxious genes?

    PubMed Central

    Morris-Rosendahl, Deborah J.

    2002-01-01

    Anxiety comprises many clinical descriptions and phenotypes. A genetic predisposition to anxiety is undoubted; however, the nature and extent of that contribution is still unclear. Methods for the genetic analysis of such complex disorders is briefly reviewed, followed by a discussion of the comorbidity of anxiety with other psychiatric disorders and their possible common genetic etiology. Extensive genetic studies of the serotonin (5-hydroxytryptamine, 5-HT) transporter (5-HTT) gene have revealed how variation in gene expression can be correlated with anxiety phenotypes. Complete genome-wide linkage scans for panic disorder (PD) susceptibility genes have suggested a locus on chromosome arm 7p, and association studies have highlighted many candidate genes. A highly significant association between phobias, panic disorder, and a duplication at chromosomal region 15q24-26 is one of the most exciting findings to date. Emerging molecular genetic technologies and the use of increasingly sophisticated animal models of anxiety provide great promise for the future of the field. PMID:22033820

  12. Genes and Vocal Learning

    ERIC Educational Resources Information Center

    White, Stephanie A.

    2010-01-01

    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…

  13. Multidimensional gene search with Genehopper.

    PubMed

    Munz, Matthias; Tönnies, Sascha; Balke, Wolf-Tilo; Simon, Eric

    2015-07-01

    The high abundance of genetic information enables researchers to gain new insights from the comparison of human genes according to their similarities. However, existing tools that allow the exploration of such gene-to-gene relationships, apply each similarity independently. To make use of multidimensional scoring, we developed a new search engine named Genehopper. It can handle two query types: (i) the typical use case starts with a term-to-gene search, i.e. an optimized full-text search for an anchor gene of interest. The web-interface can handle one or more terms including gene symbols and identifiers of Ensembl, UniProt, EntrezGene and RefSeq. (ii) When the anchor gene is defined, the user can explore its neighborhood by a gene-to-gene search as the weighted sum of nine normalized gene similarities based on sequence homology, protein domains, mRNA expression profiles, Gene Ontology Annotation, gene symbols and other features. Each weight can be adjusted by the user, allowing flexible customization of the gene search. All implemented similarities have a low pairwise correlation (max r(2) = 0.4) implying a low linear dependency, i.e. any change in a single weight has an effect on the ranking. Thus, we treated them as separate dimensions in the search space. Genehopper is freely available at http://genehopper.ifis.cs.tu-bs.de. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  14. Metallothionein MT2A A-5G Polymorphism as a Risk Factor for Chronic Kidney Disease and Diabetes: Cross-Sectional and Cohort Studies.

    PubMed

    Hattori, Yuta; Naito, Mariko; Satoh, Masahiko; Nakatochi, Masahiro; Naito, Hisao; Kato, Masashi; Takagi, Sahoko; Matsunaga, Takashi; Seiki, Toshio; Sasakabe, Tae; Suma, Shino; Kawai, Sayo; Okada, Rieko; Hishida, Asahi; Hamajima, Nobuyuki; Wakai, Kenji

    2016-07-01

    Metallothioneins (MTs) are proteins that protect cells from toxic agents such as heavy metal ions or reactive oxygen species. MT2A A-5G is a single nucleotide polymorphism in the promoter region of the MT2A gene, and the minor G allele results in lower transcription efficiency. We aimed to elucidate associations between MT2A A-5G and risks of 2 diseases potentially related to lowered MT expression, chronic kidney disease (CKD), and diabetes mellitus (DM), in a community-dwelling population. Study subjects were Nagoya city residents participating in the Japan Multi-Institutional Collaborative Cohort Study (J-MICC) Daiko Study, comprised 749 men and 2,025 women, aged 39-75 years. CKD (>stage 3) and DM were defined by standard guidelines. Associations were evaluated using logistic regression models with adjustments for age, sex and potential confounders in a cross-sectional study, and verified in a 5-year longitudinal study. Odds ratios (OR [95% confidence interval]) were calculated relative to the AA genotype. Serum MT (I + II), Cd and zinc levels were also determined by genotype. The OR of the GG genotype for CKD risk was 3.98 (1.50, 10.58) in the cross-sectional study and 5.17 (1.39, 19.28) in the longitudinal study. The OR of the GA genotype for DM was 1.86 (1.26, 2.75) in the cross-sectional study and 2.03 (1.19, 3.46) in the longitudinal study. MT2A A-5G may be associated with CKD and DM risks. This polymorphism is a promising target for evaluations of CKD and DM risks with possible involvement of low-dose chronic exposure to environmental pollutants. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology.

  15. Metallothionein MT2A A-5G Polymorphism as a Risk Factor for Chronic Kidney Disease and Diabetes: Cross-Sectional and Cohort Studies

    PubMed Central

    Hattori, Yuta; Naito, Mariko; Satoh, Masahiko; Nakatochi, Masahiro; Naito, Hisao; Kato, Masashi; Takagi, Sahoko; Matsunaga, Takashi; Seiki, Toshio; Sasakabe, Tae; Suma, Shino; Kawai, Sayo; Okada, Rieko; Hishida, Asahi; Hamajima, Nobuyuki; Wakai, Kenji

    2016-01-01

    Metallothioneins (MTs) are proteins that protect cells from toxic agents such as heavy metal ions or reactive oxygen species. MT2A A-5G is a single nucleotide polymorphism in the promoter region of the MT2A gene, and the minor G allele results in lower transcription efficiency. We aimed to elucidate associations between MT2A A-5G and risks of 2 diseases potentially related to lowered MT expression, chronic kidney disease (CKD), and diabetes mellitus (DM), in a community-dwelling population. Study subjects were Nagoya city residents participating in the Japan Multi-Institutional Collaborative Cohort Study (J-MICC) Daiko Study, comprised 749 men and 2,025 women, aged 39–75 years. CKD (>stage 3) and DM were defined by standard guidelines. Associations were evaluated using logistic regression models with adjustments for age, sex and potential confounders in a cross-sectional study, and verified in a 5-year longitudinal study. Odds ratios (OR [95% confidence interval]) were calculated relative to the AA genotype. Serum MT (I + II), Cd and zinc levels were also determined by genotype. The OR of the GG genotype for CKD risk was 3.98 (1.50, 10.58) in the cross-sectional study and 5.17 (1.39, 19.28) in the longitudinal study. The OR of the GA genotype for DM was 1.86 (1.26, 2.75) in the cross-sectional study and 2.03 (1.19, 3.46) in the longitudinal study. MT2A A-5G may be associated with CKD and DM risks. This polymorphism is a promising target for evaluations of CKD and DM risks with possible involvement of low-dose chronic exposure to environmental pollutants. PMID:27122239

  16. Enhanced construction of gene regulatory networks using hub gene information.

    PubMed

    Yu, Donghyeon; Lim, Johan; Wang, Xinlei; Liang, Faming; Xiao, Guanghua

    2017-03-23

    Gene regulatory networks reveal how genes work together to carry out their biological functions. Reconstructions of gene networks from gene expression data greatly facilitate our understanding of underlying biological mechanisms and provide new opportunities for biomarker and drug discoveries. In gene networks, a gene that has many interactions with other genes is called a hub gene, which usually plays an essential role in gene regulation and biological processes. In this study, we developed a method for reconstructing gene networks using a partial correlation-based approach that incorporates prior information about hub genes. Through simulation studies and two real-data examples, we compare the performance in estimating the network structures between the existing methods and the proposed method. In simulation studies, we show that the proposed strategy reduces errors in estimating network structures compared to the existing methods. When applied to Escherichia coli, the regulation network constructed by our proposed ESPACE method is more consistent with current biological knowledge than the SPACE method. Furthermore, application of the proposed method in lung cancer has identified hub genes whose mRNA expression predicts cancer progress and patient response to treatment. We have demonstrated that incorporating hub gene information in estimating network structures can improve the performance of the existing methods.

  17. Soybean leghemoglobin gene family: normal, pseudo, and truncated genes.

    PubMed Central

    Brisson, N; Verma, D P

    1982-01-01

    Leghemoglobin (Lb) genes in soybean represent a small family of closely related genes. Three Lb sequences isolated from a genomic library were analyzed at the nucleotide sequence level. A Lb gene present on an 11.5-kilobase (kb) EcoRI genomic fragment spans approximately 1,200 nucleotides and is interrupted at amino acid positions 32 to 33, 68 to 69, and 103 to 104. The intervening sequences, as well as the 5' and 3' flanking regions of this gene, contain the consensus sequences found in other eukaryotic genes. The length of the 5'-untranslated region is 49 bases as determined by nuclease S1 mapping. R-loop analysis of the DNA from the recombinant phage containing the 11.5-kb EcoRI genomic fragment showed that another Lb gene is located 2.5 kb away. The nucleotide sequence of the second gene showed that this gene is incomplete, containing only exons 3 and 4. The deduced amino acid sequence of this gene, although showing 76% homology with the corresponding region of the other Lb gene, is not represented in any of the known Lb proteins. Both genes are oriented in the same direction with respect to the coding strand. Analysis of the sequence present on a second genomic clone containing a 4.2-kb EcoRI fragment revealed a truncated Lb gene showing homology with the last exon and the noncoding region at the 3' end of the two other Lb genes. Images PMID:6287463

  18. Genes2FANs: connecting genes through functional association networks

    PubMed Central

    2012-01-01

    Background Protein-protein, cell signaling, metabolic, and transcriptional interaction networks are useful for identifying connections between lists of experimentally identified genes/proteins. However, besides physical or co-expression interactions there are many ways in which pairs of genes, or their protein products, can be associated. By systematically incorporating knowledge on shared properties of genes from diverse sources to build functional association networks (FANs), researchers may be able to identify additional functional interactions between groups of genes that are not readily apparent. Results Genes2FANs is a web based tool and a database that utilizes 14 carefully constructed FANs and a large-scale protein-protein interaction (PPI) network to build subnetworks that connect lists of human and mouse genes. The FANs are created from mammalian gene set libraries where mouse genes are converted to their human orthologs. The tool takes as input a list of human or mouse Entrez gene symbols to produce a subnetwork and a ranked list of intermediate genes that are used to connect the query input list. In addition, users can enter any PubMed search term and then the system automatically converts the returned results to gene lists using GeneRIF. This gene list is then used as input to generate a subnetwork from the user’s PubMed query. As a case study, we applied Genes2FANs to connect disease genes from 90 well-studied disorders. We find an inverse correlation between the counts of links connecting disease genes through PPI and links connecting diseases genes through FANs, separating diseases into two categories. Conclusions Genes2FANs is a useful tool for interpreting the relationships between gene/protein lists in the context of their various functions and networks. Combining functional association interactions with physical PPIs can be useful for revealing new biology and help form hypotheses for further experimentation. Our finding that disease genes in

  19. Industrial scale gene synthesis.

    PubMed

    Notka, Frank; Liss, Michael; Wagner, Ralf

    2011-01-01

    The most recent developments in the area of deep DNA sequencing and downstream quantitative and functional analysis are rapidly adding a new dimension to understanding biochemical pathways and metabolic interdependencies. These increasing insights pave the way to designing new strategies that address public needs, including environmental applications and therapeutic inventions, or novel cell factories for sustainable and reconcilable energy or chemicals sources. Adding yet another level is building upon nonnaturally occurring networks and pathways. Recent developments in synthetic biology have created economic and reliable options for designing and synthesizing genes, operons, and eventually complete genomes. Meanwhile, high-throughput design and synthesis of extremely comprehensive DNA sequences have evolved into an enabling technology already indispensable in various life science sectors today. Here, we describe the industrial perspective of modern gene synthesis and its relationship with synthetic biology. Gene synthesis contributed significantly to the emergence of synthetic biology by not only providing the genetic material in high quality and quantity but also enabling its assembly, according to engineering design principles, in a standardized format. Synthetic biology on the other hand, added the need for assembling complex circuits and large complexes, thus fostering the development of appropriate methods and expanding the scope of applications. Synthetic biology has also stimulated interdisciplinary collaboration as well as integration of the broader public by addressing socioeconomic, philosophical, ethical, political, and legal opportunities and concerns. The demand-driven technological achievements of gene synthesis and the implemented processes are exemplified by an industrial setting of large-scale gene synthesis, describing production from order to delivery. Copyright © 2011 Elsevier Inc. All rights reserved.

  20. Selenoprotein Gene Nomenclature.

    PubMed

    Gladyshev, Vadim N; Arnér, Elias S; Berry, Marla J; Brigelius-Flohé, Regina; Bruford, Elspeth A; Burk, Raymond F; Carlson, Bradley A; Castellano, Sergi; Chavatte, Laurent; Conrad, Marcus; Copeland, Paul R; Diamond, Alan M; Driscoll, Donna M; Ferreiro, Ana; Flohé, Leopold; Green, Fiona R; Guigó, Roderic; Handy, Diane E; Hatfield, Dolph L; Hesketh, John; Hoffmann, Peter R; Holmgren, Arne; Hondal, Robert J; Howard, Michael T; Huang, Kaixun; Kim, Hwa-Young; Kim, Ick Young; Köhrle, Josef; Krol, Alain; Kryukov, Gregory V; Lee, Byeong Jae; Lee, Byung Cheon; Lei, Xin Gen; Liu, Qiong; Lescure, Alain; Lobanov, Alexei V; Loscalzo, Joseph; Maiorino, Matilde; Mariotti, Marco; Sandeep Prabhu, K; Rayman, Margaret P; Rozovsky, Sharon; Salinas, Gustavo; Schmidt, Edward E; Schomburg, Lutz; Schweizer, Ulrich; Simonović, Miljan; Sunde, Roger A; Tsuji, Petra A; Tweedie, Susan; Ursini, Fulvio; Whanger, Philip D; Zhang, Yan

    2016-11-11

    The human genome contains 25 genes coding for selenocysteine-containing proteins (selenoproteins). These proteins are involved in a variety of functions, most notably redox homeostasis. Selenoprotein enzymes with known functions are designated according to these functions: TXNRD1, TXNRD2, and TXNRD3 (thioredoxin reductases), GPX1, GPX2, GPX3, GPX4, and GPX6 (glutathione peroxidases), DIO1, DIO2, and DIO3 (iodothyronine deiodinases), MSRB1 (methionine sulfoxide reductase B1), and SEPHS2 (selenophosphate synthetase 2). Selenoproteins without known functions have traditionally been denoted by SEL or SEP symbols. However, these symbols are sometimes ambiguous and conflict with the approved nomenclature for several other genes. Therefore, there is a need to implement a rational and coherent nomenclature system for selenoprotein-encoding genes. Our solution is to use the root symbol SELENO followed by a letter. This nomenclature applies to SELENOF (selenoprotein F, the 15-kDa selenoprotein, SEP15), SELENOH (selenoprotein H, SELH, C11orf31), SELENOI (selenoprotein I, SELI, EPT1), SELENOK (selenoprotein K, SELK), SELENOM (selenoprotein M, SELM), SELENON (selenoprotein N, SEPN1, SELN), SELENOO (selenoprotein O, SELO), SELENOP (selenoprotein P, SeP, SEPP1, SELP), SELENOS (selenoprotein S, SELS, SEPS1, VIMP), SELENOT (selenoprotein T, SELT), SELENOV (selenoprotein V, SELV), and SELENOW (selenoprotein W, SELW, SEPW1). This system, approved by the HUGO Gene Nomenclature Committee, also resolves conflicting, missing, and ambiguous designations for selenoprotein genes and is applicable to selenoproteins across vertebrates. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. MicroRNA-199a-5p Induced Autophagy and Inhibits the Pathogenesis of Ankylosing Spondylitis by Modulating the mTOR Signaling via Directly Targeting Ras Homolog Enriched in Brain (Rheb).

    PubMed

    Wang, Yahan; Luo, Jianping; Wang, Xiaogang; Yang, Bin; Cui, Liyang

    2017-01-01

    Ankylosing spondylitis (AS) is an inflammatory and immune disease leading to disability. Autophagy has been identified as a potential player in understanding the pathogenesis of AS. MiRNA-199a-5p and autophagy-related gene expression were determined by qRT-PCR or Western blot. Cytokine production was determined using ELISA assays. Proliferation was determined by MTT assay. MiRNA-199a-5p and Ras homolog enriched in brain (Rheb) were upregulated or downregulated by overexpression of plasmid or siRNA transfection. Expression of miRNA-199a-5p, and autophagy-related genes LC3, beclin1, and ATG5 was significantly decreased in T cells of AS patients. Serum concentrations of TNF-α, IL-17, and IL-23 were promoted in AS patients, compared to healthy controls. MiRNA-199a-5p expression levels also showed significant negative correlations with the Ankylosing Spondylitis Disease Activity Score (ASDAS) and modified Stoke Ankylosing Spon dylitis Spinal Score (mSASSS) of AS patients. In Jurkat T cells and T cells isolated from AS patients, miRNA-199a-5p overexpression promoted autophagy-related genes expression and decreased TNF-α, IL-17, and IL-23 levels, whereas inhibition of miRNA-199a-5p attenuated these effects. As a direct target of miRNA-199a-5p, Rheb inhibition led to a striking decrease in the phosphorylation of the mechanistic target of rapamycin (mTOR) and induced autophagy. Moreover, pcDNA3.1-Rheb effectively reduced the inhibiting effects of mTOR signaling caused by miRNA-199a-5p overexpression. All effects were offset by pretreating with rapamycin (an mTOR antagonist). AS patients with advanced spinal damage had decreased autophagy levels and that miRNA-199a-5p may induce autophagy and inhibit the pathogenesis of AS by modulating the mTOR signaling via direct targeting Rheb. © 2017 The Author(s). Published by S. Karger AG, Basel.

  2. The structure and function of tRNA genes of higher eukaryotes.

    PubMed

    Kubli, E

    1981-01-15

    The most recent findings concerning the structure and function of tRNA genes of higher eukaryotes are discussed in an exemplary way. The tRNA genes of higher organisms are either dispersed or clustered at different sites of the genome. Clusters contain tRNA genes oriented in both directions and on both strands of the DNA with spacers of various length inbetween. Some genes contain intervening sequences close to the 3' side of the anticodon. The primary transcription product possesses a 5' leader and a 3' trailer sequence which are removed by several maturation steps in a strict temporal and spacial order. Internal transcription control regions (promotors) are located at the 5' and 3' ends of the mature tRNA coding section of the tRNA gene. External sequences modulating the efficiency of the expression are present at the immediate 5' ends of the genes. Transfer RNA genes are located nonrandomly in the nucleosomes.

  3. Visual servoing of a 5-DOF mobile manipulator using a catadioptric vision system

    NASA Astrophysics Data System (ADS)

    Zhang, Y.; Mehrandezh, M.

    2007-10-01

    In this paper, a novel visual servoing technique for a 5-dof mobile manipulator with an eye-to-hand camera configuration is introduced. The proposed technique can be categorized as an image based (or 2D) visual servoing using a fixed camera in conjunction with a conic mirror (aka, a Catadioptric camera system) providing panoramic vision. Two fictitious landmarks mounted on robot's end-effector along with their mirror reflections, when viewed by the camera, provide enough information for 3D reasoning based on the four points viewed on the image plane. Instead of directly using the image features associated with these four points, five new image features are chosen to make the image Jacobian rank efficient. A dual estimation/control strategy based on Extended Kalman Filter (EKF) is utilized to (1) estimate camera's intrinsic and extrinsic parameters, and (2) track the coordinates of the landmarks and their reflections on the image plane. The relationship between the translational and rotational velocity of a frame attached to the robot's end-effector and the rate of change of the proposed image features are fully formulated. The robustness of the proposed technique in translational and rotational servoing of a 5-dof holonomic mobile manipulator is illustrated through computer simulations.

  4. Chiropractic management of a 5-year-old boy with urinary and bowel incontinence

    PubMed Central

    Kamrath, Keith R.

    2010-01-01

    Objective The purpose of this article is to describe chiropractic management of a 5-year-old boy with urinary and bowel incontinence. Clinical Features A 5-year-old boy presented with the primary symptoms of a complete lack of bowel and bladder control with prior surgical correction for lumbar meningocele, spinal lipoma, and tethered spinal cord. Examination revealed spinal and pelvic dysfunction. Intervention and Outcome Chiropractic treatment methods included using the Activator adjusting instrument and shortwave diathermy to the lumbar spine and sacrum. A total of 5 treatments were initially provided over a period of 4 weeks. After the initial treatment period, he was able to maintain satisfactory control of his bladder and bowel, day and night, for a period of approximately 6 months. A second course of treatments was initiated approximately 6 months later because of a recurrence of bladder and bowel incontinence. Four additional treatments were provided over a period of 4 weeks. This second course of treatment reestablished satisfactory control of bladder and bowel function. Conclusion For this patient, chiropractic care was successful in establishing satisfactory bladder and bowel control. PMID:21629396

  5. Decolorization of a variety of dyes by Aspergillus flavus A5p1.

    PubMed

    Ning, Cheng; Qingyun, Li; Aixing, Tang; Wei, Su; Youyan, Liu

    2018-04-01

    Aspergillus flavus: fungal strain A5p1 is reported here to decolorize a variety of dyes under broad environmental conditions. For the 15 dyes tested, the decolorization efficiencies ranged from 61.7 to 100.0% at an initial concentration of 100 mg/L. Direct Blue 71 (DB71), Direct Blue 86 (DB86), and Reactive Blue 19 (RB19) were selected as models for comparing decolorization performance. The results show that biosorption and biodegradation work together in the strain to remove the pigments; the effect of biosorption was stronger for DB71 and DB86, whereas the effect of biodegradation was stronger for RB19. For DB71 and DB86, the decolorization rate surpassed 90% with inactivated biomass under acidic conditions and with living biomass under alkaline conditions. DB19 achieved the highest removal rate of 90% under neutral conditions. The strain could effectively decolorize high concentrations of dyes up to 1000 mg/L, which was achieved mainly via biosorption at concentrations below 500 mg/L and via biodegradation at concentrations above 500 mg/L. The findings suggest that A5p1 has a strong adaptability to different dye types and environmental conditions and can, therefore, be potentially used in biological processes for the treatment of dye-containing wastewater.

  6. A common variant association study in ethnic Saudi Arabs reveals novel susceptibility loci for hypertriglyceridemia.

    PubMed

    Ram, R; Wakil, S M; Muiya, N P; Andres, E; Mazhar, N; Hagos, S; Alshahid, M; Meyer, B F; Morahan, G; Dzimiri, N

    2017-03-01

    Hypertriglyceridemia (hTG) is a lipid disorder, resulting from an elevation in triglyceride levels, with a strong genetic component. It constitutes a significant risk factor for coronary artery disease (CAD), a leading cause of death worldwide. In this study, we performed a common variant association study for hTG in ethnic Saudi Arabs. We genotyped 5501 individuals in a two-phase experiment using Affymetrix Axiom ® Genome-Wide CEU 1 Array (Affymetrix, Santa Cruz, CA) that contains a total of 587,352 single nucleotide polymorphisms (SNPs). The lead variant was the rs1558861 [1.99 (1.73-2.30); p = 7.37 × 10 -22 ], residing on chromosome (chr) 11 at the apolipoprotein A-I/A-5 (APOA1/APOA5) locus. The rs780094 [1.34 (1.21-1.49); p = 8.57 × 10 -8 ] on chr 2 at the glucokinase regulatory protein (GCKR) locus was similarly significantly associated, while the rs10911205 [1.29 (1.16-1.44); p = 3.52 × 10 -6 ] on chr1 at the laminin subunit gamma-1 (LAMC1) locus showed suggestive association with disease. Furthermore, the rs17145738 [0.68 (0.60-0.77); p = 6.69 × 10 -9 ] on chr7 at the carbohydrate-responsive element-binding protein-encoding (MLXIPL) gene locus displayed significant protective characteristics, while another variant rs6982502 [0.76 (0.68-0.84); p = 5.31 × 10 -7 ] on chr8 showed similar but weaker properties. These findings were replicated in 317 cases vs 1415 controls from the same ethnic Arab population. Our study identified several variants across the human genome that are associated with hTG in ethnic Arabs. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Patenting human genes: Chinese academic articles' portrayal of gene patents.

    PubMed

    Du, Li

    2018-04-24

    The patenting of human genes has been the subject of debate for decades. While China has gradually come to play an important role in the global genomics-based testing and treatment market, little is known about Chinese scholars' perspectives on patent protection for human genes. A content analysis of academic literature was conducted to identify Chinese scholars' concerns regarding gene patents, including benefits and risks of patenting human genes, attitudes that researchers hold towards gene patenting, and any legal and policy recommendations offered for the gene patent regime in China. 57.2% of articles were written by law professors, but scholars from health sciences, liberal arts, and ethics also participated in discussions on gene patent issues. While discussions of benefits and risks were relatively balanced in the articles, 63.5% of the articles favored gene patenting in general and, of the articles (n = 41) that explored gene patents in the Chinese context, 90.2% supported patent protections for human genes in China. The patentability of human genes was discussed in 33 articles, and 75.8% of these articles reached the conclusion that human genes are patentable. Chinese scholars view the patent regime as an important legal tool to protect the interests of inventors and inventions as well as the genetic resources of China. As such, many scholars support a gene patent system in China. These attitudes towards gene patents remain unchanged following the court ruling in the Myriad case in 2013, but arguments have been raised about the scope of gene patents, in particular that the increasing numbers of gene patents may negatively impact public health in China.

  8. Optimal Reference Genes for Gene Expression Normalization in Trichomonas vaginalis.

    PubMed

    dos Santos, Odelta; de Vargas Rigo, Graziela; Frasson, Amanda Piccoli; Macedo, Alexandre José; Tasca, Tiana

    2015-01-01

    Trichomonas vaginalis is the etiologic agent of trichomonosis, the most common non-viral sexually transmitted disease worldwide. This infection is associated with several health consequences, including cervical and prostate cancers and HIV acquisition. Gene expression analysis has been facilitated because of available genome sequences and large-scale transcriptomes in T. vaginalis, particularly using quantitative real-time polymerase chain reaction (qRT-PCR), one of the most used methods for molecular studies. Reference genes for normalization are crucial to ensure the accuracy of this method. However, to the best of our knowledge, a systematic validation of reference genes has not been performed for T. vaginalis. In this study, the transcripts of nine candidate reference genes were quantified using qRT-PCR under different cultivation conditions, and the stability of these genes was compared using the geNorm and NormFinder algorithms. The most stable reference genes were α-tubulin, actin and DNATopII, and, conversely, the widely used T. vaginalis reference genes GAPDH and β-tubulin were less stable. The PFOR gene was used to validate the reliability of the use of these candidate reference genes. As expected, the PFOR gene was upregulated when the trophozoites were cultivated with ferrous ammonium sulfate when the DNATopII, α-tubulin and actin genes were used as normalizing gene. By contrast, the PFOR gene was downregulated when the GAPDH gene was used as an internal control, leading to misinterpretation of the data. These results provide an important starting point for reference gene selection and gene expression analysis with qRT-PCR studies of T. vaginalis.

  9. Gene ORGANizer: linking genes to the organs they affect

    PubMed Central

    Gokhman, David; Kelman, Guy; Amartely, Adir; Gershon, Guy; Tsur, Shira

    2017-01-01

    Abstract One of the biggest challenges in studying how genes work is understanding their effect on the physiology and anatomy of the body. Existing tools try to address this using indirect features, such as expression levels and biochemical pathways. Here, we present Gene ORGANizer (geneorganizer.huji.ac.il), a phenotype-based tool that directly links human genes to the body parts they affect. It is built upon an exhaustive curated database that links >7000 genes to ∼150 anatomical parts using >150 000 gene-organ associations. The tool offers user-friendly platforms to analyze the anatomical effects of individual genes, and identify trends within groups of genes. We demonstrate how Gene ORGANizer can be used to make new discoveries, showing that chromosome X is enriched with genes affecting facial features, that positive selection targets genes with more constrained phenotypic effects, and more. We expect Gene ORGANizer to be useful in a variety of evolutionary, medical and molecular studies aimed at understanding the phenotypic effects of genes. PMID:28444223

  10. Hypoxia targeting gene expression for breast cancer gene therapy.

    PubMed

    Lee, Minhyung

    2009-08-10

    Gene therapy is a promising strategy to treat various inherited and acquired diseases. However, targeting gene expression to specific tissue is required to minimize side effects of gene therapy. Hypoxia is present in the microenvironment of solid tumors such as breast tumors. A hypoxic tumor targeting gene expression system has been developed for cancer gene therapy. In hypoxic tissues, hypoxia inducible factor (HIF)-1alpha is accumulated and stimulates transcription of the genes that have hypoxia response elements (HREs) in their promoters. Therefore, transcriptional regulation with a hypoxia inducible promoter is the most widely used strategy for hypoxic tumors targeting gene therapy. In breast cancer gene therapy, breast tumor specific promoters in combination with HREs have been used to induce gene expression in hypoxic breast tumors. Post-transcriptional regulation using an untranslated region (UTR) is also a useful strategy to increase gene expression in hypoxic tumor tissue. In addition, post-translational regulation with the oxygen-dependent degradation (ODD) domain is effective to eliminate therapeutic gene products and reduce side effects in normal tissue. In combination with the breast tumor specific promoters, hypoxic tumor targeting strategies will be useful for the development of a safe breast cancer gene therapy.

  11. The early growth response protein 1-miR-30a-5p-neurogenic differentiation factor 1 axis as a novel biomarker for schizophrenia diagnosis and treatment monitoring.

    PubMed

    Liu, S; Zhang, F; Shugart, Y Y; Yang, L; Li, X; Liu, Z; Sun, N; Yang, C; Guo, X; Shi, J; Wang, L; Cheng, L; Zhang, K; Yang, T; Xu, Y

    2017-01-10

    To date, diagnosis of schizophrenia is still based on clinical interviews and careful observations, which is subjective and variable, and can lead to misdiagnosis and/or delay in diagnosis. As early intervention in schizophrenia is important in improving outcomes, objective tests that can be used for schizophrenia diagnosis or treatment monitoring are thus in great need. MicroRNAs (miRNAs) negatively regulate target gene expression and their biogenesis is tightly controlled by various factors including transcription factors (TFs). Dysregulation of miRNAs in brain tissue and peripheral blood mononuclear cells (PBMNCs) from patients with schizophrenia has been well documented, but analysis of the sensitivity and specificity for potential diagnostic utility of these alternations is limited. In this study, we explored the TF-miRNA-30-target gene axis as a novel biomarker for schizophrenia diagnosis and treatment monitoring. Using bioinformatics analysis, we retrieved all TFs that control the biogenesis of miRNA 30 members as well as all target genes that are regulated by miRNA-30 members. Further, reverse transcription-quantitative PCR analysis revealed that the early growth response protein 1 (EGR1) and miR-30a-5p were remarkably downregulated, whereas neurogenic differentiation factor 1 (NEUROD1) was significantly upregulated in PBMNCs from patients in acute psychotic state. Antipsychotics treatment resulted in the elevation of EGR1 and miR-30a-5p but the reduction of NEUROD1. Receiver operating characteristic analysis showed that the EGR1-miR-30a-5p-NEUROD1 axis possessed significantly greater diagnostic value than miR-30a-5p alone. Our data suggest the EGR1-miR-30a-5p-NEUROD1 axis might serve as a promising biomarker for diagnosis and treatment monitoring for those patients in acute psychotic state.

  12. [Ascites and extreme lipid abnormalities as initial symptoms of cystic fibrosis in a 5-years-old girl--case report].

    PubMed

    Pytrus, Tomasz; Iwańczak, Barbara; Smigiel, Robert; Ryzko, Józef; Socha, Piotr; Iwańczak, Franciszek

    2009-11-01

    Cystic fibrosis is the most common, multiorgan inherited autosomal recessive disorder. The gene associated with this disease encodes the CF transmembrane conductance regulator (CFTR). The aim of this article is a presentation of 5-years-old girl with cystic fibrosis and associated liver disease as the only manifestation of CF. We described the case of a 5.5-years-old girl with ascites and peripheral edema without of the symptoms. Laboratory tests revealed hepatic cell damage with cholestasis, extreme lipid abnormalities and hypocholesterolemia. Based on positive sweat test (CI: 122 mEq/l) and genetic analysis (homozygote deltaF508) the diagnosis of cystic fibrosis was confirmed. Patient was successfully treated with nutritional treatment and pancreatic enzymes.

  13. Gene Therapy for Lung Cancer.

    PubMed

    Lara-Guerra, Humberto; Roth, Jack A

    2016-01-01

    Gene therapy was originally conceived to treat monogenic diseases. The replacement of a defective gene with a functional gene can theoretically cure the disease. In cancer, multiple genetic defects are present and the molecular profile changes during the course of the disease, making the replacement of all defective genes impossible. To overcome these difficulties, various gene therapy strategies have been adopted, including immune stimulation, transfer of suicide genes, inhibition of driver oncogenes, replacement of tumor-suppressor genes that could mediate apoptosis or anti-angiogenesis, and transfer of genes that enhance conventional treatments such as radiotherapy and chemotherapy. Some of these strategies have been tested successfully in non-small-cell lung cancer patients and the results of laboratory studies and clinical trials are reviewed herein.

  14. The autogenous immediate implant supported single-tooth restoration: a 5-year follow-up.

    PubMed

    Castelnuovo, Jacopo; Sönmez, Ayse Burçin

    2012-01-01

    When replacing a missing tooth in the esthetic zone, the implant supported single tooth restoration can result in a very natural and pleasing solution for the patient, being also a conservative procedure that preserves the adjacent remaining dentition. Immediate implant placement with an immediate provisional crown can avoid stressful and uncomfortable healing time for the patient who no longer has to wear an interim removable appliance. In selected clinical situations, excellent tooth esthetics for implant supported single tooth restorations can be achieved by using the natural extracted tooth as both provisional and final restoration. No longterm data is available today as far as the survival rate of such restorations and the predictability of such a treatment modality. This case report describes a technique for utilizing the patient's extracted tooth for the fabrication of an inconspicuous final anterior restoration, reporting a 5-year follow-up.

  15. Effect of a 5-Month Worksite Physical Activity Program on Tertiary Employees Overall Health and Fitness.

    PubMed

    Genin, Pauline Manon; Degoutte, Fabrice; Finaud, Julien; Pereira, Bruno; Thivel, David; Duclos, Martine

    2017-02-01

    This pilot study questions the effects of a worksite physical activity program on health and fitness in tertiary employees. Ninety-five employees were randomly assigned to Control (CON); Novice (NOV); Experienced group (EXP). The NOV and EXP groups followed a 5-month worksite physical activity program (at least two sessions/week). Body composition, physical activity level and physical fitness, eating habits, health perception, sleep quality, pain, and quality of life were assessed. Fat mass decreased in NOV and EXP; the distance covered during the 6-minute walking test, push-ups, squat jump increased for NOV and EXP group. Physical activity level, health perception, quality of sleep, and eating habits were improved in NOV. This study underlines for the first time the beneficial effects of such worksite programs among tertiary employees on overall health and the feasibility of its design.

  16. 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.

  17. Atlantoaxial rotatory subluxation as a cause of torticollis in a 5-year-old girl

    PubMed Central

    Bagouri, Elmunzar; Deshmukh, Sandeep; Lakshmanan, Palaniappan

    2014-01-01

    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. PMID:24832710

  18. 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.

  19. Experimental demonstration of a 5th harmonic mm-wave frequency multiplying vacuum tube

    SciTech Connect

    Toufexis, Filippos; Tantawi, Sami G.; Jensen, Aaron

    2017-06-26

    Here, we report the experimental demonstration of a 5th harmonic mm-wave frequency multiplying vacuum electronic device, which uses an over-moded spherical sector output cavity. In this device, a pencil electron beam is helically deflected in a transverse deflecting cavity before entering the output cavity. No magnetic field is required to focus or guide the beam. We built and tested a proof-of-principle device with an output frequency of 57.12 GHz. The measured peak power was 52.67 W at the 5th harmonic of the drive frequency. Power at the 4th, 6th, and 7th harmonics was 33.28 dB lower than that at themore » 5th harmonic.« less

  20. 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.

  1. 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

  2. Designing and Implementing a 5-Year Transfusion Medicine Diploma Program in China.

    PubMed

    Li, Tingting; Wang, Wenjing; Zhang, Ling; Zhou, Ye; Lai, Fucai; Fu, Yongshui; Wang, Chuanxi; Yang, Baocheng; Zhu, Weigang; Wu, Yanyun; Allain, Jean-Pierre; Stevens, Lori; Li, Chengyao

    2017-04-01

    The need for physicians and technical consultants specialized in transfusion medicine is urgent in China, as there are 20 000 hospitals and 500 blood centers in need of staff with this expertise. The progress made in transfusion medicine as a specialty has been relatively slow in China. Current Chinese medical education and service systems have not developed transfusion medicine as a stand-alone medical specialty. Most physicians receive only minimal training in transfusion medicine in medical school. This training is usually integrated into surgical training and addresses the most common technologies. In 2008, a 5-year bachelor's diploma program in transfusion medicine was established as an undergraduate specialty in Southern Medical University, Guangzhou, China. This article intends to summarize the 8 years of experience educating undergraduates in the specialty of transfusion medicine. Copyright © 2017. Published by Elsevier Inc.

  3. A 5-GHz Southern Hemishere VLBI Survey of Compact Radio Sources.I.

    NASA Astrophysics Data System (ADS)

    Shen, Z.-Q.; Wan, T.-S.; Moran, J. M.; Jauncey, D. L.; Reynolds, J. E.; Tzioumis, A. K.; Gough, R. G.; Ferris, R. H.; Sinclair, M. W.; Jiang, D.-R.; Hong, X.-Y.; Liang, S.-G.; Costa, M. E.; Tingay, S. J.; McCulloch, P. M.; Lovell, J. E. J.; King, E. A.; Nicolson, G. D.; Murphy, D. W.; Meier, D. L.; van Ommen, R. D.; Edwards, P. G.; White, G. L.

    1997-11-01

    We report the results of a 5-GHz southern hemisphere VLBI survey of compact extragalactic radio sources. These observations were undertaken with the SHEVE array plus Shanghai station in 1992 November. A sample of 22 sources was observed and images of 20 of them were obtained. Of the 20 sources imaged, 15 showed core-jet structure, 1 had a two-sided jet, and 4 had only single compact cores. Eleven of the 16 core-jet (including one two-sided jet) sources showed some evidence of bent jets. No compact doubles were found. A comparison with previous images and the temporal variability of the radio flux density showed evidence for superluminal motion in four of the sources. Five sources were high-energy (>100 MeV) γ-ray sources. Statistical analysis showed the dominance of highly polarized quasars among the detected γ-ray sources, which emphasizes the importance of beaming effect in the γ-ray emission.

  4. Brains, genes, and primates.

    PubMed

    Izpisua Belmonte, Juan Carlos; Callaway, Edward M; Caddick, Sarah J; Churchland, Patricia; Feng, Guoping; Homanics, Gregg E; Lee, Kuo-Fen; Leopold, David A; Miller, Cory T; Mitchell, Jude F; Mitalipov, Shoukhrat; Moutri, Alysson R; Movshon, J Anthony; Okano, Hideyuki; Reynolds, John H; Ringach, Dario; Sejnowski, Terrence J; Silva, Afonso C; Strick, Peter L; Wu, Jun; Zhang, Feng

    2015-05-06

    One of the great strengths of the mouse model is the wide array of genetic tools that have been developed. Striking examples include methods for directed modification of the genome, and for regulated expression or inactivation of genes. Within neuroscience, it is now routine to express reporter genes, neuronal activity indicators, and opsins in specific neuronal types in the mouse. However, there are considerable anatomical, physiological, cognitive, and behavioral differences between the mouse and the human that, in some areas of inquiry, limit the degree to which insights derived from the mouse can be applied to understanding human neurobiology. Several recent advances have now brought into reach the goal of applying these tools to understanding the primate brain. Here we describe these advances, consider their potential to advance our understanding of the human brain and brain disorders, discuss bioethical considerations, and describe what will be needed to move forward. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Brains, Genes and Primates

    PubMed Central

    Belmonte, Juan Carlos Izpisua; Callaway, Edward M.; Churchland, Patricia; Caddick, Sarah J.; Feng, Guoping; Homanics, Gregg E.; Lee, Kuo-Fen; Leopold, David A.; Miller, Cory T.; Mitchell, Jude F.; Mitalipov, Shoukhrat; Moutri, Alysson R.; Movshon, J. Anthony; Okano, Hideyuki; Reynolds, John H.; Ringach, Dario; Sejnowski, Terrence J.; Silva, Afonso C.; Strick, Peter L.; Wu, Jun; Zhang, Feng

    2015-01-01

    One of the great strengths of the mouse model is the wide array of genetic tools that have been developed. Striking examples include methods for directed modification of the genome, and for regulated expression or inactivation of genes. Within neuroscience, it is now routine to express reporter genes, neuronal activity indicators and opsins in specific neuronal types in the mouse. However, there are considerable anatomical, physiological, cognitive and behavioral differences between the mouse and the human that, in some areas of inquiry, limit the degree to which insights derived from the mouse can be applied to understanding human neurobiology. Several recent advances have now brought into reach the goal of applying these tools to understanding the primate brain. Here we describe these advances, consider their potential to advance our understanding of the human brain and brain disorders, discuss bioethical considerations, and describe what will be needed to move forward. PMID:25950631

  6. Graphene based gene transfection

    NASA Astrophysics Data System (ADS)

    Feng, Liangzhu; Zhang, Shuai; Liu, Zhuang

    2011-03-01

    Graphene as a star in materials research has been attracting tremendous attentions in the past few years in various fields including biomedicine. In this work, for the first time we successfully use graphene as a non-toxic nano-vehicle for efficient gene transfection. Graphene oxide (GO) is bound with cationic polymers, polyethyleneimine (PEI) with two different molecular weights at 1.2 kDa and 10 kDa, forming GO-PEI-1.2k and GO-PEG-10k complexes, respectively, both of which are stable in physiological solutions. Cellular toxicity tests reveal that our GO-PEI-10k complex exhibits significantly reduced toxicity to the treated cells compared to the bare PEI-10k polymer. The positively charged GO-PEI complexes are able to further bind with plasmid DNA (pDNA) for intracellular transfection of the enhanced green fluorescence protein (EGFP) gene in HeLa cells. While EGFP transfection with PEI-1.2k appears to be ineffective, high EGFP expression is observed using the corresponding GO-PEI-1.2k as the transfection agent. On the other hand, GO-PEI-10k shows similar EGFP transfection efficiency but lower toxicity compared with PEI-10k. Our results suggest graphene to be a novel gene delivery nano-vector with low cytotoxicity and high transfection efficiency, promising for future applications in non-viral based gene therapy.Graphene as a star in materials research has been attracting tremendous attentions in the past few years in various fields including biomedicine. In this work, for the first time we successfully use graphene as a non-toxic nano-vehicle for efficient gene transfection. Graphene oxide (GO) is bound with cationic polymers, polyethyleneimine (PEI) with two different molecular weights at 1.2 kDa and 10 kDa, forming GO-PEI-1.2k and GO-PEG-10k complexes, respectively, both of which are stable in physiological solutions. Cellular toxicity tests reveal that our GO-PEI-10k complex exhibits significantly reduced toxicity to the treated cells compared to the bare PEI

  7. Cnidarian Zic Genes.

    PubMed

    Layden, Michael J

    2018-01-01

    To understand the ancestral and evolved roles of zic homologs, it is important to reconstruct the putative roles of ancient zic homologs in the animal phylogeny. Most studies of zic genes have been conducted in model systems that are members of the bilaterian phylum. However, two additional phyla have zic homologs encoded in their genomes. The three animal phyla that contain zic homologs all share a common ancestor and collectively are termed the parahoxozoans (cnidarians (corals, sea anemones, and jellyfish), placozoans (Trichoplax adhaerens), and bilaterians (chordates, insects, nematodes, annelids, echinoderms, etc.). In this chapter we briefly discuss our understanding of zic genes in the parahoxozoans with a particular focus on how expression of cnidarian zic homologs in the medusozoan Hydra vulgaris and the anthozoan Nematostella vectensis informs our understanding of the putative ancestral roles zic homologs played in the cnidarian-bilaterian common ancestor.

  8. Effects of a 5-h hilly running on ankle plantar and dorsal flexor force and fatigability.

    PubMed

    Fourchet, François; Millet, Grégoire P; Tomazin, Katja; Guex, Kenny; Nosaka, Ken; Edouard, Pascal; Degache, Francis; Millet, Guillaume Y

    2012-07-01

    This study aimed to examine the effects of a 5-h hilly run on ankle plantar (PF) and dorsal flexor (DF) force and fatigability. It was hypothesised that DF fatigue/fatigability would be greater than PF fatigue/fatigability. Eight male trail long distance runners (42.5 ± 5.9 years) were tested for ankle PF and DF maximal voluntary isokinetic contraction strength and fatigue resistance tests (percent decrement score), maximal voluntary and electrically evoked isometric contraction strength before and after the run. Maximal EMG root mean square (RMS(max)) and mean power frequency (MPF) values of the tibialis anterior (TA), gastrocnemius lateralis (GL) and soleus (SOL) EMG activity were calculated. The peak torque of the potentiated high- and low-frequency doublets and the ratio of paired stimulation peak torques at 10 Hz over 100 Hz (Db10:100) were analysed for PF. Maximal voluntary isometric contraction strength of PF decreased from pre- to post-run (-17.0 ± 6.2%; P < 0.05), but no significant decrease was evident for DF (-7.9 ± 6.2%). Maximal voluntary isokinetic contraction strength and fatigue resistance remained unchanged for both PF and DF. RMS(max) SOL during maximal voluntary isometric contraction and RMS(max) TA during maximal voluntary isokinetic contraction were decreased (P < 0.05) after the run. For MPF, a significant decrease for TA (P < 0.05) was found and the ratio Db10:100 decreased for PF (-6.5 ± 6.0%; P < 0.05). In conclusion, significant isometric strength loss was only detected for PF after a 5-h hilly run and was partly due to low-frequency fatigue. This study contradicted the hypothesis that neuromuscular alterations due to prolonged hilly running are predominant for DF.

  9. Community-wide intervention and population-level physical activity: a 5-year cluster randomized trial.

    PubMed

    Kamada, Masamitsu; Kitayuguchi, Jun; Abe, Takafumi; Taguri, Masataka; Inoue, Shigeru; Ishikawa, Yoshiki; Bauman, Adrian; Lee, I-Min; Miyachi, Motohiko; Kawachi, Ichiro

    2018-04-01

    Evidence from a limited number of short-term trials indicates the difficulty in achieving population-level improvements in physical activity (PA) through community-wide interventions (CWIs). We sought to evaluate the effectiveness of a 5-year CWI for promoting PA in middle-aged and older adults using a cluster randomized design. We randomized 12 communities in Unnan, Japan, to either intervention (9) or control (3). Additionally, intervention communities were randomly allocated to three subgroups by different PA types promoted. Randomly sampled residents aged 40-79 years responded to the baseline survey (n = 4414; 74%) and were followed at 1, 3 and 5 years (78-83% response rate). The intervention was a 5-year CWI using social marketing to promote PA. The primary outcome was a change in recommended levels of PA. Compared with control communities, adults achieving recommended levels of PA increased in intervention communities [adjusted change difference = 4.6 percentage points (95% confidence interval: 0.4, 8.8)]. The intervention was effective for promoting all types of recommended PAs, i.e. aerobic (walking, 6.4%), flexibility (6.1%) and muscle-strengthening activities (5.7%). However, a bundled approach, which attempted to promote all forms of PAs above simultaneously, was not effective (1.3-3.4%, P ≥ 0.138). Linear dose-response relationships between the CWI awareness and changes in PA were observed (P ≤ 0.02). Pain intensity decreased in shoulder (intervention and control) and lower back (intervention only) but there was little change difference in all musculoskeletal pain outcomes between the groups. The 5-year CWI using the focused social marketing strategy increased the population-level of PA.

  10. 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. © The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  11. Gene Expression in Bone

    NASA Astrophysics Data System (ADS)

    D'Ambrogio, A.

    Skeletal system has two main functions, to provide mechanical integrity for both locomotion and protection and to play an important role in mineral homeostasis. There is extensive evidence showing loss of bone mass during long-term Space-Flights. The loss is due to a break in the equilibrium between the activity of osteoblasts (the cells that forms bone) and the activity of osteoclasts (the cells that resorbs bone). Surprisingly, there is scanty information about the possible altered gene expression occurring in cells that form bone in microgravity.(Just 69 articles result from a "gene expression in microgravity" MedLine query.) Gene-chip or microarray technology allows to screen thousands of genes at the same time: the use of this technology on samples coming from cells exposed to microgravity could provide us with many important informations. For example, the identification of the molecules or structures which are the first sensors of the mechanical stress derived from lack of gravity, could help in understanding which is the first event leading to bone loss due to long-term exposure to microgravity. Consequently, this structure could become a target for a custom-designed drug. It is evident that bone mass loss, observed during long-time stay in Space, represents an accelerated model of what happens in aging osteoporosis. Therefore, the discovery and design of drugs able to interfere with the bone-loss process, could help also in preventing negative physiological processes normally observed on Earth. Considering the aims stated above, my research is designed to:

  12. Gene Porter Bridwell

    NASA Technical Reports Server (NTRS)

    1994-01-01

    Gene Porter Bridwell served as the director of the Marshall Space Flight Center from January 6, 1994 until February 3, 1996, when he retired from NASA after thirty-four years service. Bridwell, a Marshall employee since 1962, had been Marshall's Space Shuttle Projects Office Director and Space Station Redesign Team deputy manager. Under Bridwell, Marshall worked to develop its role as a Center of Excellence for propulsion and for providing access to space.

  13. nanosheets for gene therapy

    NASA Astrophysics Data System (ADS)

    Kou, Zhongyang; Wang, Xin; Yuan, Renshun; Chen, Huabin; Zhi, Qiaoming; Gao, Ling; Wang, Bin; Guo, Zhaoji; Xue, Xiaofeng; Cao, Wei; Guo, Liang

    2014-10-01

    A new class of two-dimensional (2D) nanomaterial, transition metal dichalcogenides (TMDCs) such as MoS2, MoSe2, WS2, and WSe2 which have fantastic physical and chemical properties, has drawn tremendous attention in different fields recently. Herein, we for the first time take advantage of the great potential of MoS2 with well-engineered surface as a novel type of 2D nanocarriers for gene delivery and therapy of cancer. In our system, positively charged MoS2-PEG-PEI is synthesized with lipoic acid-modified polyethylene glycol (LA-PEG) and branched polyethylenimine (PEI). The amino end of positively charged nanomaterials can bind to the negatively charged small interfering RNA (siRNA). After detection of physical and chemical characteristics of the nanomaterial, cell toxicity was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Polo-like kinase 1 (PLK1) was investigated as a well-known oncogene, which was a critical regulator of cell cycle transmission at multiple levels. Through knockdown of PLK1 with siRNA carried by novel nanovector, qPCR and Western blot were used to measure the interfering efficiency; apoptosis assay was used to detect the transfection effect of PLK1. All results showed that the novel nanocarrier revealed good biocompatibility, reduced cytotoxicity, as well as high gene-carrying ability without serum interference, thus would have great potential for gene delivery and therapy.

  14. Gene Therapy for Hemophilia.

    PubMed

    Nienhuis, Arthur W; Nathwani, Amit C; Davidoff, Andrew M

    2017-05-03

    The X-linked bleeding disorder hemophilia causes frequent and exaggerated bleeding that can be life-threatening if untreated. Conventional therapy requires frequent intravenous infusions of the missing coagulation protein (factor VIII [FVIII] for hemophilia A and factor IX [FIX] for hemophilia B). However, a lasting cure through gene therapy has long been sought. After a series of successes in small and large animal models, this goal has finally been achieved in humans by in vivo gene transfer to the liver using adeno-associated viral (AAV) vectors. In fact, multiple recent clinical trials have shown therapeutic, and in some cases curative, expression. At the same time, cellular immune responses against the virus have emerged as an obstacle in humans, potentially resulting in loss of expression. Transient immune suppression protocols have been developed to blunt these responses. Here, we provide an overview of the clinical development of AAV gene transfer for hemophilia, as well as an outlook on future directions. Copyright © 2017. Published by Elsevier Inc.

  15. GENE DELIVERY TO BONE

    PubMed Central

    Evans, C. H.

    2012-01-01

    Gene delivery to bone is useful both as an experimental tool and as a potential therapeutic strategy. Among its advantages over protein delivery are the potential for directed, sustained and regulated expression of authentically processed, nascent proteins. Although no clinical trials have been initiated, there is a substantial pre-clinical literature documenting the successful transfer of genes to bone, and their intraosseous expression. Recombinant vectors derived from adenovirus, retrovirus and lentivirus, as well as non-viral vectors, have been used for this purpose. Both ex vivo and in vivo strategies, including gene-activated matrices, have been explored. Ex vivo delivery has often employed mesenchymal stem cells (MSCs), partly because of their ability to differentiate into osteoblasts. MSCs also have the potential to home to bone after systemic administration, which could serve as a useful way to deliver transgenes in a disseminated fashion for the treatment of diseases affecting the whole skeleton, such as osteoporosis or osteogenesis imperfecta. Local delivery of osteogenic transgenes, particularly those encoding bone morphogenetic proteins, has shown great promise in a number of applications where it is necessary to regenerate bone. These include healing large segmental defects in long bones and the cranium, as well as spinal fusion and treating avascular necrosis. PMID:22480730

  16. Genealogy and gene trees.

    PubMed

    Rasmuson, Marianne

    2008-02-01

    Heredity can be followed in persons or in genes. Persons can be identified only a few generations back, but simplified models indicate that universal ancestors to all now living persons have occurred in the past. Genetic variability can be characterized as variants of DNA sequences. Data are available only from living persons, but from the pattern of variation gene trees can be inferred by means of coalescence models. The merging of lines backwards in time leads to a MRCA (most recent common ancestor). The time and place of living for this inferred person can give insights in human evolutionary history. Demographic processes are incorporated in the model, but since culture and customs are known to influence demography the models used ought to be tested against available genealogy. The Icelandic data base offers a possibility to do so and points to some discrepancies. Mitochondrial DNA and Y chromosome patterns give a rather consistent view of human evolutionary history during the latest 100 000 years but the earlier epochs of human evolution demand gene trees with longer branches. The results of such studies reveal as yet unsolved problems about the sources of our genome.

  17. Independent Gene Discovery and Testing

    ERIC Educational Resources Information Center

    Palsule, Vrushalee; Coric, Dijana; Delancy, Russell; Dunham, Heather; Melancon, Caleb; Thompson, Dennis; Toms, Jamie; White, Ashley; Shultz, Jeffry

    2010-01-01

    A clear understanding of basic gene structure is critical when teaching molecular genetics, the central dogma and the biological sciences. We sought to create a gene-based teaching project to improve students' understanding of gene structure and to integrate this into a research project that can be implemented by instructors at the secondary level…

  18. Effects of CYP3A5, CYP2C19, and CYP2B6 on the clinical efficacy and adverse outcomes of sibutramine therapy: a crucial role for the CYP2B6*6 allele.

    PubMed

    Hwang, In Cheol; Park, Ji Young; Ahn, Hong Yup; Kim, Kyoung Kon; Suh, Heuy Sun; Ko, Ki Dong; Kim, Kyoung-Ah

    2014-01-20

    Various cytochrome P450 isoforms modulate sibutramine activity and influence sibutramine plasma levels and pharmacokinetics. However, there are no available data to demonstrate the association of these polymorphisms with the clinical outcomes of sibutramine administration. This study was a sub-investigation of a 12-week, double-blind, placebo-controlled trial examining the additive effect of orlistat on sibutramine. The final analysis was restricted to 101 women who had fulfilled the protocol. We evaluated the effects of genetic polymorphisms of CYP3A5, CYP2C19 and CYP2B6 on the % weight loss and the occurrence of adverse events. The change of pulse rate from baseline value was affected by both CYP2B6 and CYP3A5 genetic polymorphisms (P<.01 for CYP3A5 and P=.01 for CYP2B6). Both CYP2B6 and CYP3A5 showed gene-gene interactions (P<.01). After adjusting for significant variables in the backward stepwise regression model, the change of pulse rate and time-dependent weight reduction were significant only among the CYP2B6 genotypes (P=.027 and P<.01, respectively). The CYP2B6*6 allele influences the extent of weight reduction and pulse rate changes in patients undergoing sibutramine treatment. Copyright © 2013 Elsevier B.V. All rights reserved.

  19. Optimal gene partition into operons correlates with gene functional order

    NASA Astrophysics Data System (ADS)

    Zaslaver, Alon; Mayo, Avi; Ronen, Michal; Alon, Uri

    2006-09-01

    Gene arrangement into operons varies between bacterial species. Genes in a given system can be on one operon in some organisms and on several operons in other organisms. Existing theories explain why genes that work together should be on the same operon, since this allows for advantageous lateral gene transfer and accurate stoichiometry. But what causes the frequent separation into multiple operons of co-regulated genes that act together in a pathway? Here we suggest that separation is due to benefits made possible by differential regulation of each operon. We present a simple mathematical model for the optimal distribution of genes into operons based on a balance of the cost of operons and the benefit of regulation that provides 'just-when-needed' temporal order. The analysis predicts that genes are arranged such that genes on the same operon do not skip functional steps in the pathway. This prediction is supported by genomic data from 137 bacterial genomes. Our work suggests that gene arrangement is not only the result of random historical drift, genome re-arrangement and gene transfer, but has elements that are solutions of an evolutionary optimization problem. Thus gene functional order may be inferred by analyzing the operon structure across different genomes.

  20. Gene function prediction based on Gene Ontology Hierarchy Preserving Hashing.

    PubMed

    Zhao, Yingwen; Fu, Guangyuan; Wang, Jun; Guo, Maozu; Yu, Guoxian

    2018-02-23

    Gene Ontology (GO) uses structured vocabularies (or terms) to describe the molecular functions, biological roles, and cellular locations of gene products in a hierarchical ontology. GO annotations associate genes with GO terms and indicate the given gene products carrying out the biological functions described by the relevant terms. However, predicting correct GO annotations for genes from a massive set of GO terms as defined by GO is a difficult challenge. To combat with this challenge, we introduce a Gene Ontology Hierarchy Preserving Hashing (HPHash) based semantic method for gene function prediction. HPHash firstly measures the taxonomic similarity between GO terms. It then uses a hierarchy preserving hashing technique to keep the hierarchical order between GO terms, and to optimize a series of hashing functions to encode massive GO terms via compact binary codes. After that, HPHash utilizes these hashing functions to project the gene-term association matrix into a low-dimensional one and performs semantic similarity based gene function prediction in the low-dimensional space. Experimental results on three model species (Homo sapiens, Mus musculus and Rattus norvegicus) for interspecies gene function prediction show that HPHash performs better than other related approaches and it is robust to the number of hash functions. In addition, we also take HPHash as a plugin for BLAST based gene function prediction. From the experimental results, HPHash again significantly improves the prediction performance. The codes of HPHash are available at: http://mlda.swu.edu.cn/codes.php?name=HPHash. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. 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.

    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. Biparentalmore » (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.« less

  2. Gene therapy research in Asia.

    PubMed

    Deng, H-X; Wang, Y; Ding, Q-R; Li, D-L; Wei, Yu-Quan

    2017-09-01

    Gene therapy has shown great potential for the treatment of diseases that previously were either untreatable or treatable but not curable with conventional schemes. Recent progress in clinical gene therapy trials has emerged in various severe diseases, including primary immunodeficiencies, leukodystrophies, Leber's congenital amaurosis, haemophilia, as well as retinal dystrophy. The clinical transformation and industrialization of gene therapy in Asia have been remarkable and continue making steady progress. A total of six gene therapy-based products have been approved worldwide, including two drugs from Asia. This review aims to highlight recent progress in gene therapy clinical trials and discuss the prospects for the future in China and wider Asia.

  3. The ethics of gene therapy.

    PubMed

    Chan, Sarah; Harris, John

    2006-10-01

    Recent developments have progressed in areas of science that pertain to gene therapy and its ethical implications. This review discusses the current state of therapeutic gene technologies, including stem cell therapies and genetic modification, and identifies ethical issues of concern in relation to the science of gene therapy and its application, including the ethics of embryonic stem cell research and therapeutic cloning, the risks associated with gene therapy, and the ethics of clinical research in developing new therapeutic technologies. Additionally, ethical issues relating to genetic modification itself are considered: the significance of the human genome, the distinction between therapy and enhancement, and concerns regarding gene therapy as a eugenic practice.

  4. Detection of mutations in LRPAP1, CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2 in 298 families with early-onset high myopia by exome sequencing.

    PubMed

    Jiang, Dan; Li, Jiali; Xiao, Xueshan; Li, Shiqiang; Jia, Xiaoyun; Sun, Wenmin; Guo, Xiangming; Zhang, Qingjiong

    2014-12-18

    To evaluate variants in the LRPAP1, CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2 genes in 298 unrelated patients with early-onset high myopia (eoHM). Genomic DNA from 298 patients with eoHM was analyzed by whole exome sequencing. Variants in LRPAP1, CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2 genes were selected and analyzed with bioinformatics. Potential candidate variants were confirmed by Sanger sequencing and then validated in available family members and 192 healthy controls. A total of nine variants predicted to affect the functional residues were detected. The LRPAP1 gene showed a homozygous frameshift mutation (c.199delC, p.Q67Sfs*8) in a consanguineous family. The ZNF644 gene showed five heterozygous missense mutations (c.1106A>T, p.K369M; c.1648G>A, p.A550T; c.2014A>G, p.S672G; c.2048G>C, p.R683T, and c.2551G>C, p.D851H) in five families, but the c.1106A>T, (p.K369M) and c.1648G>A, (p.A550T) in ZNF644 did not co-segregated with high myopia in the families and should be excluded as causative mutations. The SLC39A5 gene showed a heterozygous missense variant (c.1238G>C, p.G413A) in a sporadic individual. The SCO2 gene showed two heterozygous missense variants (c.334C>T, p.R112W and c.358C>T, p.R120W) in two families. None of the variants was detected in 192 healthy controls and all were predicted to be damaging by both Polyphen-2 and SIFT, except for the previously reported p.S672G mutation in ZNF644, which was predicted to be damaging by SIFT but benign by Polyphen-2. No homozygous or compound heterozygous variants were found in CTSH and LEPREL1. Our results provide additional evidence to support the idea that mutation in LRPAP1 is associated with high myopia. Further studies are expected to evaluate the pathogenicity of the variants in CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2. Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.

  5. A 5-day high-fat, high-calorie diet impairs insulin sensitivity in healthy, young South Asian men but not in Caucasian men.

    PubMed

    Bakker, Leontine E H; van Schinkel, Linda D; Guigas, Bruno; Streefland, Trea C M; Jonker, Jacqueline T; van Klinken, Jan B; van der Zon, Gerard C M; Lamb, Hildo J; Smit, Johannes W A; Pijl, Hanno; Meinders, A Edo; Jazet, Ingrid M

    2014-01-01

    South Asians (SAs) develop type 2 diabetes at a younger age and lower BMI compared with Caucasians (Cs). The underlying cause is still poorly understood but might result from an innate inability to adapt to the Westernized diet. This study aimed to compare the metabolic adaptation to a high-fat, high-calorie (HFHC) diet between both ethnicities. Twelve healthy, young lean male SAs and 12 matched Cs underwent a two-step hyperinsulinemic-euglycemic clamp with skeletal muscle biopsies and indirect calorimetry before and after a 5-day HFHC diet. Hepatic triglyceride content (HTG) and abdominal fat distribution were assessed using magnetic resonance imaging and spectroscopy. At baseline, SAs had higher insulin clamp levels than Cs, indicating reduced insulin clearance rate. Despite the higher insulin levels, endogenous glucose production was comparable between groups, suggesting lower hepatic insulin sensitivity in SAs. Furthermore, a 5-day HFHC diet decreased the insulin-stimulated (nonoxidative) glucose disposal rate only in SA. In skeletal muscle, no significant differences were found between groups in insulin/mammalian target of rapamycin signaling, metabolic gene expression, and mitochondrial respiratory chain content. Furthermore, no differences in (mobilization of) HTG and abdominal fat were detected. We conclude that HFHC feeding rapidly induces insulin resistance only in SAs. Thus, distinct adaptation to Western food may partly explain their propensity to develop type 2 diabetes.

  6. The yeast THO complex forms a 5-subunit assembly that directly interacts with active chromatin.

    PubMed

    Gewartowski, Kamil; Cuéllar, Jorge; Dziembowski, Andrzej; Valpuesta, José María

    2012-01-01

    The THO complex is a nuclear structure whose architecture is conserved among all kingdoms and plays an important role in mRNP biogenesis connecting transcription elongation with mRNA maturation and export. Recent data indicates that the THO complex is necessary for the proper expression of some genes, assurance of genetic stability by preventing transcription-associated recombination. Yeast THO has been described as a heterotetramer (Tho2, Hpr1, Mft1 and Thp2) that performs several functions through the interaction with other proteins like Tex1 or the mRNA export factors Sub2 and Yra1, with which it forms the TRanscription and EXport complex (TREX). In this article we review the cellular role of THO, which we show to be composed of five subunits with Tex1 being also an integral part of the complex. We also show a low-resolution structure of THO and localize some of its components. We discuss the consequences of THO interaction with nucleic acids through the unfolded C-terminal region of Tho2, highlighting the importance of unfolded regions in eukaryotic proteins. Finally, we comment on THO recruitment to active chromatin, a role that is linked to mRNA biogenesis.

  7. c-Fos downregulation positively regulates EphA5 expression in a congenital hypothyroidism rat model.

    PubMed

    Song, Honghua; Zheng, Yuqin; Cai, Fuying; Ma, Yanyan; Yang, Jingyue; Wu, Youjia

    2018-04-01

    The EphA5 receptor is well established as an axon guidance molecule during neural system development and plays an important role in dendritic spine formation and synaptogenesis. Our previous study has showed that EphA5 is decreased in the developing brain of congenital hypothyroidism (CH) and the EphA5 promoter methylation modification participates in its decrease. c-Fos, a well-kown transcription factor, has been considered in association with brain development. Bioinformatics analysis showed that the EphA5 promoter region contained five putative c-fos binding sites. The chromatin immunoprecipitation (ChIP) assays were used to assess the direct binding of c-fos to the EphA5 promoter. Furthermore, dual-luciferase assays showed that these three c-fos protein binding sites were positive regulatory elements for EphA5 expression in PC12 cells. Moreover, We verified c-fos positively regulation for EphA5 expression in CH model. Q-PCR and Western blot showed that c-fos overexpression could upregulate EphA5 expression in hippocampal neurons of rats with CH. Our results suggest that c-fos positively regulates EphA5 expression in CH rat model.

  8. Pentamidine blocks the interaction between mutant S100A5 and RAGE V domain and inhibits the RAGE signaling pathway

    SciTech Connect

    Cho, Ching Chang, E-mail: ccjwo@yahoo.com.tw; Chou, Ruey Hwang, E-mail: rhchou@mail.cmu.edu.tw; Yu, Chin, E-mail: cyu.nthu@gmail.com

    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. Wemore » 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. - Highlights: • The interaction between mS100A5–RAGE V was investigated by fluorescence spectroscopy. • The interfacial residues on mS100A5–RAGE V and mS100A5–pentamidine contact surface were mapped by {sup 1}H-{sup 15}N HSQC experiments. • mS100A5–RAGE V and mS100A5–pentamidine complex models were generated from NMR restraints using HADDOCK program. • The bioactivity of the mS100A5–RAGE V and mS100A5–pentamidine complex was studied using WST-1 assay.« less

  9. Exhaled breath condensate annexin A5 levels in exercise-induced bronchoconstriction in asthma: A preliminary study.

    PubMed

    Tahan, F; Akar, H H; Saraymen, B

    2015-01-01

    The pathogenesis of exercise-induced bronchoconstriction (EIB) in asthma is incompletely understood. The role of exhaled breath condensate (EBC) annexin A5, which is an anti-inflammatory mediator, has not been investigated. The purpose of this study is to evaluate EBC annexin A5 levels in EIB in asthmatic children. Two groups of children were enrolled in this study: asthmatic children with positive (n=11) and negative (n=7) responses to exercise. The levels of pre- and post-exercise EBC annexin A5 were determined with using enzyme-linked immunosorbent assay (ELISA). We observed significant higher pre-exercise EBC annexin A5 levels in the challenge test negative children than in the challenge test positive children (p<0.05). No significant difference was observed in the post-exercise EBC annexin A5 levels between the groups (p>0.05). Also, no significant difference was observed between pre- and post-exercise EBC annexin A5 levels within each group (p>0.05). There was an inverse correlation between annexin A5 levels and a reduction in forced expiratory volume at one second percent (FEV1%) (p=0.009, r=-0.598). Our preliminary study showed that EBC annexin A5 may have a possible preventive role in EIB in asthma. Annexin A5 and related compounds may provide novel therapeutic approaches to the treatment of EIB in asthma. Copyright © 2014 SEICAP. Published by Elsevier Espana. All rights reserved.

  10. Two Variants in SLC24A5 Are Associated with “Tiger-Eye” Iris Pigmentation in Puerto Rican Paso Fino Horses

    PubMed Central

    Mack, Maura; Kowalski, Elizabeth; Grahn, Robert; Bras, Dineli; Penedo, Maria Cecilia T.; Bellone, Rebecca

    2017-01-01

    A unique eye color, called tiger-eye, segregates in the Puerto Rican Paso Fino (PRPF) horse breed and is characterized by a bright yellow, amber, or orange iris. Pedigree analysis identified a simple autosomal recessive mode of inheritance for this trait. A genome-wide association study (GWAS) with 24 individuals identified a locus on ECA 1 reaching genome-wide significance (Pcorrected = 1.32 × 10−5). This ECA1 locus harbors the candidate gene, Solute Carrier Family 24 (Sodium/Potassium/Calcium Exchanger), Member 5 (SLC24A5), with known roles in pigmentation in humans, mice, and zebrafish. Humans with compound heterozygous mutations in SLC24A5 have oculocutaneous albinism (OCA) type 6 (OCA6), which is characterized by dilute skin, hair, and eye pigmentation, as well as ocular anomalies. Twenty tiger-eye horses were homozygous for a nonsynonymous mutation in exon 2 (p.Phe91Tyr) of SLC24A5 (called here Tiger-eye 1), which is predicted to be deleterious to protein function. Additionally, eight of the remaining 12 tiger-eye horses heterozygous for the p.Phe91Tyr variant were also heterozygous for a 628 bp deletion encompassing all of exon 7 of SLC24A5 (c.875-340_1081+82del), which we will call here the Tiger-eye 2 allele. None of the 122 brown-eyed horses were homozygous for either tiger-eye-associated allele or were compound heterozygotes. Further, neither variant was detected in 196 horses from four related breeds not known to have the tiger-eye phenotype. Here, we propose that two mutations in SLC24A5 affect iris pigmentation in tiger-eye PRPF horses. Further, unlike OCA6 in humans, the Tiger-eye 1 mutation in its homozygous state or as a compound heterozygote (Tiger-eye 1/Tiger-eye 2) does not appear to cause ocular anomalies or a change in coat color in the PRPF horse. PMID:28655738

  11. Exploring new gene integration sites for gene knock-in by gene-trapping strategy.

    PubMed

    Nanchi, Isamu; Yoshimura, Yuki; Nakamura, Kazuomi; Masago, Yusaku; Ohbayashi, Tetsuya; Okuda, Tomohiko

    2015-06-01

    The knock-in mouse is a powerful tool for biological research, but the stability of expression of an integrated gene strongly depends on where it is integrated in the mouse genome. At present, there are an insufficient number of loci suitable for gene knock-in, such as the Rosa26 locus. Therefore, in this study, we developed an efficient strategy for identifying genome loci suitable for gene knock-in and characterized the properties of such loci for gene integration. For efficient discovery and characterization, we constructed a new gene-trapping vector that enables monitoring of the expression of both trapped and integrated genes using fluorescence. We successfully obtained fluorescent-positive mouse embryonic stem cell (mESC) clones with the vector. Thorough analysis of the expression of fluorescent proteins in chimera embryos generated with the obtained mESC clones, some of the gene-trapped chimera embryos showed stable and ubiquitous expression of the integrated gene. Furthermore, adult mice derived from one of the gene-trapped mESC clones showed ubiquitous expression of the integrated gene in various tissues without any unusual phenotype. This indicated that the identified locus possesses high potential for foreign gene integration. Our strategy allows for efficient discovery and characterization of mouse genome loci for gene integration.

  12. Comparative gene expression of intestinal metabolizing enzymes.

    PubMed

    Shin, Ho-Chul; Kim, Hye-Ryoung; Cho, Hee-Jung; Yi, Hee; Cho, Soo-Min; Lee, Dong-Goo; Abd El-Aty, A M; Kim, Jin-Suk; Sun, Duxin; Amidon, Gordon L

    2009-11-01

    The purpose of this study was to compare the expression profiles of drug-metabolizing enzymes in the intestine of mouse, rat and human. Total RNA was isolated from the duodenum and the mRNA expression was measured using Affymetrix GeneChip oligonucleotide arrays. Detected genes from the intestine of mouse, rat and human were ca. 60% of 22690 sequences, 40% of 8739 and 47% of 12559, respectively. Total genes of metabolizing enzymes subjected in this study were 95, 33 and 68 genes in mouse, rat and human, respectively. Of phase I enzymes, the mouse exhibited abundant gene expressions for Cyp3a25, Cyp4v3, Cyp2d26, followed by Cyp2b20, Cyp2c65 and Cyp4f14, whereas, the rat showed higher expression profiles of Cyp3a9, Cyp2b19, Cyp4f1, Cyp17a1, Cyp2d18, Cyp27a1 and Cyp4f6. However, the highly expressed P450 enzymes were CYP3A4, CYP3A5, CYP4F3, CYP2C18, CYP2C9, CYP2D6, CYP3A7, CYP11B1 and CYP2B6 in the human. For phase II enzymes, glucuronosyltransferase Ugt1a6, glutathione S-transferases Gstp1, Gstm3 and Gsta2, sulfotransferase Sult1b1 and acyltransferase Dgat1 were highly expressed in the mouse. The rat revealed predominant expression of glucuronosyltransferases Ugt1a1 and Ugt1a7, sulfotransferase Sult1b1, acetyltransferase Dlat and acyltransferase Dgat1. On the other hand, in human, glucuronosyltransferases UGT2B15 and UGT2B17, glutathione S-transferases MGST3, GSTP1, GSTA2 and GSTM4, sulfotransferases ST1A3 and SULT1A2, acetyltransferases SAT1 and CRAT, and acyltransferase AGPAT2 were dominantly detected. Therefore, current data indicated substantial interspecies differences in the pattern of intestinal gene expression both for P450 enzymes and phase II drug-metabolizing enzymes. This genomic database is expected to improve our understanding of interspecies variations in estimating intestinal prehepatic clearance of oral drugs.

  13. Gene therapy in cerebrovascular diseases.

    PubMed

    Gabriel, Rodney Allanigue; Yang, Guo-Yuan

    2007-12-01

    Several studies utilize gene therapy technology to study the molecular mechanisms and therapeutic approaches to a variety of neurological diseases. Although gene therapy for neuro-oncology and neurodegenerative diseases has advanced to the clinical arena, those of cerebrovascular nature have remained in the experimental stage and demonstrate promising results. Before gene therapy in cerebrovascular disorders can be successful, various obstacles need to be addressed. In this review, we focus on the fundamentals of gene therapy adapted to cerebrovascular diseases, which include cerebral ischemia, post-subarachnoid hemorrhagic vasospasm, arteriovenous malformations, etc. We discuss: 1) the utilization of gene delivery vehicle, through viral, non-viral, or cellular vectors; 2) the routes and specific delivery of the vector to its target cells or tissue in the central nervous system; 3) the studies that have utilized in vivo and ex vivo gene delivery approaches and their success in the attenuation of cerebrovascular injuries; and finally 4) the future of gene therapy in this field.

  14. 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.

  15. Hidden hyperchaos and electronic circuit application in a 5D self-exciting homopolar disc dynamo

    NASA Astrophysics Data System (ADS)

    Wei, Zhouchao; Moroz, Irene; Sprott, J. C.; Akgul, Akif; Zhang, Wei

    2017-03-01

    We report on the finding of hidden hyperchaos in a 5D extension to a known 3D self-exciting homopolar disc dynamo. The hidden hyperchaos is identified through three positive Lyapunov exponents under the condition that the proposed model has just two stable equilibrium states in certain regions of parameter space. The new 5D hyperchaotic self-exciting homopolar disc dynamo has multiple attractors including point attractors, limit cycles, quasi-periodic dynamics, hidden chaos or hyperchaos, as well as coexisting attractors. We use numerical integrations to create the phase plane trajectories, produce bifurcation diagram, and compute Lyapunov exponents to verify the hidden attractors. Because no unstable equilibria exist in two parameter regions, the system has a multistability and six kinds of complex dynamic behaviors. To the best of our knowledge, this feature has not been previously reported in any other high-dimensional system. Moreover, the 5D hyperchaotic system has been simulated using a specially designed electronic circuit and viewed on an oscilloscope, thereby confirming the results of the numerical integrations. Both Matlab and the oscilloscope outputs produce similar phase portraits. Such implementations in real time represent a new type of hidden attractor with important consequences for engineering applications.

  16. 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.

  17. Divorce and eating behaviors: a 5-day within-subject study of preadolescent obesity risk.

    PubMed

    Mauskopf, Susan S; O'Leary, Allison K; Banihashemi, Adria; Weiner, Michelle; Cookston, Jeffrey T

    2015-04-01

    Obesity rates have more than doubled among children and have tripled among adolescents since the 1980s, and currently more than one third of children and adolescents are overweight or obese. Parental divorce is a time of family upheaval, yet little is known about the family processes that link family structure and obesity. The current study gathered a 5-day eating behavior questionnaire from 37 preadolescents (mean=10.26 years; standard deviation=1.32; 32.4% female) and one parent to explore whether marital status was linked to obesity risk behaviors (i.e., high consumption of sugar-sweetened beverages (SSBs), low consumption of produce, skipping breakfast, and eating dinners away from the home) and whether family context (e.g., parent time spent with child, parental acceptance, and family routines) mediated that link. Results showed that preadolescents in divorced families consumed more SSBs than preadolescents in married families, and there was a trend for less-frequent breakfast consumption among preadolescents in the divorced families. Of the three family context variables, only family routines explained the link between family structure and obesity risk. This study highlights the importance of family processes during divorce to understand the etiology and prevalence of child and adolescent obesity.

  18. A 5 Gb/s CMOS adaptive equalizer for serial link

    NASA Astrophysics Data System (ADS)

    Wu, Hongbing; Wang, Jingyu; Liu, Hongxia

    2018-04-01

    A 5 Gb/s adaptive equalizer with a new adaptation scheme is presented here by using 0.13 μm CMOS process. The circuit consists of the combination of equalizer amplifier, limiter amplifier and adaptation loop. The adaptive algorithm exploits both the low frequency gain loop and the equalizer loop to minimize the inter-symbol interference (ISI) for a variety of cable characteristics. In addition, an offset cancellation loop is used to alleviate the offset influence of the signal path. The adaptive equalizer core occupies an area of 0.3567 mm2 and consumes a power consumption of 81.7 mW with 1.8 V power supply. Experiment results demonstrate that the equalizer could compensate for a designed cable loss with 0.23 UI peak-to-peak jitter. Project supported by the National Natural Science Foundation of China (No. 61376099), the Foundation for Fundamental Research of China (No. JSZL2016110B003), and the Major Fundamental Research Program of Shaanxi (No. 2017ZDJC-26).

  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. 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.

  1. Immediate restoration of single tapered implants with nonoccluding provisional crowns: a 5-year clinical prospective study.

    PubMed

    Lang, Lisa A; Turkyilmaz, Ilser; Edgin, Wendell A; Verrett, Ronald; Garcia, Lily T

    2014-04-01

    Dental literature has limited number of publications regarding long-term outcome data of immediate restoration of single missing teeth with an implant-supported provisional crown. This 5-year study evaluated hard and soft tissue responses to the immediate placement of single implant-supported provisional crowns. Twenty patients received one dental implant restored immediately with a provisional acrylic resin screw-retained crown. Crestal bone loss was evaluated from standardized periapical radiographs collected at 3-month intervals for the first 21 months followed by a 5-year evaluation. Historical controls acquired from available dental literature were used for comparison. One implant failed within 2 months of surgical placement, presenting with pain and mobility. The remaining implants demonstrated no infection, pain, or radiolucencies. Nineteen implants were clinically immobile, osseointegrated, and asymptomatic at 21 months. At 5 years, one patient died, three patients were noncompliant, and 15 implants were evaluated as functional. Mean bone loss (MBL) at 1 year and 21 months was approximately 0.5 ± 0.5 mm and 0.70 ± 0.26 mm at 5 years. There was no statistically significant difference between MBLs at p < 0.05. Immediate provisionalization of single dental implants compares favorably with conventional loading protocols. Long-term data suggest that immediate provisionalization of single dental implants is a viable treatment option. © 2012 Wiley Periodicals, Inc.

  2. HIV rapid testing in a Veterans Affairs hospital ED setting: a 5-year sustainability evaluation.

    PubMed

    Knapp, Herschel; Hagedorn, Hildi; Anaya, Henry D

    2014-08-01

    Routine HIV testing in primary care settings is now recommended in the United States. The US Department of Veterans Affairs (VA) has increased the number of patients tested for HIV, but overall HIV testing rates in VA remain low. A proven strategy for increasing such testing involves nurse-initiated HIV rapid testing (HIV RT). The purpose of this work was to use a mixed methodology approach to evaluate the 5-year sustainability of an intervention that implemented HIV RT in a VA emergency department setting in a large, urban VA medical center to reduce missed diagnostic and treatment opportunities in this vulnerable patient population. In-person semistructured interviews were conducted with providers and stakeholders. Interview notes were qualitatively coded for emerging themes. Quarterly testing rates were evaluated for a 5-year time span starting from the launch in July 2008. Findings indicate that HIV RT was sustained by the enthusiasm of 2 clinical champions who oversaw the registered nurses responsible for conducting the testing. The departure of the clinical champions was correlated with a substantial drop-off in testing. Findings also indicate potential strategies for improving sustainability including engaging senior leadership in the project, engaging line staff in the implementation planning from the start to increase ownership over the innovation, incorporating information into initial training explaining the importance of the innovation to quality patient care, providing ongoing training to maintain skills, and providing routine progress reports to staff to demonstrate the ongoing impact of their efforts. Published by Elsevier Inc.

  3. Long-term weight regain after gastric bypass: a 5-year prospective study.

    PubMed

    Magro, Daniéla Oliveira; Geloneze, Bruno; Delfini, Regis; Pareja, Bruna Contini; Callejas, Francisco; Pareja, José Carlos

    2008-06-01

    A certain weight gain occurs after obesity surgery compared to the lower weight usually observed between 18 and 24 months postsurgery. The objective of this study was to evaluate weight regain in patients submitted to gastric bypass over a 5-year follow-up period. A longitudinal prospective study was conducted on 782 obese patients of both genders. Only patients with at least 2 years of surgery were included. The percentage of excess body mass index (BMI) loss at 24, 36, 48, and 60 months postsurgery was compared to the measurements obtained at 18 months after surgery. Surgical therapeutic failure was also evaluated. Percent excess BMI loss was significant up to 18 months postsurgery (p < 0.001), with a mean difference in BMI of 1.06 kg/m2 compared to 12 months postsurgery. Percent BMI loss was no longer significant after 24 months, and weight regain became significant within 48 months after surgery (p < 0.01). Among the patients who presented weight regain, a mean 8% increase was observed within 60 months compared to the lowest weight obtained at 18 months after surgery. The percentage of surgical failure was higher in the superobese group at all times studied, reaching 18.8% at 48 months after surgery. Weight regain was observed within 24 months after surgery in approximately 50% of patients. Both weight regain and surgical failure were higher in the superobese group. Studies in regard to metabolic and hormonal mechanisms underlying weight regain might elucidate the causes of this finding.

  4. 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.

  5. A medical management of interstitial ectopic pregnancy: a 5-year clinical study.

    PubMed

    Tang, Amy; Baartz, David; Khoo, Soo Keat

    2006-04-01

    Medical treatment of the rare interstitial ectopic pregnancy with methotrexate has been considered an alternative to surgical resection. To determine the treatment success rate with a single-dose intravenous methotrexate/folinic acid regimen and to identify predictors of treatment outcome. A 5-year audit (April 2000-August 2005) was carried out, collecting clinical imaging data and serum beta-human chorionic gonadotrophin (beta-hCG). Time taken for complete beta-hCG resolution was recorded, and a negative beta-hCG result was used as an endpoint of successful outcome. Of the 13 cases, two required urgent surgery for rupture on presentation. In the remaining 11 cases, intravenous methotrexate (300 mg) was used, with oral folinic acid rescue (15 mg x 4 doses). There were no side-effects. Complete beta-hCG resolution was achieved in 10 of the 11 medically treated cases (91% success rate), requiring 21-129 days. Successful outcome was seen with initial beta-hCG level as high as 106 634 IU/L and gestation sac as large as 6 cm and a live fetus. The methotrexate/folinic acid regimen used as a one-dose treatment is safe and effective for unruptured interstitial pregnancy, with no side-effects and the advantage of avoiding invasive surgery. Subsequent tubal patency and reproductive function are yet to be ascertained.

  6. Development of a 5 MW reference gearbox for offshore wind turbines: 5 MW reference gearbox

    SciTech Connect

    Nejad, Amir Rasekhi; Guo, Yi; Gao, Zhen

    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 gearmore » 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.« less

  7. Recovery of Cronobacter sakazakii from environmental surface swabbing materials using a 5-h enrichment procedure.

    PubMed

    Lindsay, Denise; Somerton, Ben; Hill, Bruce; Shrubb, Owen

    2010-08-01

    This study aimed to reduce the time taken to detect low numbers of Cronobacter sakazakii inoculated onto environmental swabs (100, 10 or 1 cfu per swab) using a simple plating procedure for application in a dairy testing laboratory. Three types of environmental swabs (Biolab FlexiSwab, gauze swabs and the Whatman SwabCheck Polywipe sponge) were inoculated with either Cron. sakazakii in single culture or Cron. sakazakii together with Citrobacter freundii. A 5-h enrichment procedure of swabs in Cronobacter enrichment broth at 37 degrees C prior to plating was then compared with no enrichment or 24-h enrichment. The 5-h enrichment procedure was as efficient at detecting Cron. sakazakii on environmental swabs at low cell concentrations (100 cfu per swab), and in pure culture or in competition with other coliforms (Citrobacter), as pre-enrichment for 24 h. This protocol was also successful in detecting 10 cfu per swab 80% of the time. The results also indicated that the type of swab selected for use in environmental safety programmes is influential on the outcome, with the FlexiSwab and gauze swabs being the most efficient swabbing materials evaluated in this study.

  8. Characterization of Exosomal SLC22A5 (OCTN2) carnitine transporter.

    PubMed

    Console, Lara; Scalise, Mariafrancesca; Tonazzi, Annamaria; Giangregorio, Nicola; Indiveri, Cesare

    2018-02-28

    Exosomes are extracellular vesicles involved in cell-to-cell communication. Previous large scale proteomics revealed that they contain SLC proteins. However, no data on the function of exosomal SLCs is available, so far. An SLC localized in exosomes was here characterized for the first time: the carnitine transporter OCTN2 (SLC22A5). The protein was detected by Western Blot analysis in HEK293 exosomes. To investigate the functional properties of the exosomal OCTN2, the proteins extracted from vesicles were reconstituted into proteolipsomes and the transport function was measured as uptake of 3 H-carnitine. Transport was stimulated by sodium and was dependent on pH. 3 H-carnitine uptake was inhibited by Acetyl-carnitine, but not by Asn, Gln and Arg thus excluding interference by ATB 0,+ , an amino acid transporter which also recognizes carnitine. Cardiolipin failed to stimulate transport, excluding the activity of the mitochondrial Carnitine/acylcarnitine transporter. Increased level of exosomal OCTN2 was induced by treatment of HEK293 with the pro-inflammatory cytokine INFγ. All data concurred to demonstrate that OCTN2 present in exosomes is fully functional and is in its native conformation. Functional OCTN2 was detected also in human urinary exosomes, thus suggesting the OCTN2 exosomal protein as a candidate biomarker for inflammation related pathologies.

  9. Clinical evaluation of small diameter straumann implants in partially edentulous patients: a 5-year retrospective study.

    PubMed

    Yaltirik, M; Gökçen-Röhlig, B; Ozer, S; Evlioglu, G

    2011-01-01

    The aim of the present study was to retrospectively evaluate small-diameter (3.3 mm) Straumann® dental implants placed in the maxilla or the mandible over a period of 5 years in function. Twenty-eight partially edentulous patients received a total of 48 implants over a 5-year period. After the standard healing period (3 to 6 months), the implants were restored with single-tooth prostheses or fixed partial dentures. All patients were followed according to a strict maintenance program with regular recalls. The cumulative survival rates of implants were analyzed and prosthetic complications were assessed. After 5 years of function, one single 10-mm-long implant in the maxillary premolar region was lost because of recurrent peri-implant infection in a female patient. Two single 10-mm-long maxillary implants placed in the posterior region were lost due to body fracture. The cumulative 5-year survival rate of the implants was 93.75 %. The most common prosthetic complication was loosening of the occlusal screw. Within the limited observation period and the number of patients included in this study, it may be concluded that the use of small-diameter implants appears to be predictable if clinical guidelines are followed and appropriate prosthetic restorations are provided. However, it should be noted that fatigue fracture may occur.

  10. Worst-Case Energy Efficiency Maximization in a 5G Massive MIMO-NOMA System.

    PubMed

    Chinnadurai, Sunil; Selvaprabhu, Poongundran; Jeong, Yongchae; Jiang, Xueqin; Lee, Moon Ho

    2017-09-18

    In this paper, we examine the robust beamforming design to tackle the energy efficiency (EE) maximization problem in a 5G massive multiple-input multiple-output (MIMO)-non-orthogonal multiple access (NOMA) downlink system with imperfect channel state information (CSI) at the base station. A novel joint user pairing and dynamic power allocation (JUPDPA) algorithm is proposed to minimize the inter user interference and also to enhance the fairness between the users. This work assumes imperfect CSI by adding uncertainties to channel matrices with worst-case model, i.e., ellipsoidal uncertainty model (EUM). A fractional non-convex optimization problem is formulated to maximize the EE subject to the transmit power constraints and the minimum rate requirement for the cell edge user. The designed problem is difficult to solve due to its nonlinear fractional objective function. We firstly employ the properties of fractional programming to transform the non-convex problem into its equivalent parametric form. Then, an efficient iterative algorithm is proposed established on the constrained concave-convex procedure (CCCP) that solves and achieves convergence to a stationary point of the above problem. Finally, Dinkelbach's algorithm is employed to determine the maximum energy efficiency. Comprehensive numerical results illustrate that the proposed scheme attains higher worst-case energy efficiency as compared with the existing NOMA schemes and the conventional orthogonal multiple access (OMA) scheme.

  11. Dynamic analysis of a 5-MW tripod offshore wind turbine by considering fluid-structure interaction

    NASA Astrophysics Data System (ADS)

    Zhang, Li-wei; Li, Xin

    2017-10-01

    Fixed offshore wind turbines usually have large underwater supporting structures. The fluid influences the dynamic characteristics of the structure system. The dynamic model of a 5-MW tripod offshore wind turbine considering the pile-soil system and fluid structure interaction (FSI) is established, and the structural modes in air and in water are obtained by use of ANSYS. By comparing low-order natural frequencies and mode shapes, the influence of sea water on the free vibration characteristics of offshore wind turbine is analyzed. On basis of the above work, seismic responses under excitation by El-Centro waves are calculated by the time-history analysis method. The results reveal that the dynamic responses such as the lateral displacement of the foundation and the section bending moment of the tubular piles increase substantially under the influence of the added-mass and hydrodynamic pressure of sea water. The method and conclusions presented in this paper can provide a theoretical reference for structure design and analysis of offshore wind turbines fixed in deep seawater.

  12. Relationship between OSCE scores and other typical medical school performance indicators: a 5-year cohort study.

    PubMed

    Dong, Ting; Saguil, Aaron; Artino, Anthony R; Gilliland, William R; Waechter, Donna M; Lopreaito, Joseph; Flanagan, Amy; Durning, Steven J

    2012-09-01

    Objective Structured Clinical Examinations (OSCEs) are used at the majority of U.S. medical schools. Given the high resource demands with constructing and administering OSCEs, understanding how OSCEs relate to typical performance measures in medical school could help educators more effectively design curricula and evaluation to optimize student instruction and assessment. To investigate the correlation between second-year and third-year OSCE scores, as well as the associations between OSCE scores and several other typical measures of students' medical school performance. We tracked the performance of a 5-year cohort (classes of 2007-2011). We studied the univariate correlations among OSCE scores, U.S. Medical Licensing Examination (USMLE) scores, and medical school grade point average. We also examined whether OSCE scores explained additional variance in the USMLE Step 2 Clinical Knowledge score beyond that explained by the Step 1 score. The second- and third-year OSCE scores were weakly correlated. Neither second- nor third-year OSCE score was strongly correlated with USMLE scores or medical school grade point average. Our findings suggest that OSCEs capture a viewpoint that is different from typical assessment measures that largely reflect multiple choice questions; these results also support tenets of situated cognition theory.

  13. 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. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Preliminary engineering design and cost of Advanced Compressed-Air Storage (ACAS) A-5 hybrid

    NASA Astrophysics Data System (ADS)

    Sosnowicz, E. J.; Blackman, J.; Woodhull, A. S.; Zaugg, P.

    1981-08-01

    The advanced compressed air energy (ACAS) plant investiated operates on a partial adiabatic, partial fuel fired cycle. Only a limited advancement in state-of-the-art technology is projected for this hybrid arrangement. The A-5 hybrid systems stores the heat of compression from the low pressure and intermediate pressure compressors in a thermal energy store (TES). The heat collected in the TES is available for preheating the air from the storage cavern prior to its entering the low pressure turbine combustor. This reduces the amount of fuel consumed during power generation. The fuel heat rate for the hybrid cycle is 2660 Btu/kWh as compared to approximately 4000 Btu/kWh for a conventional CAES plant. A virtual stand-off between the hybrid plant and a conventional CAES plant at 235 mills/kWh in 1990 dollars is shown. With a lower cost and increased fuel cost projections, the hybrid system operating cost is less than that for a conventional CAES plant.

  15. Neutronic analysis of the conversion of HEU to LEU fuel for a 5-MW MTR core

    SciTech Connect

    Pazirandeh, A.; Bartsch, G.

    1987-01-01

    In recent years, due to cessation of highly enriched uranium (HEU) fuel supply, practical steps have been taken to substitute HEU fuel in almost all research reactors by medium-enriched uranium or low-enriched uranium (LEU) fuels. In this study, a neutronic calculation of a 5-MW research reactor core fueled with HEU (93% /sup 235/U) is presented. In order to assess the performance of the core with the LEU (< 20%) fuel replacement, while keeping fuel element geometry nearly unchanged, several different /sup 235/U loadings were examined. The core consists of 22 standard fuel elements (SFEs) and 6 control fuel elements (CFEs).more » Each fuel elements has 18 curved plates of which two end plates are dummies. Initial /sup 235/U content is 195 g /sup 235/U/SFE and 9.7 g /sup 235/U/CFE or /PFE. In all calculations the permitted changes to the fuel elements are (a) 18 active plates per SFE, (b) fuel plates assumed to be flat, and (c) 8 or 9 active plates per CFE.« less

  16. Prognosis of heart failure with preserved ejection fraction: a 5 year prospective population-based study.

    PubMed

    Tribouilloy, Christophe; Rusinaru, Dan; Mahjoub, Haïfa; Soulière, Vicky; Lévy, Franck; Peltier, Marcel; Slama, Michel; Massy, Ziad

    2008-02-01

    This study was designed to identify the characteristics and long-term prognosis of heart failure with preserved ejection fraction (HFPEF) in patients hospitalized for a first episode of HF. Consecutive patients (n = 799) hospitalized for a first episode of HF during 2000 in the Somme department (France) were recruited. EF was available in 662 (83%) patients, representing the study population. Patients with HFPEF (55.6% of cases) were significantly older, with a high proportion of women. During the 5 year follow-up, 370 patients (56%) died. Patients with HFPEF had a significantly lower 5 year survival than the age- and sex-matched general population (43 vs. 72%). Five year survival rates were not significantly different in patients with preserved and reduced EF (43 vs. 46%; P = 0.95). Both groups had similar relative 5 year survival rates compared with the general population. Multivariable analysis identified age, stroke, chronic obstructive pulmonary disease, cancer, diabetes, low glomerular filtration rate, and hyponatraemia as independent predictors of 5 year mortality in patients with HFPEF. Heart failure with preserved ejection fraction has a poor prognosis, comparable with that of HF with reduced EF, with a 5 year survival rate after a first episode of 43% and a high excess mortality compared with the general population.

  17. Clinical performance of bonded ceramic inlays/onlays: A 5- to 18-year retrospective longitudinal study.

    PubMed

    Borgia Botto, Ernesto; Baró, Rosario; Borgia Botto, José Luis

    2016-08-01

    This retrospective longitudinal study evaluated the clinical performance of bonded ceramic inlays/onlays, placed by the first author in his private practice, in a 5 to 18-year period. The patients evaluated had been treated in the office for at least 7 years and were still in the practice up to year 2013. 130 randomly selected patients agreed to participate in the study. 93 bonded ceramic inlays/onlays (BCRs), were placed on posterior teeth in 47 subjects. Gender, age, tooth preparation, number, type, extent, location, quality and survival of the restorations, ceramic materials, luting resins cements, parafunctional habits, secondary caries and maintenance therapy were the variables evaluated. Cohen 's Kappa coefficient, on the quality analysis of the restorations, ranged from 0.78 to 1. Fisher 's exact test, Chi Square test, Kruskal-Wallis test and Mann-Whitney non-parametric test were indicated to analyze significant differences. At the initial examination, 87 (93.5%) restorations were in function and six failed (6.5%). 81 (93%) were rated as clinical successes. The observed mean survival time of those that remained functional was 11 years. The standard deviation was 4 years, with a 95% CI for the overall observed mean survival time (10 years-11 years, 9 months). 87 of 93 BCRs had a functional success of 93.5%, with an observed mean survival of 11 years. The clinical performance of bonded ceramic onlays was very acceptable. Bonded ceramic onlays showed a predictable, esthetic, and functional treatment, with acceptable longevity.

  18. Investigating highly replicated asthma genes as candidate genes for allergic rhinitis.

    PubMed

    Andiappan, Anand Kumar; Nilsson, Daniel; Halldén, Christer; Yun, Wang De; Säll, Torbjörn; Cardell, Lars Olaf; Tim, Chew Fook

    2013-05-10

    Asthma genetics has been extensively studied and many genes have been associated with the development or severity of this disease. In contrast, the genetic basis of allergic rhinitis (AR) has not been evaluated as extensively. It is well known that asthma is closely related with AR since a large proportion of individuals with asthma also present symptoms of AR, and patients with AR have a 5-6 fold increased risk of developing asthma. Thus, the relevance of asthma candidate genes as predisposing factors for AR is worth investigating. The present study was designed to investigate if SNPs in highly replicated asthma genes are associated with the occurrence of AR. A total of 192 SNPs from 21 asthma candidate genes reported to be associated with asthma in 6 or more unrelated studies were genotyped in a Swedish population with 246 AR patients and 431 controls. Genotypes for 429 SNPs from the same set of genes were also extracted from a Singapore Chinese genome-wide dataset which consisted of 456 AR cases and 486 controls. All SNPs were subsequently analyzed for association with AR and their influence on allergic sensitization to common allergens. A limited number of potential associations were observed and the overall pattern of P-values corresponds well to the expectations in the absence of an effect. However, in the tests of allele effects in the Chinese population the number of significant P-values exceeds the expectations. The strongest signals were found for SNPs in NPSR1 and CTLA4. In these genes, a total of nine SNPs showed P-values <0.001 with corresponding Q-values <0.05. In the NPSR1 gene some P-values were lower than the Bonferroni correction level. Reanalysis after elimination of all patients with asthmatic symptoms excluded asthma as a confounding factor in our results. Weaker indications were found for IL13 and GSTP1 with respect to sensitization to birch pollen in the Swedish population. Genetic variation in the majority of the highly replicated asthma

  19. A Randomized Controlled Trial Comparing the Efficacy of Cyp3a5 Genotype-Based With Body-Weight-Based Tacrolimus Dosing After Living Donor Kidney Transplantation.

    PubMed

    Shuker, N; Bouamar, R; van Schaik, R H N; Clahsen-van Groningen, M C; Damman, J; Baan, C C; van de Wetering, J; Rowshani, A T; Weimar, W; van Gelder, T; Hesselink, D A

    2016-07-01

    Patients expressing the cytochrome P450 (CYP) 3A5 gene require a higher tacrolimus dose to achieve therapeutic exposure compared with nonexpressers. This randomized-controlled study investigated whether adaptation of the tacrolimus starting dose according to CYP3A5 genotype increases the proportion of kidney transplant recipients being within the target tacrolimus predose concentration range (10-15 ng/mL) at first steady-state. Two hundred forty living-donor, renal transplant recipients were assigned to either receive a standard, body-weight-based or a CYP3A5 genotype-based tacrolimus starting dose. At day 3, no difference in the proportion of patients having a tacrolimus exposure within the target range was observed between the standard-dose and genotype-based groups: 37.4% versus 35.6%, respectively; p = 0.79. The proportion of patients with a subtherapeutic (i.e. <10 ng/mL) or a supratherapeutic (i.e. >15 ng/mL) Tac predose concentration in the two groups was also not significantly different. The incidence of acute rejection was comparable between both groups (p = 0.82). Pharmacogenetic adaptation of the tacrolimus starting dose does not increase the number of patients having therapeutic tacrolimus exposure early after transplantation and does not lead to improved clinical outcome in a low immunological risk population. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

  20. Influence of CYP3A4 and CYP3A5 polymorphisms on tacrolimus and sirolimus exposure in stable kidney transplant recipients.

    PubMed

    Tamashiro, Erika Y; Felipe, Claudia R; Genvigir, Fabiana D V; Rodrigues, Alice C; Campos, Antony B; Hirata, Rosario D C; Tedesco-Silva, Helio; Medina-Pestana, Jose O

    2017-05-24

    Polymorphisms in genes encoding for drug-metabolizing enzymes and drug transporters are among multiple factors that modulate the pharmacokinetic variability of tacrolimus (TAC) and sirolimus (SRL). This study aimed to evaluate the influence of single nucleotide polymorphisms (SNPs) on TAC and SRL dose-adjusted concentrations (C0/D) in stable kidney transplant recipients. This is an exploratory and prospective study, which includes 46 stable kidney transplant recipients. These patients were monitored from the 3rd to the 24th month after transplantation. The SRL group consisted of 25 patients receiving TAC, prednisone (PRED), and mycophenolate sodium (MPS), which were converted from TAC to SRL at 3rd month after transplantation. The TAC group consisted of 21 patients who underwent treatment with TAC, PRED, and MPS. Both groups were genotyped for CYP3A4 rs2242480 (g.20230G>A), CYP3A5 rs15524 (g.31611C>T), CYP2C8 rs10509681 (c.1196A>G) and ABCB1 rs1045642 (c.3435C>T), rs1128503 (c.1236C>T), and rs2032582 (c.2677G>T/A) polymorphisms. In the TAC group, CYP3A4 rs2242480 A allele carriers were associated with lower TAC C0/D. For CYP3A5 rs15524 SNP, C0/D was higher among patients carrying TT genotype when compared with CT and CC genotype carriers in the SRL and, more consistently, in the TAC groups. For ABCB1 rs1045642 SNP, TT genotype was associated with reduced SRL C0/D, but only at month 15. CYP3A4 rs2242480 and CYP3A5 rs15524 SNPs resulted in significant changes in SRL and TAC C0/D at different times after transplantation.

  1. Network analysis reveals crosstalk between autophagy genes and disease genes.

    PubMed

    Wang, Ji-Ye; Yao, Wei-Xuan; Wang, Yun; Fan, Yi-Lei; Wu, Jian-Bing

    2017-03-15

    Autophagy is a protective and life-sustaining process in which cytoplasmic components are packaged into double-membrane vesicles and targeted to lysosomes for degradation. Accumulating evidence supports that autophagy is associated with several pathological conditions. However, research on the functional cross-links between autophagy and disease genes remains in its early stages. In this study, we constructed a disease-autophagy network (DAN) by integrating known disease genes, known autophagy genes and protein-protein interactions (PPI). Dissecting the topological properties of the DAN suggested that nodes that both autophagy and disease genes (inter-genes), are topologically important in the DAN structure. Next, a core network from the DAN was extracted to analyze the functional links between disease and autophagy genes. The genes in the core network were significantly enriched in multiple disease-related pathways, suggesting that autophagy genes may function in various disease processes. Of 17 disease classes, 11 significantly overlapped with autophagy genes, including cancer diseases, metabolic diseases and hematological diseases, a finding that is supported by the literatures. We also found that autophagy genes have a bridging role in the connections between pairs of disease classes. Altogether, our study provides a better understanding of the molecular mechanisms underlying human diseases and the autophagy process.

  2. Mobile gene cassettes: a fundamental resource for bacterial evolution.

    PubMed

    Michael, Carolyn A; Gillings, Michael R; Holmes, Andrew J; Hughes, Lesley; Andrew, Nigel R; Holley, Marita P; Stokes, H W

    2004-07-01

    Horizontal gene transfer increases genetic diversity in prokaryotes to a degree not allowed by the limitations of reproduction by binary fission. The integron/gene cassette system is one of the most recently characterized examples of a system that facilitates horizontal gene transfer. This system, discovered in the context of multidrug resistance, is recognized in a clinical context for its role in allowing pathogens to adapt to the widespread use of antibiotics. Recent studies suggest that gene cassettes are common and encode functions relevant to many adaptive traits. To estimate the diversity of mobile cassettes in a natural environment, a molecular technique was developed to provide representative distributions of cassette populations at points within a sampling area. Subsequently, statistical methods analogous to those used for calculating species diversity were employed to assess the diversity of gene cassettes within the sample area in addition to gaining an estimate of cassette pool size. Results indicated that the number of cassettes within a 5x10-m sample area was large and that the overall mobile cassette metagenome was likely to be orders of magnitude larger again. Accordingly, gene cassettes appear to be capable of mobilizing a significant genetic resource and consequently have a substantial impact on bacterial adaptability.

  3. Genes for sexual behavior.

    PubMed

    Yamamoto, D; Nakano, Y

    1998-05-08

    The mating behavior of Drosophila melanogaster is a stereotyped sequence of fixed action patterns, composed of orientation, tapping, singing, licking, attempted copulation and copulation. Mutations that block a unique aspect of mating behavior were isolated and analyzed at the cellular and molecular levels. The wild-type counterparts of the mutated genes were shown to rescue the phenotypes by their ubiquitous or targeted expression in some of the mutants. This strategy of artificial control of fly behavior opens up an avenue for studies to identify the neural center for individual behavioral actions.

  4. Dynamic effects of CYP3A5 polymorphism on dose requirement and trough concentration of tacrolimus in renal transplant recipients.

    PubMed

    Chen, P; Li, J; Li, J; Deng, R; Fu, Q; Chen, J; Huang, M; Chen, X; Wang, C

    2017-02-01

    Tacrolimus is a widely used immunosuppressive drug with marked pharmacokinetic variability partly due to CYP3A5 polymorphism. Our study aimed to investigate the dynamic effects of CYP3A5 genotypes on dose requirement and trough concentration (C 0 ) of tacrolimus in renal transplant recipients. A total of 194 Chinese renal transplant recipients received oral tacrolimus twice daily. Whole-blood C 0 of tacrolimus were measured on the 3rd day, 7th day, 14th day, 1st month, 3rd month and 6th month post-transplantation. CYP3A5 genotypes were determined and the recipients were categorized as CYP3A5 expressers (CYP3A5*1 allele carriers) and non-expressers (homozygous CYP3A5*3). The correlated serum creatinine, haematocrit and albumin were also detected. The allele frequencies for CYP3A5*1/*1, *1/*3 and *3/*3 were 7·7%, 44·8% and 47·4%, respectively. There were no significant variability in serum creatinine, haematocrit and albumin values between CYP3A5 expressers and non-expressers. Larger doses were administered to CYP3A5 expressers than to non-expressers after surgery except the initial dose. C 0 were much lower in CYP3A5 expressers than in non-expressers on the 3rd day, 7th day, 14th day and 1st month post-transplantation (P < 0·01); however, no significant differences were found on the 3rd and 6th months post-transplantation. All of the dose-adjusted C 0 in CYP3A5 expressers were significantly lower than non-expressers (P < 0·01). Less of the recipients achieving target C 0 (4-8 ng/mL) were found in CYP3A5 expressers than in non-expressers after initial dose (35·7% vs. 50%). Meanwhile, CYP3A5 non-expressers were detected having higher C 0 (>8 ng/mL) during 3 months post-transplantation. Besides, the proportions in the two groups both increased gradually over time and up to 91·8% and 94% on the 6th month, respectively. There are no significant differences in serum creatinine, haematocrit and albumin values between CYP3A5 expressers and non-expressers. CYP3A5

  5. Genes and Disease: Prader-Willi Syndrome

    MedlinePlus

    ... MD): National Center for Biotechnology Information (US); 1998-. Genes and Disease [Internet]. Show details National Center for ... 45K) PDF version of this title (3.8M) Gene sequence Genome view see gene locations Entrez Gene ...

  6. Adenovirus Vectors for Gene Therapy, Vaccination and Cancer Gene Therapy

    PubMed Central

    Wold, William S.M.; Toth, Karoly

    2015-01-01

    Adenovirus vectors are the most commonly employed vector for cancer gene therapy. They are also used for gene therapy and as vaccines to express foreign antigens. Adenovirus vectors can be replication-defective; certain essential viral genes are deleted and replaced by a cassette that expresses a foreign therapeutic gene. Such vectors are used for gene therapy, as vaccines, and for cancer therapy. Replication-competent (oncolytic) vectors are employed for cancer gene therapy. Oncolytic vectors are engineered to replicate preferentially in cancer cells and to destroy cancer cells through the natural process of lytic virus replication. Many clinical trials indicate that replication-defective and replication-competent adenovirus vectors are safe and have therapeutic activity. PMID:24279313

  7. Human AZU-1 gene, variants thereof and expressed gene products

    DOEpatents

    Chen, Huei-Mei; Bissell, Mina

    2004-06-22

    A human AZU-1 gene, mutants, variants and fragments thereof. Protein products encoded by the AZU-1 gene and homologs encoded by the variants of AZU-1 gene acting as tumor suppressors or markers of malignancy progression and tumorigenicity reversion. Identification, isolation and characterization of AZU-1 and AZU-2 genes localized to a tumor suppressive locus at chromosome 10q26, highly expressed in nonmalignant and premalignant cells derived from a human breast tumor progression model. A recombinant full length protein sequences encoded by the AZU-1 gene and nucleotide sequences of AZU-1 and AZU-2 genes and variant and fragments thereof. Monoclonal or polyclonal antibodies specific to AZU-1, AZU-2 encoded protein and to AZU-1, or AZU-2 encoded protein homologs.

  8. 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. [Reserved] 1.263A-5 Section 1.263A-5... incurred by certain free-lance authors, photographers, and artists. [Reserved] ...

  9. 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. [Reserved] 1.263A-5 Section 1.263A-5... incurred by certain free-lance authors, photographers, and artists. [Reserved] ...

  10. 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. [Reserved] 1.263A-5 Section 1.263A-5... incurred by certain free-lance authors, photographers, and artists. [Reserved] ...

  11. 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. [Reserved] 1.263A-5 Section 1.263A-5... incurred by certain free-lance authors, photographers, and artists. [Reserved] ...

  12. 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. [Reserved] 1.263A-5 Section 1.263A-5... certain free-lance authors, photographers, and artists. [Reserved] ...

  13. 17 CFR 270.17a-5 - Pro rata distribution neither “sale” nor “purchase.”

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Pro rata distribution neither âsaleâ nor âpurchase.â 270.17a-5 Section 270.17a-5 Commodity and Securities Exchanges SECURITIES AND... among its common stockholders without giving any election to any stockholder as to the specific assets...

  14. 17 CFR 270.17a-5 - Pro rata distribution neither “sale” nor “purchase.”

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 3 2013-04-01 2013-04-01 false Pro rata distribution neither âsaleâ nor âpurchase.â 270.17a-5 Section 270.17a-5 Commodity and Securities Exchanges SECURITIES AND... among its common stockholders without giving any election to any stockholder as to the specific assets...

  15. 17 CFR 270.17a-5 - Pro rata distribution neither “sale” nor “purchase.”

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 4 2014-04-01 2014-04-01 false Pro rata distribution neither âsaleâ nor âpurchase.â 270.17a-5 Section 270.17a-5 Commodity and Securities Exchanges SECURITIES AND... among its common stockholders without giving any election to any stockholder as to the specific assets...

  16. 17 CFR 270.17a-5 - Pro rata distribution neither “sale” nor “purchase.”

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Pro rata distribution neither âsaleâ nor âpurchase.â 270.17a-5 Section 270.17a-5 Commodity and Securities Exchanges SECURITIES AND... among its common stockholders without giving any election to any stockholder as to the specific assets...

  17. 17 CFR 270.17a-5 - Pro rata distribution neither “sale” nor “purchase.”

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 3 2012-04-01 2012-04-01 false Pro rata distribution neither âsaleâ nor âpurchase.â 270.17a-5 Section 270.17a-5 Commodity and Securities Exchanges SECURITIES AND... among its common stockholders without giving any election to any stockholder as to the specific assets...

  18. Gene trap and gene inversion methods for conditional gene inactivation in the mouse

    PubMed Central

    Xin, Hong-Bo; Deng, Ke-Yu; Shui, Bo; Qu, Shimian; Sun, Qi; Lee, Jane; Greene, Kai Su; Wilson, Jason; Yu, Ying; Feldman, Morris; Kotlikoff, Michael I.

    2005-01-01

    Conditional inactivation of individual genes in mice using site-specific recombinases is an extremely powerful method for determining the complex roles of mammalian genes in developmental and tissue-specific contexts, a major goal of post-genomic research. However, the process of generating mice with recombinase recognition sequences placed at specific locations within a gene, while maintaining a functional allele, is time consuming, expensive and technically challenging. We describe a system that combines gene trap and site-specific DNA inversion to generate mouse embryonic stem (ES) cell clones for the rapid production of conditional knockout mice, and the use of this system in an initial gene trap screen. Gene trapping should allow the selection of thousands of ES cell clones with defined insertions that can be used to generate conditional knockout mice, thereby providing extensive parallelism that eliminates the time-consuming steps of targeting vector construction and homologous recombination for each gene. PMID:15659575

  19. Seminar program for postgraduate specialty training in general practice: proposal for a 5-year thematic catalogue.

    PubMed

    Sommer, Susanne; Baum, Erika; Magez, Julia; Chenot, Jean-Francois; Weckmann, Gesine; Steinhäuser, Jost; Heim, Susanne; Schneider, Dagmar; Fuchs, Stephan

    2017-01-01

    Introduction : In different German regions, seminar programs have been conducted for General practice residents. In each region, selection and teaching of learning content is conducted in a different manner. So far, no structured, standardized curriculum has been implemented nationwide. We have investigated, if the development of a common 5-year program of learning topics is conceivable between the different university departments of General practice in Germany. Method: The seminar program working group of the DEGAM (German College of General Practitioners and Family Physicians) has conducted an online survey based on information gathered via preliminary telephone conference (n=7; physicians with postgraduate teaching experience) among all German university departments of General Practice and two non-university teaching institutions, identified via the internet. 884 topics were extracted from 14 Seminar programs. The topics were entered in a database, discussed and categorized: Practice management/practice work flow/standardized documentation forms/quality management (n=33 topics), common acute and chronic diseases, including disease management programs (n=29 topics), communication, neurological, psychological and psychiatric consultations (n=24 topics), common medical problems, including eye, ear, nose, throat, skin and pediatric problems (n=99 Topics) family physicians general approach, including epidemiology, shared decision making, test of time (n=42 Topics). These topics have been rated for priority and desirable number of teaching-units. Results: A catalogue of 111 topics was designed, encompassing 160 teaching units. There is a suggestion of wide topics collections plus an add-on catalogue. Conclusion : A proposal for a 5-year-thematic catalogue for postgraduate training of general practice residents in Germany has been developed. This newly developed curriculum has the potential to improve knowledge and skills that have not been covered during in-house and

  20. A 5-year retrospective audit of prescribing by a critical care outreach team.

    PubMed

    Wilson, Mark

    2018-05-01

    UK prescribing legislation changes made in 2006 and 2012 enabled appropriately qualified nurses to prescribe any licensed medication, and all controlled drugs in schedule 2-5 of the Misuse of Drugs Regulations 2001, for any medical condition within their clinical competence. Critical Care Outreach nurses who are independent nurse prescribers are ideally placed to ensure that acutely ill patients receive treatment without delay. The perceived challenge was how Critical Care Outreach nurses would be able to safely prescribe for a diverse patient group. This study informs this developing area of nurse prescribing in critical care practice. The aims of the audit were to: identify which medications were prescribed; develop a critical care outreach formulary; identify the frequency, timing and number of prescribing decisions being made; identify if prescribing practice changed over the years and provide information for our continuing professional development. This article reports on data collected from a 5-year retrospective audit; of prescribing activity undertaken by nine independent nurse prescribers working in a 24/7 Critical Care Outreach team of a 600-bedded district general hospital in the UK. In total, 8216 medication items were prescribed, with an average of 2·6 prescribed per shift. The most commonly prescribed items were intravenous fluids and analgesia, which were mostly prescribed at night and weekends. The audit has shown that Critical Care Outreach nurse prescribing is feasible in a whole hospital patient population. The majority of prescribing occurred after 16:00 and at night. Further research would be beneficial, particularly looking at patient outcomes following reviews from prescribing critical care outreach nurses. The audit is one of the only long-term studies that describes prescribing practice in Critical Care Outreach teams in the UK. © 2017 British Association of Critical Care Nurses.

  1. Ketanserin, a 5-HT2 receptor antagonist, decreases nicotine self-administration in rats

    PubMed Central

    Levin, Edward D.; Slade, Susan; Johnson, Michael; Petro, Ann; Horton, Kofi; Williams, Paul; Rezvani, Amir H.; Rose, Jed E.

    2008-01-01

    Nicotine intake constitutes a principal mechanism for tobacco addiction. In addition to primary effects on nicotinic acetylcholine receptors, nicotine has cascading effects, which may underlie its neurobehavioral actions. Nicotine induces serotonin (5-HT) release, which has not classically been thought to be involved in tobacco addiction. However, addiction can be characterized more as a disorder of compulsion than a disorder of enjoyment. 5-HT mechanisms play key roles in compulsive disorders. Nicotine-induced 5-HT release may be a key to tobacco addiction. Ketanserin, a 5-HT2a and 2c receptor antagonist, significantly attenuates nicotine effects on attention and memory. These studies were conducted to determine if ketanserin would reduce nicotine self-administration in rats. Male Sprague- Dawley rats (N=12) were given initial food pellet training and then 10 sessions of nicotine self-administration training (0.03 mg/kg/infusion, i.v.). Then the rats were administered ketanserin (1 or 2 mg/kg, s.c.) or the saline vehicle. Ketanserin (2 mg/kg) significantly decreased nicotine self-administration. This did not seem to be due to sedative or amnestic effects of ketanserin. In a second study, the effects of repeated administration of 2 mg/kg ketanserin (N=11) vs. saline injections (N=10) were examined. In the initial phase, the acute effectiveness of ketanserin in significantly reducing nicotine self-administration was replicated. The effect became attenuated during the following several sessions, but the significant effect became re-established during the final phases of this two-week study. 5-HT mechanisms play critical roles in the maintenance of nicotine self-administration. Better understanding of those roles may help lead to new 5-HT-based treatments for tobacco addiction. PMID:18950618

  2. Evaluation, treatment, and outcomes of suprascapular neuropathy: a 5-year review.

    PubMed

    Hill, Larisa J N; Jelsing, Elena J; Terry, Marisa J; Strommen, Jeffrey A

    2014-09-01

    To report our diagnostic and treatment experiences, and patient outcomes, in patients with suprascapular neuropathy (SSN). Retrospective cohort study. A tertiary medical center. 65 patients with electromyographically (EMG)-confirmed SSN. A 5-year retrospective chart review of patients with EMG-confirmed SSN. Descriptive statistics were used to summarize demographics, risk factors, causes, EMG findings, diagnostic evaluation, treatments, and self-reported outcomes. Exact Mantel-Haenszel χ(2) tests and Fisher exact tests were used to assess correlation between these measures. The 3 most common causes of SSN were trauma (32 patients), an inflammatory process (ie, brachial neuritis) (14), and the presence of a cyst (13). Remaining cases were related to a rotator cuff tear or were due to overuse. No cases were attributed to notch abnormalities. At the time of follow-up (a mean of 50 months [range, 15-84 months] after EMG), 50% of subjects returned to activity with no restrictions (excellent outcome) and 40% returned to activity with restrictions (good outcome), regardless of cause and treatment. EMG findings, specifically the presence/absence of fibrillation potentials, did not predict recovery. SSN should be considered in patients with shoulder pain and weakness. Magnetic resonance imaging and ultrasound help to exclude a structural process. Identifying a structural cause, specifically a cyst or rotator cuff tear, is important because it appears that these patients have improved recovery with return to normal activities when treated surgically. Although EMG data did not have prognostic value in this study, the data were limited and further study is warranted. Regardless of cause or treatment, most patients with SSN returned to activities in some capacity. Copyright © 2014 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.

  3. Quality of reporting in oncology phase II trials: A 5-year assessment through systematic review.

    PubMed

    Langrand-Escure, Julien; Rivoirard, Romain; Oriol, Mathieu; Tinquaut, Fabien; Rancoule, Chloé; Chauvin, Frank; Magné, Nicolas; Bourmaud, Aurélie

    2017-01-01

    Phase II clinical trials are a cornerstone of the development in experimental treatments They work as a "filter" for phase III trials confirmation. Surprisingly the attrition ratio in Phase III trials in oncology is significantly higher than in any other medical specialty. This suggests phase II trials in oncology fail to achieve their goal. Objective The present study aims at estimating the quality of reporting in published oncology phase II clinical trials. A literature review was conducted among all phase II and phase II/III clinical trials published during a 5-year period (2010-2015). All articles electronically published by three randomly-selected oncology journals with Impact-Factors>4 were included: Journal of Clinical Oncology, Annals of Oncology and British Journal of Cancer. Quality of reporting was assessed using the Key Methodological Score. 557 articles were included. 315 trials were single-arm studies (56.6%), 193 (34.6%) were randomized and 49 (8.8%) were non-randomized multiple-arm studies. The Methodological Score was equal to 0 (lowest level), 1, 2, 3 (highest level) respectively for 22 (3.9%), 119 (21.4%), 270 (48.5%) and 146 (26.2%) articles. The primary end point is almost systematically reported (90.5%), while sample size calculation is missing in 66% of the articles. 3 variables were independently associated with reporting of a high standard: presence of statistical design (p-value <0.001), multicenter trial (p-value = 0.012), per-protocol analysis (p-value <0.001). Screening was mainly performed by a sole author. The Key Methodological Score was based on only 3 items, making grey zones difficult to translate. This literature review highlights the existence of gaps concerning the quality of reporting. It therefore raised the question of the suitability of the methodology as well as the quality of these trials, reporting being incomplete in the corresponding articles.

  4. A 5-year review of pattern of placenta previa in Ilorin, Nigeria

    PubMed Central

    Omokanye, L. O.; Olatinwo, A. W. O.; Salaudeen, A. G.; Ajiboye, A. D.; Durowade, K. A.

    2017-01-01

    Background: Placenta previa, a major cause of obstetric hemorrhage, is potentially life-threatening to the mother and frequently results in high perinatal morbidity and mortality. Methodology: This is a retrospective study of all cases of placenta previa managed at the University of Ilorin Teaching Hospital over a 5-year from January 2011 to December 2015. A pro forma template was used to harvest information from case notes of patients involved in the study. Results: There were a total of 10,250 deliveries over the 5-year study and 164 cases of placenta previa were managed during this period; giving an incidence of 1.6% of the total deliveries. Of these patients, 65.9% were unbooked while 34.1% were booked. 110 (67%) were above 30 years of age and 51.2% were grand multiparous women. The majority (81.7%) of the patients belonged to the low socioeconomic class. Painless vaginal bleeding (62.2%), intrapartum hemorrhage (22.6%), and abnormal lie presentation (8.5%) were the most common mode of presentation. Vaginal delivery occurred in (29.3%) of patients while 70. 7% were delivered through cesarean section. There was a significant association between patients’ age, parity, booking status, and types of placenta previa (P < 0.05). Similarly, there was a significant association between gestational age at delivery, mode of delivery, intraoperative blood loss, and birth weight at delivery and types of placenta previa (P < 0.05). Perinatal mortality was 12.2%, 15.6% of babies had severe birth asphyxia, and there was no maternal mortality. Conclusion: From this study, the risk factors for placenta previa are advanced maternal age above 35 years, grand multiparity, and booking status. Early recognition, appropriate referral of these patients and availability of ultrasound facilities, blood transfusion facilities, improvement in neonatal facilities and trained personnel will go a long way in reducing the perinatal mortality from placenta previa. PMID:28539861

  5. A 5-year review of pattern of placenta previa in Ilorin, Nigeria.

    PubMed

    Omokanye, L O; Olatinwo, A W O; Salaudeen, A G; Ajiboye, A D; Durowade, K A

    2017-01-01

    Placenta previa, a major cause of obstetric hemorrhage, is potentially life-threatening to the mother and frequently results in high perinatal morbidity and mortality. This is a retrospective study of all cases of placenta previa managed at the University of Ilorin Teaching Hospital over a 5-year from January 2011 to December 2015. A pro forma template was used to harvest information from case notes of patients involved in the study. There were a total of 10,250 deliveries over the 5-year study and 164 cases of placenta previa were managed during this period; giving an incidence of 1.6% of the total deliveries. Of these patients, 65.9% were unbooked while 34.1% were booked. 110 (67%) were above 30 years of age and 51.2% were grand multiparous women. The majority (81.7%) of the patients belonged to the low socioeconomic class. Painless vaginal bleeding (62.2%), intrapartum hemorrhage (22.6%), and abnormal lie presentation (8.5%) were the most common mode of presentation. Vaginal delivery occurred in (29.3%) of patients while 70. 7% were delivered through cesarean section. There was a significant association between patients' age, parity, booking status, and types of placenta previa ( P < 0.05). Similarly, there was a significant association between gestational age at delivery, mode of delivery, intraoperative blood loss, and birth weight at delivery and types of placenta previa ( P < 0.05). Perinatal mortality was 12.2%, 15.6% of babies had severe birth asphyxia, and there was no maternal mortality. From this study, the risk factors for placenta previa are advanced maternal age above 35 years, grand multiparity, and booking status. Early recognition, appropriate referral of these patients and availability of ultrasound facilities, blood transfusion facilities, improvement in neonatal facilities and trained personnel will go a long way in reducing the perinatal mortality from placenta previa.

  6. [Heatstroke in dogs in southern Germany. A retrospective study over a 5.5-year period].

    PubMed

    Teichmann, S; Turković, V; Dörfelt, R

    2014-01-01

    Heatstroke is a life-threating emergency in dogs. The aim of this retrospective study was to analyse the sources of heat stroke in dogs, predisposing and prognostic factors, results of physical examination and clinical pathology as well as the course of this condition and appropriate treatment. Patient histories of 12 dogs diagnosed with heat stroke over a 5.5-year period were analysed retrospectively. Normality was tested using the Kolmogrow-Smirnow Test and analysed using T-tests, the Chi-square test and the Mann-Whitney U-test. P-values < 0.05 were considered significant. Heat stroke occurred most frequently during summer, particularly in the afternoon. The most common cause of heat stroke was heat exposition in a car. Brachycephalic breeds were overrepresented. The most common clinical signs were polypnoea, tachycardia, hyperthermia and depression to prostration as well as gastrointestinal and neurological symptoms. Clinical pathology results included haemoconcentration, thrombocytopenia, hyperkalemia, prolonged activated partial thromboplastin time and azotemia. Therapies employed included oxygen application, cooling, fluid therapy and administration of gastrointestinal protectants, antiemetics and antibiotics. Duration of hospitalization was 1-6 days. The overall mortality rate was 50%. Most of the non-survivors died or were euthanized within 24-48 hours after presentation. All animals remaining alive after 3 days survived and could be discharged from hospital. Heat stroke is a life-threating condition, which can lead to shock, sepsis, coagulation disorders and multiorgan failure. Early recognition and appropriate treatment are important factors for a positive outcome. Furthermore, intensive monitoring and rapid therapy adaption as required are pivotal.

  7. 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

  8. Effect of buspirone, a 5-HT1A receptor agonist, on esophageal motility in healthy volunteers.

    PubMed

    Di Stefano, M; Papathanasopoulos, A; Blondeau, K; Vos, R; Boecxstaens, V; Farré, R; Rommel, N; Tack, J

    2012-07-01

    There are limited data concerning the effects of 5-HT(1A) receptor activation on esophageal motility. Sumatriptan, a 5-HT(1A) receptor agonist, was recently reported to enhance esophageal peristalsis after intravenous administration. Buspirone, an orally available 5-HT(1A) receptor agonist, was shown to modulate gastroduodenal motor function. Our aim was to evaluate the effect of buspirone on esophageal motility of healthy volunteers. On two separate visits, 20 healthy volunteers aged 21-29 years (nine women) underwent esophageal manometry before and 10, 30, and 60 minutes after the administration of buspirone 20-mg or placebo capsule, according to a double-blind crossover design. At each time point, we compared buspirone and placebo effects on: resting pressure of the lower esophageal sphincter (LES); residual pressure and duration of LES relaxation; amplitude, duration, and onset velocity of esophageal body contractions, during 10 swallows of 5 mL of water. Significant analysis of variance differences (P < 0.05) are presented as mean ± standard deviation. Buspirone significantly increased mean distal esophageal wave amplitude (151 vs. 87 mmHg, P < 0.05) and duration (6.1 vs. 4.2 seconds, P < 0.05). Similarly, buspirone significantly increased mean LES resting pressure (26 vs. 21 mmHg, P < 0.05) and mean residual LES pressure (7.9 vs. 2 mmHg, P < 0.05), whereas reduced mean LES relaxation duration (7.2 vs. 8.0 seconds, P < 0.05) and mean distal onset velocity (7.6 vs. 14.7 cm/second, P < 0.05). Buspirone enhances esophageal peristalsis and LES function in healthy volunteers. Further study is warranted on the effects of buspirone on esophageal function and symptoms in patients with ineffective esophageal motility. © 2011 Copyright the Authors. Journal compilation © 2011, Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus.

  9. Fatal injuries in rural and urban areas in northern Finland: a 5-year retrospective study.

    PubMed

    Raatiniemi, L; Steinvik, T; Liisanantti, J; Ohtonen, P; Martikainen, M; Alahuhta, S; Dehli, T; Wisborg, T; Bakke, H K

    2016-05-01

    Finland has the fourth highest injury mortality rate in the European Union. To better understand the causes of the high injury rate, and prevent these fatal injuries, studies are needed. Therefore, we set out to complete an analysis of the epidemiology of fatal trauma, and any contributory role for alcohol, long suspected to promote fatal injuries. As a study area, we chose the four northernmost counties of Finland; their mix of remote rural areas and urban centres allowed us to correlate mortality rates with 'rurality'. The Causes of Death Register was consulted to identify deaths from external causes over a 5-year time period. Data were retrieved from death certificates, autopsy reports and medical records. The municipalities studied were classified as either rural or urban. Of 2915 deaths categorized as occurring from external causes during our study period, 1959 were eligible for inclusion in our study. The annual crude mortality rate was 54 per 100,000 inhabitants; this rate was higher in rural vs. urban municipalities (65 vs. 45 per 100,000 inhabitants/year). Additionally, a greater number of pre-hospital deaths from accidental high-energy trauma occurred in rural areas (78 vs. 69%). 42% of all pre-hospital deaths occurred under the influence of alcohol. The crude mortality rate for fatal injuries was high overall as compared to other studies, and elevated in rural areas, where pre-hospital deaths were more common. Almost half of pre-hospital deaths occurred under the influence of alcohol. © 2016 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.

  10. 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

  11. Temporal profiling of the adipocyte proteome during differentiation using a 5-plex SILAC based strategy

    PubMed Central

    Ruch, Travis; Kim, Jae-Woo; Mortensen, Peter; Otto, Tamara; Nalli, Anuradha; Tang, Qi-Qun; Lane, M. Daniel; Chaerkady, Raghothama; Pandey, Akhilesh

    2008-01-01

    The adipose tissue has important secretory and endocrine functions in humans. The regulation of adipocyte differentiation has been actively pursued using transcriptomic methods over the last several years. Quantitative proteomics has emerged as a promising approach to obtain temporal profiles of biological processes such as differentiation. Stable isotope labeling with amino acids in cell culture (SILAC) is a simple and robust method for labeling proteins in vivo. Here, we describe the development and application of a five-plex SILAC experiment using four different heavy stable isotopic forms of arginine to study the nuclear proteome and the secretome during the course of adipocyte differentiation. Tandem mass spectrometry analysis using a quadrupole time-of-flight instrument resulted in identification of a total 882 proteins from these two proteomes. Of these proteins, 427 were identified on the basis of one or more arginine containing peptides that allowed quantitation. In addition to previously reported molecules that are differentially expressed during the process of adipogenesis (e.g. adiponectin and lipoprotein lipase), we identified several proteins whose differential expression during adipocyte differentiation has not been documented previously. For example, THO complex 4, a context-dependent transcriptional activator in the T-cell receptor alpha enhancer complex, showed highest expression at middle stage of adipogenesis while SNF2 alpha, a chromatin remodeling protein, was downregulated upon initiation of adipogenesis and remained so during subsequent time points. This study using a 5-plex SILAC to investigate dynamics illustrates the power of this approach to identify differentially expressed proteins in a temporal fashion. PMID:18947249

  12. Retained Austenite Transformation during Heat Treatment of a 5 Wt Pct Cr Cold Work Tool Steel

    NASA Astrophysics Data System (ADS)

    Rehan, M. Arbab; Medvedeva, Anna; Svensson, Lars-Erik; Karlsson, Leif

    2017-11-01

    Retained austenite transformation was studied for a 5 wt pct Cr cold work tool steel tempered at 798 K and 873 K (525 °C and 600 °C) followed by cooling to room temperature. Tempering cycles with variations in holding times were conducted to observe the mechanisms involved. Phase transformations were studied with dilatometry, and the resulting microstructures were characterized with X-ray diffraction and scanning electron microscopy. Tempering treatments at 798 K (525 °C) resulted in retained austenite transformation to martensite on cooling. The martensite start ( M s ) and martensite finish ( M f ) temperatures increased with longer holding times at tempering temperature. At the same time, the lattice parameter of retained austenite decreased. Calculations from the M s temperatures and lattice parameters suggested that there was a decrease in carbon content of retained austenite as a result of precipitation of carbides prior to transformation. This was in agreement with the resulting microstructure and the contraction of the specimen during tempering, as observed by dilatometry. Tempering at 873 K (600 °C) resulted in precipitation of carbides in retained austenite followed by transformation to ferrite and carbides. This was further supported by the initial contraction and later expansion of the dilatometry specimen, the resulting microstructure, and the absence of any phase transformation on cooling from the tempering treatment. It was concluded that there are two mechanisms of retained austenite transformation occurring depending on tempering temperature and time. This was found useful in understanding the standard tempering treatment, and suggestions regarding alternative tempering treatments are discussed.

  13. Skeletal effects and growth in children with chronic kidney disease: a 5-year prospective study.

    PubMed

    Swolin-Eide, Diana; Hansson, Sverker; Magnusson, Per

    2013-05-01

    This study was designed to follow the evolving process of growth, bone modeling and remodeling in children with chronic kidney disease (CKD) who are at risk of developing CKD-mineral bone disorder (CKD-MBD). Fifteen patients, 4-15 years, were included with a median glomerular filtration rate of 46 (range 12-74) mL/min/1.73 m(2). Growth, bone mineral density (BMD) and markers of bone and mineral metabolism were investigated over a 5-year period. The median height standard deviation score was -0.65 at the start and 0.1 after 5 years, with a range from -1.7 to 1.7, which implies that growth was acceptable. Total body, femoral neck, and lumbar spine BMD increased over the study period (p < 0.0001). None had total body BMD Z-scores and lumbar spine Z-scores below -2.0 at follow-up. Most bone markers were within the reference intervals, but the formation markers of alkaline phosphatase and type I procollagen intact amino-terminal propeptide (PINP) were slightly increased in about one-third of the patients after 5 years. Eleven out of 15 CKD patients had increased parathyroid hormone levels at baseline and 10 patients after 5 years had increased parathyroid hormone levels. Taken together, this is the first 5-year longitudinal study of skeletal effects, growth and bone turnover in children with CKD. Growth and BMD Z-scores were well preserved on a group basis; however, these parameters varied significantly on an individual basis. We suggest, therefore, that it is difficult to state an overall recommendation and growth, bone mass, and markers of bone and mineral metabolism should be monitored and treated individually in CKD children.

  14. A 5-year exercise program in children improves muscle strength without affecting fracture risk.

    PubMed

    Fritz, Jesper; Cöster, Marcus E; Stenevi-Lundgren, Susanna; Nilsson, Jan-Åke; Dencker, Magnus; Rosengren, Björn E; Karlsson, Magnus K

    2016-04-01

    High level of physical activity (PA) is associated with great muscle strength and high fracture risk. This prospective controlled population-based study evaluated how a pediatric PA intervention program influenced muscle strength and fracture risk. We carried out a school-based exercise intervention program with 200 min of PA per week for 5 years in 335 girls and 408 boys aged 6-9 years at study start. An age-matched control cohort including 756 girls and 782 boys continued with 60 min of PA per week. We registered fractures during the study period and calculated rate ratio. In a sub-sample, including 74 girls and 107 boys in the intervention and 51 girls and 54 boys in the control group, we measured knee flexion and extension strength by a computerized dynamometer and leg composition by dual energy X-ray absorptiometry. Group comparisons were adjusted for differences in age, baseline value for the measured parameter and changes in height. Children in the intervention group had a rate ratio to sustain a fracture of 1.03 (0.78, 1.36) (mean and 95 % confidence interval) (p = 0.79). The annual gain in flexion peak torque muscle strength was greater in both girls (at 60°/s) [1.1 Nm (0.5, 1.8), p < 0.01] and boys (at 180°/s) [0.7 Nm (0.1, 1.2), p < 0.05] in the intervention than in the control group, while leg composition was similar. Increased PA during a 5-year period, starting in the pre-pubertal period, improves the gain in muscle strength without affecting the fracture risk.

  15. Scabies increased the risk of chronic kidney disease: a 5-year follow-up study.

    PubMed

    Chung, S-D; Wang, K-H; Huang, C-C; Lin, H-C

    2014-03-01

    The most documented complication of scabies has been reported to be infection by group A streptococci, which has in turn been suggested to contribute to the development of glomerulonephritis. This study aimed to investigate the risk of chronic kidney disease (CKD) subsequent to scabies utilizing a population-based dataset in Taiwan. This retrospective matched-cohort study included 5071 subjects with scabies and 25 355 randomly selected comparison subjects. We individually tracked each subject for a 5-year period to identify those who subsequently received a diagnosis of CKD during the follow-up period. Stratified Cox proportional hazards regressions were performed to compute the hazard ratio (HR) of CKD during the 5-year follow-up period. The incidence rate of CKD during the 5-year follow-up period was 9.66 (8.51-10.93) per 1,000 person-years and 6.24 (5.82-6.69) per 1000 person-years for subjects with and without scabies respectively. The HR for CKD during the 5-year follow-up period for subjects with scabies was 1.34 (95% CI = 1.15-1.56) that of comparison subjects after adjusting for monthly income, hypertension, diabetes, obesity, stroke, coronary heart disease, chronic obstructive pulmonary disease, tobacco use disorder, hyperlipidemia and alcohol abuse during the 5-year follow-up period. Male subjects with scabies were 1.40 (95% CI = 1.14-1.71) times more likely than comparison subjects to suffer from subsequent CKD, and female study subjects were 1.27 (95% CI = 1.05-1.61) times more likely. We concluded that there was an increased risk for CKD among patients suffering from scabies. © 2013 The Authors Journal of the European Academy of Dermatology and Venereology © 2013 European Academy of Dermatology and Venereology.

  16. Development of Irritable Bowel Syndrome Features Over a 5-year Period.

    PubMed

    Clevers, Egbert; Tack, Jan; Törnblom, Hans; Ringström, Gisela; Luyckx, Koen; Simrén, Magnus; Van Oudenhove, Lukas

    2018-03-03

    There are few data from longitudinal studies of the gastrointestinal and psychologic features of irritable bowel syndrome (IBS). We studied within-person correlations among features of IBS, along with progression of gastrointestinal (GI) symptoms and quality of life, and factors associated with changes over time. We performed a longitudinal study of 276 patients with IBS in Sweden (70% female; ages, 19-76 years) who completed questionnaires, each year for 5 years, about their GI symptom severity, quality of life, GI-specific anxiety, general anxiety, depression, and coping resources. We performed within-person correlation analyses, latent class growth analysis, and random-intercept cross-lagged panel analysis. Within-person correlations with GI symptom severity were strongest for quality of life (r = -0.56) and GI-specific anxiety (r = 0.47). Progression of GI symptom severity was defined based on 3 classes; the class with the highest mean levels of GI, depression, and (GI-specific) anxiety symptoms at baseline did not improve over the 5-year period, contrary to the other classes. GI-specific anxiety was associated with an increase in GI symptom severity and decrease in quality of life 1 year later (P < .05) but other features of IBS were not. In a 5-year study of patients with IBS in Sweden, we found 3 classes of GI symptom development. We found levels of GI-specific anxiety to associate with GI symptom severity and quality of life 1 year later. Clinicians should be aware of GI-specific anxiety in patients with IBS, to identify patients at risk for lack of long-term symptom improvement with standard medical treatment. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

  17. Tetraspanin genes in plants.

    PubMed

    Wang, Feng; Vandepoele, Klaas; Van Lijsebettens, Mieke

    2012-07-01

    Tetraspanins represent a four-transmembrane protein superfamily with a conserved structure and amino acid residues that are present in mammals, insects, fungi and plants. Tetraspanins interact with each other or with other membrane proteins to form tetraspanin-enriched microdomains that play important roles in development, pathogenesis and immune responses via facilitating cell-cell adhesion and fusion, ligand binding and intracellular trafficking. Here, we emphasize evolutionary aspects within the plant kingdom based on genomic sequence information. A phylogenetic tree based on 155 tetraspanin genes of 11 plant species revealed ancient and fast evolving clades. Tetraspanins were only present in multicellular plants, were often duplicated in the plant genomes and predicted by the electronic Fluorescent Pictograph for gene expression analysis to be either functionally redundant or divergent. Tetraspanins contain a large extracellular loop with conserved cysteines that provide the binding sites for the interactions. The Arabidopsis thaliana TETRASPANIN1/TORNADO2/EKEKO has a function in leaf and root patterning and TETRASPANIN3 was identified in the plasmodesmatal proteome, suggesting a role in cell-cell communication during plant development. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  18. Conotoxin Gene Superfamilies

    PubMed Central

    Robinson, Samuel D.; Norton, Raymond S.

    2014-01-01

    Conotoxins are the peptidic components of the venoms of marine cone snails (genus Conus). They are remarkably diverse in terms of structure and function. Unique potency and selectivity profiles for a range of neuronal targets have made several conotoxins valuable as research tools, drug leads and even therapeutics, and has resulted in a concerted and increasing drive to identify and characterise new conotoxins. Conotoxins are translated from mRNA as peptide precursors, and cDNA sequencing is now the primary method for identification of new conotoxin sequences. As a result, gene superfamily, a classification based on precursor signal peptide identity, has become the most convenient method of conotoxin classification. Here we review each of the described conotoxin gene superfamilies, with a focus on the structural and functional diversity present in each. This review is intended to serve as a practical guide to conotoxin superfamilies and to facilitate interpretation of the increasing number of conotoxin precursor sequences being identified by targeted-cDNA sequencing and more recently high-throughput transcriptome sequencing. PMID:25522317

  19. Vectors for cancer gene therapy.

    PubMed

    Zhang, J; Russell, S J

    1996-09-01

    Many viral and non-viral vector systems have now been developed for gene therapy applications. In this article, the pros and cons of these vector systems are discussed in relation to the different cancer gene therapy strategies. The protocols used in cancer gene therapy can be broadly divided into six categories including gene transfer to explanted cells for use as cell-based cancer vaccines; gene transfer to a small number of tumour cells in situ to achieve a vaccine effect; gene transfer to vascular endothelial cells (VECs) lining the blood vessels of the tumour to interfere with tumour angiogenesis; gene transfer to T lymphocytes to enhance their antitumour effector capability; gene transfer to haemopoietic stem cells (HSCs) to enhance their resistance to cytotoxic drugs and gene transfer to a large number of tumour cells in situ to achieve nonimmune tumour reduction with or without bystander effect. Each of the six strategies makes unique demands on the vector system and these are discussed with reference to currently available vectors. Aspects of vector biology that are in need of further development are discussed in some detail. The final section points to the potential use of replicating viruses as delivery vehicles for efficient in vivo gene transfer to disseminated cancers.

  20. Gene therapy for neurological disorders.

    PubMed

    Choong, Chi-Jing; Baba, Kousuke; Mochizuki, Hideki

    2016-01-01

    Many nervous system disorders are minimally responsive to existing treatments but they are potential candidates for gene therapy, an approach that can correct the genetic abnormalities contributing to its pathogenesis at molecular level. Gene therapy involves either the introduction of a replacement allele into cells to compensate for loss of gene function or the silencing of dominant mutant allele that is pathologic to cells. This review discusses the currently available gene therapy techniques, potential problems derived from gene therapy strategies and the recent development of gene therapy to treat neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and strokes. Gene therapy may revolutionize the treatment of neurological disorders in the coming decades but there are still great challenges ahead. The strength of gene therapy has been emphasized in the overexpression of therapeutic genes. However, in a number of dominantly inherited nervous system diseases, the ideal therapeutic goal would be to inhibit the expression of disease-causing allele. Gene silencing strategies by single-stranded antisense oligonucleotides and RNA interference represent a major breakthrough. Clinical trials using these approaches for dominant diseases are likely to be implemented in the near future.

  1. Aberrant Gene Expression in Humans

    PubMed Central

    Yang, Ence; Ji, Guoli; Brinkmeyer-Langford, Candice L.; Cai, James J.

    2015-01-01

    Gene expression as an intermediate molecular phenotype has been a focus of research interest. In particular, studies of expression quantitative trait loci (eQTL) have offered promise for understanding gene regulation through the discovery of genetic variants that explain variation in gene expression levels. Existing eQTL methods are designed for assessing the effects of common variants, but not rare variants. Here, we address the problem by establishing a novel analytical framework for evaluating the effects of rare or private variants on gene expression. Our method starts from the identification of outlier individuals that show markedly different gene expression from the majority of a population, and then reveals the contributions of private SNPs to the aberrant gene expression in these outliers. Using population-scale mRNA sequencing data, we identify outlier individuals using a multivariate approach. We find that outlier individuals are more readily detected with respect to gene sets that include genes involved in cellular regulation and signal transduction, and less likely to be detected with respect to the gene sets with genes involved in metabolic pathways and other fundamental molecular functions. Analysis of polymorphic data suggests that private SNPs of outlier individuals are enriched in the enhancer and promoter regions of corresponding aberrantly-expressed genes, suggesting a specific regulatory role of private SNPs, while the commonly-occurring regulatory genetic variants (i.e., eQTL SNPs) show little evidence of involvement. Additional data suggest that non-genetic factors may also underlie aberrant gene expression. Taken together, our findings advance a novel viewpoint relevant to situations wherein common eQTLs fail to predict gene expression when heritable, rare inter-individual variation exists. The analytical framework we describe, taking into consideration the reality of differential phenotypic robustness, may be valuable for investigating

  2. Identifying driver genes in cancer by triangulating gene expression, gene location, and survival data.

    PubMed

    Rouam, Sigrid; Miller, Lance D; Karuturi, R Krishna Murthy

    2014-01-01

    Driver genes are directly responsible for oncogenesis and identifying them is essential in order to fully understand the mechanisms of cancer. However, it is difficult to delineate them from the larger pool of genes that are deregulated in cancer (ie, passenger genes). In order to address this problem, we developed an approach called TRIAngulating Gene Expression (TRIAGE through clinico-genomic intersects). Here, we present a refinement of this approach incorporating a new scoring methodology to identify putative driver genes that are deregulated in cancer. TRIAGE triangulates - or integrates - three levels of information: gene expression, gene location, and patient survival. First, TRIAGE identifies regions of deregulated expression (ie, expression footprints) by deriving a newly established measure called the Local Singular Value Decomposition (LSVD) score for each locus. Driver genes are then distinguished from passenger genes using dual survival analyses. Incorporating measurements of gene expression and weighting them according to the LSVD weight of each tumor, these analyses are performed using the genes located in significant expression footprints. Here, we first use simulated data to characterize the newly established LSVD score. We then present the results of our application of this refined version of TRIAGE to gene expression data from five cancer types. This refined version of TRIAGE not only allowed us to identify known prominent driver genes, such as MMP1, IL8, and COL1A2, but it also led us to identify several novel ones. These results illustrate that TRIAGE complements existing tools, allows for the identification of genes that drive cancer and could perhaps elucidate potential future targets of novel anticancer therapeutics.

  3. Ancient origins of axial patterning genes: Hox genes and ParaHox genes in the Cnidaria.

    PubMed

    Finnerty, J R; Martindale, M Q

    1999-01-01

    Among the bilaterally symmetrical, triploblastic animals (the Bilateria), a conserved set of developmental regulatory genes are known to function in patterning the anterior-posterior (AP) axis. This set includes the well-studied Hox cluster genes, and the recently described genes of the ParaHox cluster, which is believed to be the evolutionary sister of the Hox cluster (Brooke et al. 1998). The conserved role of these axial patterning genes in animals as diverse as frogs and flies is believed to reflect an underlying homology (i.e., all bilaterians derive from a common ancestor which possessed an AP axis and the developmental mechanisms responsible for patterning the axis). However, the origin and early evolution of Hox genes and ParaHox genes remain obscure. Repeated attempts have been made to reconstruct the early evolution of Hox genes by analyzing data from the triphoblastic animals, the Bilateria (Schubert et al. 1993; Zhang and Nei 1996). A more precise dating of Hox origins has been elusive due to a lack of sufficient information from outgroup taxa such as the phylum Cnidaria (corals, hydras, jellyfishes, and sea anemones). In combination with outgroup taxa, another potential source of information about Hox origins is outgroup genes (e.g., the genes of the ParaHox cluster). In this article, we present cDNA sequences of two Hox-like genes (anthox2 and anthox6) from the sea anemone, Nematostella vectensis. Phylogenetic analysis indicates that anthox2 (= Cnox2) is homologous to the GSX class of ParaHox genes, and anthox6 is homologous to the anterior class of Hox genes. Therefore, the origin of Hox genes and ParaHox genes occurred prior to the evolutionary split between the Cnidaria and the Bilateria and predated the evolution of the anterior-posterior axis of bilaterian animals. Our analysis also suggests that the central Hox class was invented in the bilaterian lineage, subsequent to their split from the Cnidaria.

  4. The molecular evolution of cytochrome P450 genes within and between drosophila species.

    PubMed

    Good, Robert T; Gramzow, Lydia; Battlay, Paul; Sztal, Tamar; Batterham, Philip; Robin, Charles

    2014-04-20

    We map 114 gene gains and 74 gene losses in the P450 gene family across the phylogeny of 12 Drosophila species by examining the congruence of gene trees and species trees. Although the number of P450 genes varies from 74 to 94 in the species examined, we infer that there were at least 77 P450 genes in the ancestral Drosophila genome. One of the most striking observations in the data set is the elevated loss of P450 genes in the Drosophila sechellia lineage. The gain and loss events are not evenly distributed among the P450 genes-with 30 genes showing no gene gains or losses whereas others show as many as 20 copy number changes among the species examined. The P450 gene clades showing the fewest number of gene gain and loss events tend to be those evolving with the most purifying selection acting on the protein sequences, although there are exceptions, such as the rapid rate of amino acid replacement observed in the single copy phantom (Cyp306a1) gene. Within D. melanogaster, we observe gene copy number polymorphism in ten P450 genes including multiple cases of interparalog chimeras. Nonallelic homologous recombination (NAHR) has been associated with deleterious mutations in humans, but here we provide a second possible example of an NAHR event in insect P450s being adaptive. Specifically, we find that a polymorphic Cyp12a4/Cyp12a5 chimera correlates with resistance to an insecticide. Although we observe such interparalog exchange in our within-species data sets, we have little evidence of it between species, raising the possibility that such events may occur more frequently than appreciated but are masked by subsequent sequence change. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  5. GeneMark.hmm: new solutions for gene finding.

    PubMed Central

    Lukashin, A V; Borodovsky, M

    1998-01-01

    The number of completely sequenced bacterial genomes has been growing fast. There are computer methods available for finding genes but yet there is a need for more accurate algorithms. The GeneMark. hmm algorithm presented here was designed to improve the gene prediction quality in terms of finding exact gene boundaries. The idea was to embed the GeneMark models into naturally derived hidden Markov model framework with gene boundaries modeled as transitions between hidden states. We also used the specially derived ribosome binding site pattern to refine predictions of translation initiation codons. The algorithm was evaluated on several test sets including 10 complete bacterial genomes. It was shown that the new algorithm is significantly more accurate than GeneMark in exact gene prediction. Interestingly, the high gene finding accuracy was observed even in the case when Markov models of order zero, one and two were used. We present the analysis of false positive and false negative predictions with the caution that these categories are not precisely defined if the public database annotation is used as a control. PMID:9461475

  6. Bayesian assignment of gene ontology terms to gene expression experiments

    PubMed Central

    Sykacek, P.

    2012-01-01

    Motivation: Gene expression assays allow for genome scale analyses of molecular biological mechanisms. State-of-the-art data analysis provides lists of involved genes, either by calculating significance levels of mRNA abundance or by Bayesian assessments of gene activity. A common problem of such approaches is the difficulty of interpreting the biological implication of the resulting gene lists. This lead to an increased interest in methods for inferring high-level biological information. A common approach for representing high level information is by inferring gene ontology (GO) terms which may be attributed to the expression data experiment. Results: This article proposes a probabilistic model for GO term inference. Modelling assumes that gene annotations to GO terms are available and gene involvement in an experiment is represented by a posterior probabilities over gene-specific indicator variables. Such probability measures result from many Bayesian approaches for expression data analysis. The proposed model combines these indicator probabilities in a probabilistic fashion and provides a probabilistic GO term assignment as a result. Experiments on synthetic and microarray data suggest that advantages of the proposed probabilistic GO term inference over statistical test-based approaches are in particular evident for sparsely annotated GO terms and in situations of large uncertainty about gene activity. Provided that appropriate annotations exist, the proposed approach is easily applied to inferring other high level assignments like pathways. Availability: Source code under GPL license is available from the author. Contact: peter.sykacek@boku.ac.at PMID:22962488

  7. Stratified gene expression analysis identifies major amyotrophic lateral sclerosis genes.

    PubMed

    Jones, Ashley R; Troakes, Claire; King, Andrew; Sahni, Vibhu; De Jong, Simone; Bossers, Koen; Papouli, Efterpi; Mirza, Muddassar; Al-Sarraj, Safa; Shaw, Christopher E; Shaw, Pamela J; Kirby, Janine; Veldink, Jan H; Macklis, Jeffrey D; Powell, John F; Al-Chalabi, Ammar

    2015-05-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons resulting in progressive paralysis. Gene expression studies of ALS only rarely identify the same gene pathways as gene association studies. We hypothesized that analyzing tissues by matching on degree of disease severity would identify different patterns of gene expression from a traditional case-control comparison. We analyzed gene expression changes in 4 postmortem central nervous system regions, stratified by severity of motor neuron loss. An overall comparison of cases (n = 6) and controls (n = 3) identified known ALS gene, SOX5, as showing differential expression (log2 fold change = 0.09, p = 5.5 × 10(-5)). Analyses stratified by disease severity identified expression changes in C9orf72 (p = 2.77 × 10(-3)), MATR3 (p = 3.46 × 10(-3)), and VEGFA (p = 8.21 × 10(-4)), all implicated in ALS through genetic studies, and changes in other genes in pathways involving RNA processing and immune response. These findings suggest that analysis of gene expression stratified by disease severity can identify major ALS genes and may be more efficient than traditional case-control comparison. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Bayesian assignment of gene ontology terms to gene expression experiments.

    PubMed

    Sykacek, P

    2012-09-15

    Gene expression assays allow for genome scale analyses of molecular biological mechanisms. State-of-the-art data analysis provides lists of involved genes, either by calculating significance levels of mRNA abundance or by Bayesian assessments of gene activity. A common problem of such approaches is the difficulty of interpreting the biological implication of the resulting gene lists. This lead to an increased interest in methods for inferring high-level biological information. A common approach for representing high level information is by inferring gene ontology (GO) terms which may be attributed to the expression data experiment. This article proposes a probabilistic model for GO term inference. Modelling assumes that gene annotations to GO terms are available and gene involvement in an experiment is represented by a posterior probabilities over gene-specific indicator variables. Such probability measures result from many Bayesian approaches for expression data analysis. The proposed model combines these indicator probabilities in a probabilistic fashion and provides a probabilistic GO term assignment as a result. Experiments on synthetic and microarray data suggest that advantages of the proposed probabilistic GO term inference over statistical test-based approaches are in particular evident for sparsely annotated GO terms and in situations of large uncertainty about gene activity. Provided that appropriate annotations exist, the proposed approach is easily applied to inferring other high level assignments like pathways. Source code under GPL license is available from the author. peter.sykacek@boku.ac.at.

  9. Major psychological factors affecting acceptance of gene-recombination technology.

    PubMed

    Tanaka, Yutaka

    2004-12-01

    The purpose of this study was to verify the validity of a causal model that was made to predict the acceptance of gene-recombination technology. A structural equation model was used as a causal model. First of all, based on preceding studies, the factors of perceived risk, perceived benefit, and trust were set up as important psychological factors determining acceptance of gene-recombination technology in the structural equation model. An additional factor, "sense of bioethics," which I consider to be important for acceptance of biotechnology, was added to the model. Based on previous studies, trust was set up to have an indirect influence on the acceptance of gene-recombination technology through perceived risk and perceived benefit in the model. Participants were 231 undergraduate students in Japan who answered a questionnaire with a 5-point bipolar scale. The results indicated that the proposed model fits the data well, and showed that acceptance of gene-recombination technology is explained largely by four factors, that is, perceived risk, perceived benefit, trust, and sense of bioethics, whether the technology is applied to plants, animals, or human beings. However, the relative importance of the four factors was found to vary depending on whether the gene-recombination technology was applied to plants, animals, or human beings. Specifically, the factor of sense of bioethics is the most important factor in acceptance of plant gene-recombination technology and animal gene-recombination technology, and the factors of trust and perceived risk are the most important factors in acceptance of human being gene-recombination technology.

  10. Generalist genes and learning disabilities.

    PubMed

    Plomin, Robert; Kovas, Yulia

    2005-07-01

    The authors reviewed recent quantitative genetic research on learning disabilities that led to the conclusion that genetic diagnoses differ from traditional diagnoses in that the effects of relevant genes are largely general rather than specific. This research suggests that most genes associated with common learning disabilities--language impairment, reading disability, and mathematics disability--are generalists in 3 ways. First, genes that affect common learning disabilities are largely the same genes responsible for normal variation in learning abilities. Second, genes that affect any aspect of a learning disability affect other aspects of the disability. Third, genes that affect one learning disability are also likely to affect other learning disabilities. These quantitative genetic findings have far-reaching implications for molecular genetics and neuroscience as well as psychology. Copyright 2005 APA, all rights reserved.

  11. Gene targeting with retroviral vectors

    SciTech Connect

    Ellis, J.; Bernstein, A.

    1989-04-01

    The authors have designed and constructed integration-defective retroviral vectors to explore their potential for gene targeting in mammalian cells. Two nonoverlapping deletion mutants of the bacterial neomycin resistance (neo) gene were used to detect homologous recombination events between viral and chromosomal sequences. Stable neo gene correction events were selected at a frequency of approximately 1 G418/sup r/ cell per 3 x 10/sup 6/ infected cells. Analysis of the functional neo gene in independent targeted cell clones indicated that unintegrated retroviral linear DNA recombined with the target by gene conversion for variable distances into regions of nonhomology. In addition, transient neomore » gene correction events which were associated with the complete loss of the chromosomal target sequences were observed. These results demonstrated that retroviral vectors can recombine with homologous chromosomal sequences in rodent and human cells.« less

  12. Gene therapy for psychiatric disorders.

    PubMed

    Gelfand, Yaroslav; Kaplitt, Michael G

    2013-01-01

    Gene therapy has become of increasing interest in clinical neurosurgery with the completion of numerous clinical trials for Parkinson disease, Alzheimer disease, and pediatric genetic disorders. With improved understanding of the dysfunctional circuitry mediating various psychiatric disorders, deep brain stimulation for refractory psychiatric diseases is being increasingly explored in human patients. These factors are likely to facilitate development of gene therapy for psychiatric diseases. Because delivery of gene therapy agents would require the same surgical techniques currently being employed for deep brain stimulation, neurosurgeons are likely to lead the development of this field, as has occurred in other areas of clinical gene therapy for neurologic disorders. We review the current state of gene therapy for psychiatric disorders and focus specifically on particular areas of promising research that may translate into human trials for depression, drug addiction, obsessive-compulsive disorder, and schizophrenia. Issues that are relatively unique to psychiatric gene therapy are also discussed. Copyright © 2013. Published by Elsevier Inc.

  13. Gene Therapy for Cartilage Repair

    PubMed Central

    Madry, Henning; Orth, Patrick; Cucchiarini, Magali

    2011-01-01

    The concept of using gene transfer strategies for cartilage repair originates from the idea of transferring genes encoding therapeutic factors into the repair tissue, resulting in a temporarily and spatially defined delivery of therapeutic molecules to sites of cartilage damage. This review focuses on the potential benefits of using gene therapy approaches for the repair of articular cartilage and meniscal fibrocartilage, including articular cartilage defects resulting from acute trauma, osteochondritis dissecans, osteonecrosis, and osteoarthritis. Possible applications for meniscal repair comprise meniscal lesions, meniscal sutures, and meniscal transplantation. Recent studies in both small and large animal models have demonstrated the applicability of gene-based approaches for cartilage repair. Chondrogenic pathways were stimulated in the repair tissue and in osteoarthritic cartilage using genes for polypeptide growth factors and transcription factors. Although encouraging data have been generated, a successful translation of gene therapy for cartilage repair will require an ongoing combined effort of orthopedic surgeons and of basic scientists. PMID:26069580

  14. Hepatocyte isolation from resected benign tissues: Results of a 5-year experience

    PubMed Central

    Meng, Fan-Ying; Liu, Li; Liu, Jun; Li, Chun-You; Wang, Jian-Ping; Yang, Feng-Hui; Chen, Zhi-Shui; Zhou, Ping

    2016-01-01

    AIM To analyze retrospectively a 5-year experience of human hepatocyte isolation from resected liver tissues with benign disease. METHODS We established a method of modified four-step retrograde perfusion to isolate primary human hepatocytes. Samples were collected from the resected livers of patients with intrahepatic duct calculi (n = 7) and liver hemangioma (n = 17). Only the samples weighing ≥ 15 g were considered suitable for hepatocyte isolation. By using the standard trypan blue exclusion technique, hepatocyte viability and yield were immediately determined after isolation. RESULTS Twenty-four liver specimens, weighing 15-42 g, were immediately taken from the margin of the removed samples and transferred to the laboratory for hepatocyte isolation. Warm ischemia time was 5-35 min and cold ischemia time was 15-45 min. For the 7 samples of intrahepatic duct calculi, the method resulted in a hepatocyte yield of 3.49 ± 2.31 × 106 hepatocytes/g liver, with 76.4% ± 10.7% viability. The 17 samples of liver hemangioma had significantly higher yield of cells (5.4 ± 1.71 × 106 cells/g vs 3.49 ± 2.31 × 106 cells/g, P < 0.05) than the samples of intrahepatic duct calculi. However, there seems to be no clear difference in cell viability (80.3% ± 9.67% vs 76.4% ± 10.7%, P > 0.05). We obtained a cell yield of 5.31 ± 1.87 × 106 hepatocytes/g liver when the samples weighed > 20 g. However, for the tissues weighing ≤ 20 g, a reduction in yield was found (3.08 ± 1.86 × 106 cells/g vs 5.31 ± 1.87 × 106 cells/g, P < 0.05). CONCLUSION Benign diseased livers are valuable sources for large-number hepatocyte isolation. Our study represents the largest number of primary human hepatocytes isolated from resected specimens from patients with benign liver disease. We evaluated the effect of donor liver characteristics on cell isolation, and we found that samples of liver hemangioma can provide better results than intrahepatic duct calculi, in terms of cell yield

  15. Quality of reporting in oncology phase II trials: A 5-year assessment through systematic review

    PubMed Central

    Langrand-Escure, Julien; Rivoirard, Romain; Oriol, Mathieu; Tinquaut, Fabien; Rancoule, Chloé; Chauvin, Frank; Magné, Nicolas; Bourmaud, Aurélie

    2017-01-01

    Background Phase II clinical trials are a cornerstone of the development in experimental treatments They work as a "filter" for phase III trials confirmation. Surprisingly the attrition ratio in Phase III trials in oncology is significantly higher than in any other medical specialty. This suggests phase II trials in oncology fail to achieve their goal. Objective The present study aims at estimating the quality of reporting in published oncology phase II clinical trials. Data sources A literature review was conducted among all phase II and phase II/III clinical trials published during a 5-year period (2010–2015). Study eligibility criteria All articles electronically published by three randomly-selected oncology journals with Impact-Factors>4 were included: Journal of Clinical Oncology, Annals of Oncology and British Journal of Cancer. Intervention Quality of reporting was assessed using the Key Methodological Score. Results 557 articles were included. 315 trials were single-arm studies (56.6%), 193 (34.6%) were randomized and 49 (8.8%) were non-randomized multiple-arm studies. The Methodological Score was equal to 0 (lowest level), 1, 2, 3 (highest level) respectively for 22 (3.9%), 119 (21.4%), 270 (48.5%) and 146 (26.2%) articles. The primary end point is almost systematically reported (90.5%), while sample size calculation is missing in 66% of the articles. 3 variables were independently associated with reporting of a high standard: presence of statistical design (p-value <0.001), multicenter trial (p-value = 0.012), per-protocol analysis (p-value <0.001). Limitations Screening was mainly performed by a sole author. The Key Methodological Score was based on only 3 items, making grey zones difficult to translate. Conclusions & implications of key findings This literature review highlights the existence of gaps concerning the quality of reporting. It therefore raised the question of the suitability of the methodology as well as the quality of these trials

  16. Epidemiology and Risk Factors of Maxillofacial Injuries in Brazil, a 5-year Retrospective Study.

    PubMed

    Conceição, Luciana Domingues; da Silveira, Isadora Augusta; Nascimento, Gustavo Giacomelli; Lund, Rafael Guerra; da Silva, Ricardo Henrique Alves; Leite, Fábio Renato Manzolli

    2018-06-01

    The etiology and epidemiology of maxillofacial injuries varies widely in different regions of the world due to socioeconomic status, cultural aspects in addition to road traffic and drug consumption. The aim of this study is to determine major causes and epidemiological characteristics of maxillofacial trauma in a 5-year period. Reports of corporal trauma (n = 25,632) from 2007 to 2011 in the Department of Forensic Medicine were analyzed as to the presence of maxillofacial injuries. Data were submitted to Chi square test and to multivariate Poisson regression. 3262 reports referred maxillofacial trauma. The majority were men (55.8%), single (68.9%), most of them white (75.7%). The average age was 28.9 years (SD = 8.42), and victims with age between 16 and 30 years old were the most affected (48.0%). Women comprised 44% of total sample, 67.8% (971) were single, 76% (1.076) white and 46% (691) aged between 16 and 30 years old. Middle third injuries were associated after adjustment with females (PR 1.05; 95% CI 1.01-1.11), non-white subjects (PR 1.06; 95% CI 1.01-1.12) and physical aggression (PR 1.07; 95% CI 1.02-1.13). Injuries in the oral region was more prevalent in men (PR 1.24; 95% CI 1.09-1.41), in those aged between 16 and 30 (PR 1.97; 95% CI 1.48-2.61) and in subjects with injuries caused by traffic accident (PR 1.21; 95% CI 1.02-1.44). The presence of injuries in the lower third of face remained associated in the final model only with traffic accident (PR 1.75; 95% CI 1.43-2.15). Health care practitioners must recognize vulnerable population and most prevalent sites of lesion to identify cases of violence.

  17. Motorcycle helmets and cervical spine injuries: a 5-year experience at a Level 1 trauma center.

    PubMed

    Page, Paul S; Wei, Zhikui; Brooks, Nathaniel P

    2018-03-06

    OBJECTIVE Motorcycle helmets have been shown to decrease the incidence and severity of traumatic brain injury due to motorcycle crashes. Despite this proven efficacy, some previous reports and speculation suggest that helmet use is associated with a higher likelihood of cervical spine injury (CSI). In this study, the authors examine 1061 cases of motorcycle crash victims who were treated during a 5-year period at a Level 1 trauma center to investigate the association of helmet use with the incidence and severity of CSI. The authors hypothesized that wearing a motorcycle helmet during a motorcycle crash is not associated with an increased risk of CSI and may provide some protective advantage to the wearer. METHODS The authors performed a retrospective review of all cases in which the patient had been involved in a motorcycle crash and was evaluated at a single Level 1 trauma center in Wisconsin between January 1, 2010, and January 1, 2015. Biometric, clinical, and imaging data were obtained from a trauma registry database. The patients were then divided into 2 distinct groups based on whether or not they were wearing helmets at the time of the accident. Baseline and functional characteristics were compared between the 2 groups. The Student t-test was used for continuous variables, and Pearson's chi-square analysis was used for categorical variables. RESULTS In total, 1061 patient charts were examined containing data on 738 unhelmeted (69.6%) and 323 helmeted (30.4%) motorcycle riders. On average, helmeted riders had a much lower Injury Severity Score (p < 0.001). Cervical spine injury occurred in 114 unhelmeted riders (15.4%) compared with only 24 helmeted riders (7.4%) (p < 0.001), with an adjusted odds ratio of 2.3 (95% CI 1.44-3.61, p = 0.0005). In the unhelmeted group, 10.8% of patients were found to have a cervical spine fracture compared with only 4.6% of patients in the helmeted group (p = 0.001). Additionally, ligamentous injury occurred more frequently in

  18. A 5-year followup study of asymptomatic men with testicular microlithiasis.

    PubMed

    DeCastro, Brian J; Peterson, Andrew C; Costabile, Raymond A

    2008-04-01

    Testicular microlithiasis is an imaging entity of the testicle with questionable significance as a marker for testicular cancer. In 2001 we reported on a large prospective screening study establishing the prevalence of testicular microlithiasis to be 5.6% in a healthy asymptomatic population of Army volunteers 18 to 35 years old. In contrast, testicular cancer develops in only 5 of 100,000 men. Two-year followup of 63 of the 84 patients with testicular microlithiasis showed that none of these men had testicular cancer or scrotal masses. Here we report the 5-year followup in this cohort of men with testicular microlithiasis at risk for testicular cancer. According to the original parameters of the screening study we performed a history, genitourinary examination and scrotal ultrasound on 1,504 healthy army volunteers 18 to 35 years old during summer military training. Testicular microlithiasis was defined as greater than 6 echogenic signals found on ultrasound. We identified 84 patients with testicular microlithiasis (5.6%). These men were entered into the followup phase of the study and instructed regarding testicular self-examination and the need for followup. They were told to report any changes in their examination or a finding of testicular mass or cancer. Five years after the initial screening study we attempted to contact all remaining 84 men by e-mail, standard mail and telephone. Of the original 84 men with testicular microlithiasis identified in the original screening study, 63 have been contacted via e-mail and by telephone (75%). Of the 63 subjects a mixed germ cell tumor developed in 1 patient 64 months after the initial screening study. Compared to the incidence of testicular cancer in the general population the odds ratio of developing t