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Sample records for nqo1 c609t polymorphisms

  1. NQO1 C609T polymorphism and colorectal cancer susceptibility: a meta-analysis

    PubMed Central

    Zheng, Bo'an; Wang, Zishu

    2014-01-01

    Introduction A few studies have reported an association between NADP(H): quinine oxidoreductase 1 (NQO1) C609T polymorphism and susceptibility to colorectal cancer (CRC). However, the results were inconsistent rather than conclusive. We performed a meta-analysis to examine this association in various populations. Material and methods Eligible articles were identified by a search of several databases up until June 30, 2013. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of the association. Results Overall, 14 case-control studies with 4,461 cases and 5,474 controls were included in this meta-analysis. The results indicated that the NQO1 C609T polymorphism was significantly associated with CRC susceptibility (summary ORs (95% CIs): 1.30 (1.07–1.59) for CT vs. CC, 1.64 (1.15–2.33) for TT vs. CC, 1.34 (1.10–1.64) for TT/CT vs. CC, and 1.43 (1.10–1.87) for TT vs. CT/CC). Subgroup analyses indicated that the T allele was significantly associated with CRC susceptibility in both Asians and Caucasians, and was also observed in high quality studies and hospital-based case-control studies. Specifically, we found a positive association between the NQO1 C609T polymorphism and CRC susceptibility in smokers, but not in non-smokers. Conclusions The results of this meta-analysis suggest that the NQO1 C609T polymorphism significantly contributes to increased susceptibility to CRC in both Asians and Caucasians. PMID:25276147

  2. Associations of NQO1 C609T and NQO1 C465T polymorphisms with acute leukemia risk: a PRISMA-compliant meta-analysis

    PubMed Central

    He, Hairong; Zhai, Xiaoyu; Liu, Xiaomin; Zheng, Jie; Zhai, Yajing; Gao, Fan; Chen, Yonghua; Lu, Jun

    2017-01-01

    Objective The NAD(P)H:quinone oxidoreductase (NQO1) C609T and C465T polymorphisms have been widely thought to be associated with the risk of acute leukemia (AL) in recent years, but the correlations are still unclear. A meta-analysis is generally acknowledged as one of the best methods for secondary research, and so it was applied in this study with the aim of elucidating how the NQO1 C609T and C465T polymorphisms are related to the risk of AL. Methods Relevant studies were searched in the PubMed, EMBASE, CNKI, and Wanfang databases, and the obtained data were analyzed using Stata (version 12.1). The allele-contrast model was applied, and odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate relationship strengths. Meta-regression was used to identify sources of heterogeneity, and subgroup analyses were conducted. Publication bias was analyzed using funnel plots, with the trim-and-fill method used to analyze the effect of publication bias on pooled results. In addition, sensitivity analysis, the fail-safe number method, and cumulative analysis by publication year were performed to measure the stability of the obtained results. Results This meta-analysis included 28 relevant studies involving 5,953 patients and 8,667 controls. Overall, the C609T polymorphism was associated with the risk of acute lymphoblastic leukemia (ALL; OR =1.18, 95% CI =1.00–1.39, P=0.05). Meanwhile, race was found to be a potential source of heterogeneity for the relationship between the C609T polymorphism and acute myeloid leukemia (AML) risk, and the subgroup analysis identified the C609T polymorphism as a risk factor for AML in Asians (OR =1.34, 95% CI =1.03–1.74, P=0.03). The number of studies about C465T polymorphism was too small to pool the data. Conclusion There are increased risks of ALL in all subjects and of AML in Asians for carriers of the NQO1 C609T polymorphism. Further studies are needed to verify the associations of the C465T polymorphism with the

  3. Associations of NQO1 C609T and NQO1 C465T polymorphisms with acute leukemia risk: a PRISMA-compliant meta-analysis.

    PubMed

    He, Hairong; Zhai, Xiaoyu; Liu, Xiaomin; Zheng, Jie; Zhai, Yajing; Gao, Fan; Chen, Yonghua; Lu, Jun

    2017-01-01

    The NAD(P)H:quinone oxidoreductase (NQO1) C609T and C465T polymorphisms have been widely thought to be associated with the risk of acute leukemia (AL) in recent years, but the correlations are still unclear. A meta-analysis is generally acknowledged as one of the best methods for secondary research, and so it was applied in this study with the aim of elucidating how the NQO1 C609T and C465T polymorphisms are related to the risk of AL. Relevant studies were searched in the PubMed, EMBASE, CNKI, and Wanfang databases, and the obtained data were analyzed using Stata (version 12.1). The allele-contrast model was applied, and odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate relationship strengths. Meta-regression was used to identify sources of heterogeneity, and subgroup analyses were conducted. Publication bias was analyzed using funnel plots, with the trim-and-fill method used to analyze the effect of publication bias on pooled results. In addition, sensitivity analysis, the fail-safe number method, and cumulative analysis by publication year were performed to measure the stability of the obtained results. This meta-analysis included 28 relevant studies involving 5,953 patients and 8,667 controls. Overall, the C609T polymorphism was associated with the risk of acute lymphoblastic leukemia (ALL; OR =1.18, 95% CI =1.00-1.39, P=0.05). Meanwhile, race was found to be a potential source of heterogeneity for the relationship between the C609T polymorphism and acute myeloid leukemia (AML) risk, and the subgroup analysis identified the C609T polymorphism as a risk factor for AML in Asians (OR =1.34, 95% CI =1.03-1.74, P=0.03). The number of studies about C465T polymorphism was too small to pool the data. There are increased risks of ALL in all subjects and of AML in Asians for carriers of the NQO1 C609T polymorphism. Further studies are needed to verify the associations of the C465T polymorphism with the risk of AL.

  4. The NQO1 polymorphism C609T (Pro187Ser) and cancer susceptibility: a comprehensive meta-analysis

    PubMed Central

    Lajin, B; Alachkar, A

    2013-01-01

    Background: Evidence is increasingly emerging about multiple roles for the NAD(P)H quinone oxidoreductase 1 enzyme in cancer. The C609T (rs1800566, Pro187Ser) null polymorphism of the NQO1 gene contributes significantly to the variation in enzymatic activity across different populations. NQO1 C609T polymorphism was thoroughly investigated with respect to cancer susceptibility. The results were inconsistent partly due to low sample sizes. The aim of the present work was to perform a meta-analysis to assess association for all common cancer sites separately and in combination. Methods: Our meta-analysis involved 92 studies including 21 178 cases and 25 157 controls. Statistical analysis involved individual cancer sites and the combined cancer risk. Association was tested under different genetic models. Results: We found a statistically significant association between the variant T allele and overall cancer risk in the worldwide population (for the TT vs CC model, OR=1.18 (1.07–1.31), P=0.002, I2=36%). Stratified analysis revealed that this association was largely attributed to the Caucasian ethnicity (for the TT vs CC model, OR=1.28 (1.12–1.46), P=0.0002, I2=1%). Stratification by tumour site showed significant association for bladder cancer in the worldwide population (for the TT vs CC model, OR=1.70 (1.17–2.46), P=0.005, I2=0%), and in the Asian population (for the TT vs CC model, 1.48 (1.14–1.93), P=0.003, I2=16%). Positive association was also found for gastric cancer in the worldwide population under the dominant model (OR=1.34 (1.09–1.65), P=0.006, I2=15%). Conclusion: Our results indicate that the C609T polymorphism of the NQO1 gene is an important genetic risk factor in cancer. PMID:23860519

  5. The relationship between NQO1 C609T and CAT C-262Tgenetic polymorphisms and the risk of age-related cataracts.

    PubMed

    Zarei, Narjes; Saadat, Iraj; Farvardin-Jahromi, Majid

    2015-09-01

    Cataract is multi-factorial eye disease identified by the disturbance of the transparent ocular lens. There is significant evidence suggesting oxidative damage as a major cause of initiation and progression of numerous diseases including cataracts. NAD(P)H:quinone oxidoreductase 1 (NQO1; OMIM: 125860) and catalase (CAT, OMIM: 115500) are antioxidant enzymes that prevent cells from oxidative stress. The aim of the present study was to investigate the association between NQO1 C609T (Pro189Ser, rs1800566) and CAT promoter C-262T (rs1001179) genetic polymorphisms and the susceptibility to cataracts. A case-control study including 190 cataracts cases and 190 healthy subjects was carried out. Genotype distributions of NQO1 and CAT polymorphisms were examined using polymerase chain reactions and a restriction fragment length polymorphism (PCR-RFLP) approach to investigate the possible role of these polymorphisms as risk factors in the development of cataracts. Variant CT heterozygous and TT genotypes of the NQO1 C609T polymorphism were found to be associated with an increased risk of cataracts (CT vs CC, OR=1.61, 95%CI: 1.02-2.52, P=0.038), (CT/TT vs CC, OR=1.56, 95%CI: 1.02-2.4, P=0.040). In addition, compared to indoor work places and the CC genotype of NQO1, outdoor work places and CT/TT genotypes of NQO1 were found to increase the risk of age-related cataracts (OR=2.75, 95%CI: 1.20-6.33, P=0.017). The analysis did not reveal, however, any statistically significant (P>0.05) difference between CAT C-262T polymorphism and the risk of cataracts.

  6. The relationship between NQO1 C609T and CAT C-262Tgenetic polymorphisms and the risk of age-related cataracts

    PubMed Central

    Zarei, Narjes; Saadat, Iraj; Farvardin-Jahromi, Majid

    2015-01-01

    Cataract is multi-factorial eye disease identified by the disturbance of the transparent ocular lens. There is significant evidence suggesting oxidative damage as a major cause of initiation and progression of numerous diseases including cataracts. NAD(P)H:quinone oxidoreductase 1 (NQO1; OMIM: 125860) and catalase (CAT, OMIM: 115500) are antioxidant enzymes that prevent cells from oxidative stress. The aim of the present study was to investigate the association between NQO1 C609T (Pro189Ser, rs1800566) and CAT promoter C-262T (rs1001179) genetic polymorphisms and the susceptibility to cataracts. A case-control study including 190 cataracts cases and 190 healthy subjects was carried out. Genotype distributions of NQO1 and CAT polymorphisms were examined using polymerase chain reactions and a restriction fragment length polymorphism (PCR-RFLP) approach to investigate the possible role of these polymorphisms as risk factors in the development of cataracts. Variant CT heterozygous and TT genotypes of the NQO1 C609T polymorphism were found to be associated with an increased risk of cataracts (CT vs CC, OR=1.61, 95%CI: 1.02-2.52, P=0.038), (CT/TT vs CC, OR=1.56, 95%CI: 1.02-2.4, P=0.040). In addition, compared to indoor work places and the CC genotype of NQO1, outdoor work places and CT/TT genotypes of NQO1 were found to increase the risk of age-related cataracts (OR=2.75, 95%CI: 1.20-6.33, P=0.017). The analysis did not reveal, however, any statistically significant (P>0.05) difference between CAT C-262T polymorphism and the risk of cataracts. PMID:27844006

  7. NQO1 rs1800566 (C609T), PON1 rs662 (Q192R), and PON1 rs854560 (L55M) polymorphisms segregate the risk of childhood acute leukemias according to age range distribution.

    PubMed

    de Aguiar Gonçalves, Bruno Alves; Vasconcelos, Gisele M; Thuler, Luiz Claudio Santos; Andrade, Camilla; Faro, Alessandra; Pombo-de-Oliveira, Maria S; Emerenciano, Mariana; de Camargo, Beatriz; Bernstain, Luna; Neves, Cynthia Curvello; Agareno, Jozina Maria de Andrade; de Carvalho, Lilian Maria Burlacchini; Araújo, Flávia Nogueira Serafim; de Brito, Nilma Pimentel; Magalhães, Isis Q; Cordoba, José Carlos; Pimenta, Flávia; Gadelha, Andreia; Cartaxo, Eloísa; Basegio, Rosania Maria; Mnayarji, Atalla; Souza, Marcelo S; Arencibia, Alejandro; Melaragno, Renato; Cóser, Virgínia Maria; Lafayete, Thereza Christina; Koifman, Sergio

    2012-11-01

    The risk of developing childhood leukemia has been associated with gene polymorphisms that decrease the activity of detoxifying metabolic enzymes and enzymes involved in systemic oxidative stress. We investigated the NQO1 and PON1 polymorphisms for associations with susceptibility to childhood leukemia. Samples from 1,027 Brazilian children (519 acute lymphoblastic leukemia, ALL; 107 acute myeloid leukemia, AML; 401 controls) were analyzed. TaqMAN real-time assays were used to determine the NQO1 rs1800566 (C609T), PON1 rs662 (Q192R), and PON1 rs854560 (L55M) frequencies. Logistic regression was used to evaluate the association of polymorphisms with cases and controls, with age and somatic fusion genes (MLL-r and ETV6-RUNX1) as covariables. Children with at least one NQO1 variant allele were at lower risk for developing infant AML (odds ratio (OR) 0.26, 95 % confidence interval (CI) 0.10-0.68); no association was detected for ALL. PON1 rs854560 (L55M) was associated with an increased risk of developing childhood leukemia (LM + MM, OR 1.93, 95 % CI 1.32-2.81). The PON1 rs662 R192R genotype had a statistically significant decreased frequency in ALL (OR 0.64, 95 % CI 0.43-0.93). Infant ALL cases were more likely to harbor homozygous PON1 rs854560 alleles than controls (OR 1.72, 95 % CI 1.03-2.89); at least one M allele was associated with an increased risk of ALL in children older than 1 year (OR 1.99, 95 % CI 1.17-3.3). The NQO1 rs1800566 (C609T), PON1 rs854560 (L55M), and PON1 rs662 (Q192R) polymorphisms modified risk depending on leukemia subtype (decreased in AML, increased and decreased in ALL, respectively), age strata, and variant genotype combinations.

  8. RAS mutations in early age leukaemia modulated by NQO1 rs1800566 (C609T) are associated with second-hand smoking exposures.

    PubMed

    Andrade, Francianne Gomes; Furtado-Silva, Juliana Montibeller; Gonçalves, Bruno Alves de Aguiar; Thuler, Luiz Claudio Santos; Barbosa, Thayana Conceição; Emerenciano, Mariana; Siqueira, André; Pombo-de-Oliveira, Maria S

    2014-02-26

    Deregulation of the MAPK genes signalling caused by somatic mutations have been implied in leukaemia pathogenesis, including RAS mutation (RASmut) in acute myeloid leukaemia (AML), which has been associated with intra-uterine chemical exposures. A case-case study was conducted in order to explore maternal and child exposures to tobacco smoking associations with early age leukaemia (EAL). Covariables of reference were MLL rearrangements (MLL-r), RASmut and NQO1 rs1800566 (C609T). Samples from 150 acute lymphoblastic leukaemia (ALL) and 85 AML were included. Maternal exposures were assessed using a structured questionnaire with demographic, personal habits and residence history information. Restriction fragment length polymorphism and denaturing high performance liquid chromatography were used to screen FLT3, KRAS, and NRAS mutations; direct sequencing was performed to validate the results. NQO1 polymorphism was detected by real-time allelic discrimination technique. Overall, RASmut were detected in 28.7% of EAL cases; BRAFmut was found only in one AML patient. Higher rate of KRASmut was found in ALL (30.3%) compared to AML (20.8%) with MLL-r; RASmut showed an association with second-hand tobacco smoking exposures (OR, 3.06, 95% CI, 1.03-9.07). A considerable increased risk for EAL with the combination of RASmut and NQO1 609CT (OR, 4.24, 95% CI, 1.24-14.50) was observed. Our data demonstrated the increased risk association between maternal smoking and EAL with MLL-r. Additionally, suggests that children second-hand tobacco exposures are associated with increased risk of EAL with RASmut modulated by NQO1 rs1800566 (C609T).

  9. RAS mutations in early age leukaemia modulated by NQO1 rs1800566 (C609T) are associated with second-hand smoking exposures

    PubMed Central

    2014-01-01

    Background Deregulation of the MAPK genes signalling caused by somatic mutations have been implied in leukaemia pathogenesis, including RAS mutation (RASmut) in acute myeloid leukaemia (AML), which has been associated with intra-uterine chemical exposures. A case-case study was conducted in order to explore maternal and child exposures to tobacco smoking associations with early age leukaemia (EAL). Methods Covariables of reference were MLL rearrangements (MLL-r), RASmut and NQO1 rs1800566 (C609T). Samples from 150 acute lymphoblastic leukaemia (ALL) and 85 AML were included. Maternal exposures were assessed using a structured questionnaire with demographic, personal habits and residence history information. Restriction fragment length polymorphism and denaturing high performance liquid chromatography were used to screen FLT3, KRAS, and NRAS mutations; direct sequencing was performed to validate the results. NQO1 polymorphism was detected by real-time allelic discrimination technique. Results Overall, RASmut were detected in 28.7% of EAL cases; BRAFmut was found only in one AML patient. Higher rate of KRASmut was found in ALL (30.3%) compared to AML (20.8%) with MLL-r; RASmut showed an association with second-hand tobacco smoking exposures (OR, 3.06, 95% CI, 1.03-9.07). A considerable increased risk for EAL with the combination of RASmut and NQO1 609CT (OR, 4.24, 95% CI, 1.24-14.50) was observed. Conclusions Our data demonstrated the increased risk association between maternal smoking and EAL with MLL-r. Additionally, suggests that children second-hand tobacco exposures are associated with increased risk of EAL with RASmut modulated by NQO1 rs1800566 (C609T). PMID:24571676

  10. Correlation between NAD(P)H: quinone oxidoreductase 1 C609T polymorphism and increased risk of esophageal cancer: evidence from a meta-analysis

    PubMed Central

    Diao, Jingfang; Bao, Jie; Peng, Jianxin; Mo, Jiaqiang; Ye, Qing; He, Junming

    2016-01-01

    NAD(P)H: quinone oxidoreductase 1 (NQO1) C609T gene polymorphisms have been reported to influence the risk for esophageal cancer (EC) in many studies. However, the results remain controversial and ambiguous. We performed a meta-analysis, which included 13 independent studies with a total of 2357 subjects, to examine the association between NQO1 C609T polymorphism and EC. The association was assessed by five different gene models. The overall analysis suggested that the variant allele and genotypes were significantly related to increased risk of EC (odds ratio [OR] T versus C = 1.15, 95% confidence interval [CI] 0.95–1.40, probability of rejection [POR] = 0.014; OR TT versus CC = 1.32, 95% CI 1.01–1.73, POR = 0.045; OR TC versus CC = 1.32, 95% CI 0.98–1.21, POR = 0.128; OR TT + TC versus CC = 1.10, 95% CI 1.00–1.20, POR = 0.05; OR TT versus CC + TC = 1.26, 95% CI 0.95–1.57, POR = 0.103). Sensitivity analysis confirmed the reliability of these findings. Our study shows that individuals carrying the NQO1 C609T variant allele and genotypes are more susceptible to EC. PMID:28203294

  11. Association of HMOX1 and NQO1 Polymorphisms with Metabolic Syndrome Components

    PubMed Central

    Martínez-Hernández, Angélica; Córdova, Emilio J.; Rosillo-Salazar, Oscar; García-Ortíz, Humberto; Contreras-Cubas, Cecilia; Islas-Andrade, Sergio; Revilla-Monsalve, Cristina; Salas-Labadía, Consuelo; Orozco, Lorena

    2015-01-01

    Metabolic syndrome (MetS) is among the most important public health problems worldwide, and is recognized as a major risk factor for various illnesses, including type 2 diabetes mellitus, obesity, and cardiovascular diseases. Recently, oxidative stress has been suggested as part of MetS aetiology. The heme oxygenase 1 (HMOX1) and NADH:quinone oxidoreductase 1 (NQO1) genes are crucial mediators of cellular defence against oxidative stress. In the present study, we analysed the associations of HMOX1 (GT)n and NQO1 C609T polymorphisms with MetS and its components. Our study population comprised 735 Mexican Mestizos unrelated volunteers recruited from different tertiary health institutions from Mexico City. In order to know the HMOX1 (GT)n and NQO1 C609T allele frequencies in Amerindians, we included a population of 241 Amerindian native speakers. Their clinical and demographic data were recorded. The HMOX1 (GT)n polymorphism was genotyped using PCR and fluorescence technology. NQO1 C609T polymorphism genotyping was performed using TaqMan probes. Short allele (<25 GT repeats) of the HMOX1 polymorphism was associated with high systolic and diastolic blood pressure, and the T allele of the NQO1 C609T polymorphism was associated with increased triglyceride levels and decreased HDL-c levels, but only in individuals with MetS. This is the first study to analyse the association between MetS and genes involved in oxidative stress among Mexican Mestizos. Our data suggest that polymorphisms of HMOX1 and NQO1 genes are associated with a high risk of metabolic disorders, including high systolic and diastolic blood pressure, hypertriglyceridemia, and low HDL-c levels in Mexican Mestizo individuals. PMID:25933176

  12. Investigation of NQO1 genetic polymorphism, NQO1 gene expression and PAH-DNA adducts in ESCC. A case-control study from Iran.

    PubMed

    Marjani, H A; Biramijamal, F; Rakhshani, N; Hossein-Nezhad, A; Malekzadeh, R

    2010-02-09

    We evaluated the effect of NQO1 genetic variation on PAH-DNA adducts in esophageal squamous cell carcinoma (ESCC) in northeast Iran. Golestan Province in northeast of Iran has one of the highest esophageal cancer incidences in the world. The study included 93 ESCC cases and 50 control individuals who were seen at the clinical cancer center in Golestan province. NQO1 C609T genotypes were determined by PCR-RFLP analysis. NQO1 gene expression in tissue samples was determined by quantitative real-time PCR. Immunohistochemical techniques were used to detect PAH-DNA adducts in ESCC and normal esophageal tissues. The distributions of NQO1 genetic polymorphism between cases and the control group were not significantly different. NQO1 gene expression was not higher in tumor tissues than in normal esophageal tissues adjacent to the ESCC; expression was higher in tumor tissues that had the NQO1 T allele. NQO1 gene expression was high in normal esophageal tissues. The level of PAH-DNA adducts was significantly higher in ESCC tissues of cases than in normal tissues adjacent to tumor tissues and in normal esophageal tissues of healthy controls. There were no significant differences between the adduct levels of normal esophageal tissues of patients and controls. There was also no significant relationship between cigarette smoking and PAH-DNA adducts. We concluded that PAHs are a risk factor for ESCC and that PAH-DNA adducts have potential as a biomarker for risk of ESCC.

  13. Site-to-site interdomain communication may mediate different loss-of-function mechanisms in a cancer-associated NQO1 polymorphism.

    PubMed

    Medina-Carmona, Encarnación; Neira, Jose L; Salido, Eduardo; Fuchs, Julian E; Palomino-Morales, Rogelio; Timson, David J; Pey, Angel L

    2017-03-14

    Disease associated genetic variations often cause intracellular enzyme inactivation, dysregulation and instability. However, allosteric communication of mutational effects to distant functional sites leading to loss-of-function remains poorly understood. We characterize here interdomain site-to-site communication by which a common cancer-associated single nucleotide polymorphism (c.C609T/p.P187S) reduces the activity and stability in vivo of NAD(P)H:quinone oxidoreductase 1 (NQO1). NQO1 is a FAD-dependent, two-domain multifunctional stress protein acting as a Phase II enzyme, activating cancer pro-drugs and stabilizing p53 and p73α oncosuppressors. We show that p.P187S causes structural and dynamic changes communicated to functional sites far from the mutated site, affecting the FAD binding site located at the N-terminal domain (NTD) and accelerating proteasomal degradation through dynamic effects on the C-terminal domain (CTD). Structural protein:protein interaction studies reveal that the cancer-associated polymorphism does not abolish the interaction with p73α, indicating that oncosuppressor destabilization largely mirrors the low intracellular stability of p.P187S. In conclusion, we show how a single disease associated amino acid change may allosterically perturb several functional sites in an oligomeric and multidomain protein. These results have important implications for the understanding of loss-of-function genetic diseases and the identification of novel structural hot spots as targets for pharmacological intervention.

  14. Site-to-site interdomain communication may mediate different loss-of-function mechanisms in a cancer-associated NQO1 polymorphism

    NASA Astrophysics Data System (ADS)

    Medina-Carmona, Encarnación; Neira, Jose L.; Salido, Eduardo; Fuchs, Julian E.; Palomino-Morales, Rogelio; Timson, David J.; Pey, Angel L.

    2017-03-01

    Disease associated genetic variations often cause intracellular enzyme inactivation, dysregulation and instability. However, allosteric communication of mutational effects to distant functional sites leading to loss-of-function remains poorly understood. We characterize here interdomain site-to-site communication by which a common cancer-associated single nucleotide polymorphism (c.C609T/p.P187S) reduces the activity and stability in vivo of NAD(P)H:quinone oxidoreductase 1 (NQO1). NQO1 is a FAD-dependent, two-domain multifunctional stress protein acting as a Phase II enzyme, activating cancer pro-drugs and stabilizing p53 and p73α oncosuppressors. We show that p.P187S causes structural and dynamic changes communicated to functional sites far from the mutated site, affecting the FAD binding site located at the N-terminal domain (NTD) and accelerating proteasomal degradation through dynamic effects on the C-terminal domain (CTD). Structural protein:protein interaction studies reveal that the cancer-associated polymorphism does not abolish the interaction with p73α, indicating that oncosuppressor destabilization largely mirrors the low intracellular stability of p.P187S. In conclusion, we show how a single disease associated amino acid change may allosterically perturb several functional sites in an oligomeric and multidomain protein. These results have important implications for the understanding of loss-of-function genetic diseases and the identification of novel structural hot spots as targets for pharmacological intervention.

  15. Site-to-site interdomain communication may mediate different loss-of-function mechanisms in a cancer-associated NQO1 polymorphism

    PubMed Central

    Medina-Carmona, Encarnación; Neira, Jose L.; Salido, Eduardo; Fuchs, Julian E.; Palomino-Morales, Rogelio; Timson, David J.; Pey, Angel L.

    2017-01-01

    Disease associated genetic variations often cause intracellular enzyme inactivation, dysregulation and instability. However, allosteric communication of mutational effects to distant functional sites leading to loss-of-function remains poorly understood. We characterize here interdomain site-to-site communication by which a common cancer-associated single nucleotide polymorphism (c.C609T/p.P187S) reduces the activity and stability in vivo of NAD(P)H:quinone oxidoreductase 1 (NQO1). NQO1 is a FAD-dependent, two-domain multifunctional stress protein acting as a Phase II enzyme, activating cancer pro-drugs and stabilizing p53 and p73α oncosuppressors. We show that p.P187S causes structural and dynamic changes communicated to functional sites far from the mutated site, affecting the FAD binding site located at the N-terminal domain (NTD) and accelerating proteasomal degradation through dynamic effects on the C-terminal domain (CTD). Structural protein:protein interaction studies reveal that the cancer-associated polymorphism does not abolish the interaction with p73α, indicating that oncosuppressor destabilization largely mirrors the low intracellular stability of p.P187S. In conclusion, we show how a single disease associated amino acid change may allosterically perturb several functional sites in an oligomeric and multidomain protein. These results have important implications for the understanding of loss-of-function genetic diseases and the identification of novel structural hot spots as targets for pharmacological intervention. PMID:28291250

  16. GSTM1, GSTT1, and NQO1 polymorphisms in cervical carcinogenesis.

    PubMed

    Nunobiki, Osamu; Ueda, Masatsugu; Akise, Hikari; Izuma, Shinji; Torii, Kiyo; Okamoto, Yoshiaki; Tanaka, Ichiro; Noda, Sadamu; Akashi, Kyoko; Higashida, Taro

    2015-07-01

    The aim of the study is to investigate the clinical significance of glutathione-S-transferase GSTM1, GSTT1, and NQO1 c.609C>T (rs1800566) genetic polymorphisms in cervical carcinogenesis. GSTM1, GSTT1, and NQO1 polymorphisms together with human papillomavirus (HPV) types were examined in a total of 192 cervical smear in exfoliated cervical cell samples using polymerase chain reaction (PCR) system and real-time polymerase chain reaction (PCR) system. The 19 patients with high-grade squamous intraepithelial lesion had statistically higher frequency of null GSTT1 genotype than 9 with low-grade squamous intraepithelial lesion (LSIL) among the 67 patients with high-risk HPV (P = 0.024). The 24 patients with HSIL had also statistically higher frequency of NQO1 (CT+TT) genotype than 14 with LSIL among the 67 patients with high-risk HPV (P = 0.024). GSTT1 null and NQO1 genotype in cervical cell samples may be associated with more severe precancerous lesions of the cervix in a Japanese population.

  17. Polymorphisms in xenobiotic metabolizing genes (EPHX1, NQO1 and PON1) in lymphoma susceptibility: a case control study

    PubMed Central

    2013-01-01

    Background The interplay between genetic susceptibility and carcinogenic exposure is important in the development of haematopoietic malignancies. EPHX1, NQO1 and PON1 are three genes encoding proteins directly involved in the detoxification of potential carcinogens. Methods We have studied the prevalence of three functional polymorphisms affecting these genes rs1051740 EPHX1, rs1800566 NQO1 and rs662 PON1 in 215 patients with lymphoma and 214 healthy controls. Results Genotype frequencies for EPHX and NQO1 polymorphisms did not show any correlation with disease. In contrast, the GG genotype in the PON1 polymorphism was found to be strongly associated with the disease (15.3% vs. 4.7%; OR = 3.7 CI (95%): 1.8-7.7; p < 0.001). According to the pathological diagnosis this association was related to follicular (p = 0.004) and diffuse large B-cell (p = 0.016) lymphomas. Conclusions Despite the fact that further confirmation is needed, this study shows that the PON1 GG genotype in rs662 polymorphism could be a risk factor for B-cell lymphomas. PMID:23651475

  18. A Functional NQO1 609C>T Polymorphism and Risk of Gastrointestinal Cancers: A Meta-Analysis

    PubMed Central

    Yu, Hongping; Liu, Hongliang; Wang, Li-E; Wei, Qingyi

    2012-01-01

    Background The functional polymorphism (rs1800566) in the NQO1 gene, a 609C>T substitution, leading to proline-to-serine amino-acid and enzyme activity changes, has been implicated in cancer risk, but individually published studies showed inconclusive results. Methodology/Principal Findings We performed a meta-analysis of 20 publications with a total of 5,491 cases and 5,917 controls, mainly on gastrointestinal (GI) cancers. We summarized the data on the association between the NQO1 609C>T polymorphism and risk of GI cancers and performed subgroup analyses by ethnicity, cancer site, and study quality. We found that the variant CT heterozygous and CT/TT genotypes of the NQO1 609 C>T polymorphism were associated with a modestly increased risk of GI cancers (CT vs. CC: OR = 1.10, 95% CI = 1.01 – 1.19, Pheterogeneity = 0.27, I2 = 0.15; CT/TT vs. CC: OR = 1.11, 95%CI = 1.02 – 1.20, Pheterogeneity = 0.14; I2 = 0.27). Following further stratified analyses, the increased risk was only observed in subgroups of Caucasians, colorectal cancer in Caucasians, and high quality studies. Conclusions This meta-analysis suggests that the NQO1 609T allele is a low-penetrance risk factor for GI cancers. Although the effect on GI cancers may be modified by ethnicity and cancer sites, small sample seizes of the subgroup analyses suggest that further larger studies are needed, especially for non-colorectal GI cancers in Caucasians and GI cancers in Asians. PMID:22272361

  19. NQO1 609C>T polymorphism interaction with tobacco smoking and alcohol drinking increases colorectal cancer risk in a Chinese population.

    PubMed

    Peng, Xian-E; Jiang, Ying-Ying; Shi, Xi-Shun; Hu, Zhi-Jian

    2013-05-25

    NAD (P)H:quinone oxidoreductase (NQO1) catalyzes the activation of some environmental procarcinogens present in tobacco smoke or the diet. We conducted a hospital-based case-control study to evaluate the potential association between NQO1 609C>T polymorphisms and colorectal cancer risk in a Chinese population. The study population comprised 672 histologically confirmed colorectal cancer patients and 672 frequency-matched control subjects without cancer or systemic illness. We used PCR restriction fragment length polymorphism-based methods for genotyping analyses and unconditional logistic regression model for statistical evaluations. The risk of colorectal cancer increased with the level of smoking and decreased with the consumption of tea, fresh fruits, and vegetables. In addition, we found that the NQO1 609 CT and TT genotypes were associated with an increased risk of colorectal cancer (CT: adjusted OR=2.02, 95% CI=1.55-2.57; TT: adjusted OR=2.51, 95% CI=1.82-3.47), compared with the CC genotype. Moreover, NQO1 609C>T appeared to have a multiplicative joint effect with both tobacco smoking and alcoholic drinking (P for multiplicative interactions were 0.0001 and 0.013, respectively) on colorectal cancer risk. Our findings suggest that the NQO1 609C>T polymorphism plays an important role in the development of colorectal cancer in the Chinese population, which is strengthened by alcohol drinking or tobacco smoking. Copyright © 2013 Elsevier B.V. All rights reserved.

  20. Genetic association of NQO1 609C>T polymorphism with risk of gastrointestinal cancer: evidence from case-control studies

    PubMed Central

    Liu, Haixia; Zhou, Sixin; Ma, Lin; Yang, Jun; Yang, Hao

    2015-01-01

    Background: Numerous studies have evaluated the association between NQO1 609C>T polymorphism and gastrointestinal (GI) cancer. However, the results remain inconclusive. To obtain a more precise estimation of the relation, we conducted an analysis of all available case-control studies. Methods: Eligible studies were identified by searching the databases and finally 19 articles were included in the meta-analysis. Odds ratio (OR) with 95% confidence interval (95% CI) was applied to assess the association between NQO1 609C>T polymorphism and GI cancer risk. Z test was used to evaluate the significance of OR and 95% CI. Results: In the overall analysis, there existed a significant association between NQO1 609C>T polymorphism and GI cancer susceptibility (T vs. C: OR = 1.07, 95% CI = 1.01-1.14). The subgroup analysis based on ethnicity showed that NQO1 609C>T polymorphism was associated with susceptibility to GI cancer in mixed population (TT vs. CC: OR = 2.21, 95% CI = 1.44-3.40; TT vs. CT + CC: OR = 2.26, 95% CI = 1.48-3.44; Allele T vs. Allele C: OR = 1.24, 95% CI = 1.05-1.47). For the subgroup analysis according to source of control, a remark relationship of 609C>T with increased risk of GI cancer was observed in HB population (Allele T vs. Allele C: OR = 1.07, 95% CI = 1.01-1.14). Conclusion: Our results demonstrated that NQO1 609C>T polymorphism might be associated with susceptibility to GI cancer. PMID:26131202

  1. Conformational dynamics is key to understanding loss-of-function of NQO1 cancer-associated polymorphisms and its correction by pharmacological ligands

    PubMed Central

    Encarnación, Medina-Carmona; Palomino-Morales, Rogelio J.; Fuchs, Julian E.; Esperanza, Padín-Gonzalez; Noel, Mesa-Torres; Salido, Eduardo; Timson, David J.; Pey, Angel L.

    2016-01-01

    Protein dynamics is essential to understand protein function and stability, even though is rarely investigated as the origin of loss-of-function due to genetic variations. Here, we use biochemical, biophysical, cell and computational biology tools to study two loss-of-function and cancer-associated polymorphisms (p.R139W and p.P187S) in human NAD(P)H quinone oxidoreductase 1 (NQO1), a FAD-dependent enzyme which activates cancer pro-drugs and stabilizes several oncosuppressors. We show that p.P187S strongly destabilizes the NQO1 dimer in vitro and increases the flexibility of the C-terminal domain, while a combination of FAD and the inhibitor dicoumarol overcome these alterations. Additionally, changes in global stability due to polymorphisms and ligand binding are linked to the dynamics of the dimer interface, whereas the low activity and affinity for FAD in p.P187S is caused by increased fluctuations at the FAD binding site. Importantly, NQO1 steady-state protein levels in cell cultures correlate primarily with the dynamics of the C-terminal domain, supporting a directional preference in NQO1 proteasomal degradation and the use of ligands binding to this domain to stabilize p.P187S in vivo. In conclusion, protein dynamics are fundamental to understanding loss-of-function in p.P187S, and to develop new pharmacological therapies to rescue this function. PMID:26838129

  2. Conformational dynamics is key to understanding loss-of-function of NQO1 cancer-associated polymorphisms and its correction by pharmacological ligands

    NASA Astrophysics Data System (ADS)

    Encarnación, Medina-Carmona; Palomino-Morales, Rogelio J.; Fuchs, Julian E.; Esperanza, Padín-Gonzalez; Noel, Mesa-Torres; Salido, Eduardo; Timson, David J.; Pey, Angel L.

    2016-02-01

    Protein dynamics is essential to understand protein function and stability, even though is rarely investigated as the origin of loss-of-function due to genetic variations. Here, we use biochemical, biophysical, cell and computational biology tools to study two loss-of-function and cancer-associated polymorphisms (p.R139W and p.P187S) in human NAD(P)H quinone oxidoreductase 1 (NQO1), a FAD-dependent enzyme which activates cancer pro-drugs and stabilizes several oncosuppressors. We show that p.P187S strongly destabilizes the NQO1 dimer in vitro and increases the flexibility of the C-terminal domain, while a combination of FAD and the inhibitor dicoumarol overcome these alterations. Additionally, changes in global stability due to polymorphisms and ligand binding are linked to the dynamics of the dimer interface, whereas the low activity and affinity for FAD in p.P187S is caused by increased fluctuations at the FAD binding site. Importantly, NQO1 steady-state protein levels in cell cultures correlate primarily with the dynamics of the C-terminal domain, supporting a directional preference in NQO1 proteasomal degradation and the use of ligands binding to this domain to stabilize p.P187S in vivo. In conclusion, protein dynamics are fundamental to understanding loss-of-function in p.P187S, and to develop new pharmacological therapies to rescue this function.

  3. Polymorphisms in TP53 (rs1042522), p16 (rs11515 and rs3088440) and NQO1 (rs1800566) genes in Thai cervical cancer patients with HPV 16 infection.

    PubMed

    Chansaenroj, Jira; Theamboonlers, Apiradee; Junyangdikul, Pairoj; Swangvaree, Sukumarn; Karalak, Anant; Chinchai, Teeraporn; Poovorawan, Yong

    2013-01-01

    The risk of cervical cancer development in women infected with HPV varies in relation to the individual host's genetic makeup. Many studies on polymorphisms as genetic factors have been aimed at analyzing associations with cervical cancer. In this study, single nucleotide polymorphisms (SNPs) in 3 genes were investigated in relation to cervical cancer progression in HPV16 infected women with lesions. Two thousand cervical specimens were typed by PCR sequencing methods for TP53 (rs1042522), p16 (rs11515 and rs3088440) and NQO1 (rs1800566). Ninety two HPV16 positive cases and thirty two normal cases were randomly selected. Analysis of TP53 (rs1042522) showed a significantly higher frequency in cancer samples (OR=1.22, 95%CI=1.004-1.481, p-value=0.016) while differences in frequency were not significant within each group (p-value=0.070). The genotype distributions of p16 (rs11515 and rs3088440) and NQO1 (rs1800566) did not show any significantly higher frequency in cancer samples (p-value=0.106, 0.675 and 0.132, respectively) or within each group (p-value=0.347, 0.939 and 0.111, respectively). The results indicated that the polymorphism in TP53 (rs1042522) might be associated with risk of cervical cancer development in HPV16 infected women. Further studies of possible mechanisms of influence on cervical cancer development would be useful to manage HPV infected patients.

  4. Implications of NQO1 in cancer therapy

    PubMed Central

    Oh, Eun-Taex; Park, Heon Joo

    2015-01-01

    NAD(P)H:quinone oxidoreductase (NQO1), an obligatory two-electron reductase, is a ubiquitous cytosolic enzyme that catalyzes the reduction of quinone substrates. The NQO1- mediated two-electron reduction of quinones can be either chemoprotection/detoxification or a chemotherapeutic response, depending on the target quinones. When toxic quinones are reduced by NQO1, they are conjugated with glutathione or glucuronic acid and excreted from the cells. Based on this protective effect of NQO1, the use of dietary compounds to induce the expression of NQO1 has emerged as a promising strategy for cancer prevention. On the other hand, NQO1-mediated two-electron reduction converts certain quinone compounds (such as mitomycin C, E09, RH1 and β-lapachone) to cytotoxic agents, leading to cell death. It has been known that NQO1 is expressed at high levels in numerous human cancers, including breast, colon, cervix, lung, and pancreas, as compared with normal tissues. This implies that tumors can be preferentially damaged relative to normal tissue by cytotoxic quinone drugs. Importantly, NQO1 has been shown to stabilize many proteins, including p53 and p33ING1b, by inhibiting their proteasomal degradation. This review will summarize the biological roles of NQO1 in cancer, with emphasis on recent findings and the potential of NQO1 as a therapeutic target for the cancer therapy. [BMB Reports 2015; 48(11): 609-617] PMID:26424559

  5. Association between exposure-relevant polymorphisms in CYP1B1, EPHX1, NQO1, GSTM1, GSTP1 and GSTT1 and risk of colorectal cancer in a Czech population.

    PubMed

    Hlavata, Ivona; Vrana, David; Smerhovsky, Zdenek; Pardini, Barbara; Naccarati, Alessio; Vodicka, Pavel; Novotny, Jan; Mohelnikova-Duchonova, Beatrice; Soucek, Pavel

    2010-11-01

    Associations of functional single nucleotide polymorphisms in cytochrome P450 1B1, epoxide hydrolase 1, NAD(P)H:quinone oxidoreductase 1, glutathione S-transferase Pi-1 and deletions of glutathione S-transferases Mu-1 and θ-1 with colorectal cancer risk were investigated in a hospital-based case-control study on 495 matched pairs of Czech Caucasians. Polymorphisms were assessed by polymerase chain reaction restriction fragment length polymorphism-based methods, allele-specific multiplex and allelic discrimination by real-time polymerase chain reaction. Carriers of variant Ser allele in codon 453 of cytochrome P450 1B1 (rs1800440) were at a significantly lower risk of colorectal cancer compared to carriers of the wild-type allele (adjusted odds ratio, aOR=0.68, CI=0.51-0.89, p=0.006). The combination of polymorphisms in codons 453 and 432 (rs1056836) of cytochrome P450 1B1 further increased the protective effect (aOR=0.53, CI=0.34-0.83, p=0.005). The glutathione S-transferase Mu-1 deletion was associated with a moderately elevated colorectal cancer risk (aOR=1.30, CI=1.01-1.68, p=0.044). Combination of glutathione S-transferase Mu-1 and θ-1 deletion was associated with a significantly higher colorectal cancer risk compared to the presence of both full-length genes (aOR=1.58, CI=1.01-2.47, p=0.044). Genetic polymorphisms in glutathione S-transferase Pi-1, NAD(P)H:quinone oxidoreductase 1, epoxide hydrolase 1 and deduced epoxid hydrolase 1 activity did not modify the risk of colorectal cancer. These results provide further evidence that interaction between metabolic gene variants contributes to colorectal carcinogenesis.

  6. NQO1-Knockout Mice Are Highly Sensitive to Clostridium Difficile Toxin A-Induced Enteritis.

    PubMed

    Nam, Seung Taek; Hwang, Jung Hwan; Kim, Dae Hong; Lu, Li Fang; Hong, Ji; Zhang, Peng; Yoon, I Na; Hwang, Jae Sam; Chung, Hyo Kyun; Shong, Minho; Lee, Chul-Ho; Kim, Ho

    2016-08-28

    Clostridium difficile toxin A causes acute gut inflammation in animals and humans. It is known to downregulate the tight junctions between colonic epithelial cells, allowing luminal contents to access body tissues and trigger acute immune responses. However, it is not yet known whether this loss of the barrier function is a critical factor in the progression of toxin A-induced pseudomembranous colitis. We previously showed that NADH:quinone oxidoreductase 1 (NQO1) KO (knockout) mice spontaneously display weak gut inflammation and a marked loss of colonic epithelial tight junctions. Moreover, NQO1 KO mice exhibited highly increased inflammatory responses compared with NQO1 WT (wild-type) control mice when subjected to DSS-induced experimental colitis. Here, we tested whether toxin A could also trigger more severe inflammatory responses in NQO1 KO mice compared with NQO1 WT mice. Indeed, our results show that C. difficile toxin A-mediated enteritis is significantly enhanced in NQO1 KO mice compared with NQO1 WT mice. The levels of fluid secretion, villus disruption, and epithelial cell apoptosis were also higher in toxin A-treated NQO1 KO mice compared with WT mice. The previous and present results collectively show that NQO1 is involved in the formation of tight junctions in the small intestine, and that defects in NQO1 enhance C. difficile toxin A-induced acute inflammatory responses, presumably via the loss of epithelial cell tight junctions.

  7. Overexpression of NAD(P)H:quinone oxidoreductase 1 (NQO1) and genomic gain of the NQO1 locus modulates breast cancer cell sensitivity to quinones.

    PubMed

    Glorieux, Christophe; Sandoval, Juan Marcelo; Dejeans, Nicolas; Ameye, Geneviève; Poirel, Hélène Antoine; Verrax, Julien; Calderon, Pedro Buc

    2016-01-15

    Alterations in the expression of antioxidant enzymes are associated with changes in cancer cell sensitivity to chemotherapeutic drugs (menadione and β-lapachone). Mechanisms of acquisition of resistance to pro-oxidant drugs were investigated using a model of oxidative stress-resistant MCF-7 breast cancer cells (Resox cells). FISH experiments were performed in tumor biopsy and breast cancer cells to characterize the pattern of the NQO1 gene. SNP-arrays were conducted to detect chromosomal imbalances. Finally, the importance of NQO1 overexpression in the putative acquisition of either drug resistance or an increased sensitivity to quinones by cancer cells was investigated by immunoblotting and cytotoxicity assays. Genomic gain of the chromosomal band 16q22 was detected in Resox cells compared to parental breast cancer MCF-7 cells and normal human mammary epithelial 250MK cells. This genomic gain was associated with amplification of the NQO1 gene in one tumor biopsy as well as in breast cancer cell lines. Using different breast cell models, we found that NQO1 overexpression was a main determinant for a potential chemotherapy resistance or an increased sensitivity to quinone-bearing compounds. Because NQO1 is frequently modified in tumors at genomic and transcriptomic levels, the impact of NQO1 modulation on breast cancer cell sensitivity places NQO1 as a potential link between cancer redox alterations and resistance to chemotherapy. Thus, the NQO1 gene copy number and NQO1 activity should be considered when quinone-bearing molecules are being utilized as potential drugs against breast tumors. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Gene polymorphisms and the risk of warfarin-induced bleeding complications at therapeutic international normalized ratio (INR).

    PubMed

    Pourgholi, Leyla; Goodarzynejad, Hamidreza; Mandegary, Ali; Ziaee, Shayan; Talasaz, Azita Hajhosseini; Jalali, Arash; Boroumand, Mohammadali

    2016-10-15

    Bleeding episodes commonly occur in patients on warfarin treatment even in those within therapeutic range of international normalized ratio (INR). The objective of this study was to investigate the effects of the 8 examined polymorphisms on the risk of bleeding complications in a sample of Iranian patients. A total of 552 warfarin treated patients who maintained on a target INR level of 2.0-3.5 for at least three consecutive intervals were enrolled from those attended our anticoagulation clinics. Ninety-two bleeding events were observed in 87 patients. The presences of the examined polymorphisms were analyzed using polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP). Patients with the T allele in NQO1*2 (CT or TT genotypes) had a higher risk of bleeding than patients with the CC genotype (adjusted OR: 2.25, 95% CI: 1.37 to 3.70, P=0.001). Those who were carriers of CYP2C9 one-variant haplotypes (*1/*2 or *1/*3) were also found to be associated with the higher risk of bleeding events. Compared to reference group (*1/*1), the odds of bleeding increased for carriers of one variant allele (*1/*2 or *1/*3) (adjusted OR: 1.75, 95% CI: 1.03 to 2.97, P=0.039). Variant VKORC1, Factor VII, and EPHX1 genotypes were not significantly associated with the risk of bleeding events. The SNP C609T within NQO1 and haplotypes of CYP2C9 (1*2 or 1*3) are independently associated to bleeding complications of warfarin at normal INR. Further studies are required to confirm such associations in diverse racial and ethnic populations. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. NQO1 protein expression predicts poor prognosis of non-small cell lung cancers.

    PubMed

    Li, Zhenling; Zhang, Yue; Jin, Tiefeng; Men, Jiguang; Lin, Zhenhua; Qi, Peng; Piao, Yingshi; Yan, Guanghai

    2015-03-31

    High-level expression of quinoneoxidoreductase 1 (NQO1) has been correlated with many types of human cancers, suggesting that NQO1 plays important roles in tumor occurrence and progression. This study attempted to explore the role of NQO1 in tumor progression and prognostic evaluation of non-small cell lung cancer (NSCLC). Total 164 tissue samples, including 150 NSCLC paired with the adjacent non-tumor tissues and 14 normal lung tissues, were picked-up for immunohistochemical (IHC) staining of the NQO1 protein, and immunofluorescence (IF) staining was also performed to detect the subcellular localization of the NQO1 protein in A549 human lung cancer cells. The correlation between NQO1 expression and clinicopathological characteristics were evaluated by Chi-square test and Fisher's exact tests. The disease-free survival (DFS) and overall survival (OS) rates of NSCLC patients were calculated by the Kaplan-Meier method, and univariate and multivariate analyses were performed using the Cox proportional hazards regression model. The NQO1 protein showed a mainly cytoplasmic staining pattern in lung cancer cells, including adenocarcinoma and squamous cell carcinoma (SCC). Both positive rate and strongly positive rate of NQO1 protein expression were significantly higher in NSCLC (59.3% and 28.0%) than that in adjacent non tumor (8.0% and 1.3%) and normal lung tissues (0%). The positive rate of NQO1 was related with clinical stage and lymph node metastasis, and the strongly positive rate of NQO1 protein was significantly correlated with tumor size, poor differentiation, advanced clinical stage and lymph node metastasis in NSCLC. Additionally, survival analyses showed that the patients with NQO1 positive expression had lower OS rates compared with those with NQO1 negative expression in the groups of T1-2, T3-4, without LN metastasis and stage I-II of NSCLC, respectively; however, in the groups of patients with LN metastasis or III-IV stages, OS rate was not correlated with

  10. NQO1-activated Phenothiazinium Redox Cyclers for the Targeted Bioreductive Induction of Cancer Cell Apoptosis

    PubMed Central

    Wondrak, Georg T.

    2009-01-01

    Altered redox signaling and regulation in cancer cells represent a chemical vulnerability that can be targeted by selective chemotherapeutic intervention. Here, we demonstrate that 3,7-diaminophenothiazinium-based redoxcyclers (PRC) induce selective cancer cell apoptosis by NAD(P)H:quinone oxidoreductase (NQO1)-dependent bioreductive generation of cellular oxidative stress. Using PRC lead compounds including toluidine blue against human metastatic G361 melanoma cells, apoptosis occurred with phosphatidylserine-externalization, loss of mitochondrial transmembrane potential, cytochrome C release, caspase-3 activation, and massive ROS production. Consistent with reductive activation and subsequent redoxcycling as the mechanism of PRC cytotoxicity, co-incubation with catalase achieved cell protection, whereas reductive antioxidants enhanced PRC-cytotoxicity. Unexpectedly, human A375 melanoma cells were resistant to PRC-induced apoptosis, and PRC-sensitive G361 cells were protected by preincubation with the NQO1-inhibitor dicoumarol. Indeed, NQO1 specific enzymatic activity was nine fold higher in G361 than in A375 cells. The critical role of NQO1 in PRC-bioactivation and cytotoxicity was confirmed, when NQO1-transfected breast cancer cells (MCF7-DT15) stably overexpressing active NQO1 displayed strongly enhanced PRC-sensitivity as compared to vector-control transfected cells with base line NQO1 activity. Based on the known overexpression of NQO1 in various tumors these findings suggest the feasibility of developing PRC lead compounds into tumor-selective bioreductive chemotherapeutics. PMID:17603928

  11. NQO1 inhibits proteasome-mediated degradation of HIF-1α

    PubMed Central

    Oh, Eun-Taex; Kim, Jung-whan; Kim, Joon Mee; Kim, Soo Jung; Lee, Jae-Seon; Hong, Soon-Sun; Goodwin, Justin; Ruthenborg, Robin J.; Jung, Myung Gu; Lee, Hae-June; Lee, Chul-Ho; Park, Eun Sung; Kim, Chulhee; Park, Heon Joo

    2016-01-01

    Overexpression of NQO1 is associated with poor prognosis in human cancers including breast, colon, cervix, lung and pancreas. Yet, the molecular mechanisms underlying the pro-tumorigenic capacities of NQO1 have not been fully elucidated. Here we show a previously undescribed function for NQO1 in stabilizing HIF-1α, a master transcription factor of oxygen homeostasis that has been implicated in the survival, proliferation and malignant progression of cancers. We demonstrate that NQO1 directly binds to the oxygen-dependent domain of HIF-1α and inhibits the proteasome-mediated degradation of HIF-1α by preventing PHDs from interacting with HIF-1α. NQO1 knockdown in human colorectal and breast cancer cell lines suppresses HIF-1 signalling and tumour growth. Consistent with this pro-tumorigenic function for NQO1, high NQO1 expression levels correlate with increased HIF-1α expression and poor colorectal cancer patient survival. These results collectively reveal a function of NQO1 in the oxygen-sensing mechanism that regulates HIF-1α stability in cancers. PMID:27966538

  12. Depleting Tumor-NQO1 Potentiates Anoikis and Inhibits Growth of NSCLC.

    PubMed

    Madajewski, Brian; Boatman, Michael A; Chakrabarti, Gaurab; Boothman, David A; Bey, Erik A

    2016-01-01

    The fundamental role that NAD(P)H/quinone oxidoreductase 1 (NQO1) plays, in normal cells, as a cytoprotective enzyme guarding against stress induced by reactive oxygen species (ROS) is well documented. However, what is not known is whether the observed overexpression of NQO1 in neoplastic cells contributes to their survival. The current study discovered that depleting NQO1 expression in A549 and H292 lung adenocarcinoma cells caused an increase in ROS formation, inhibited anchorage-independent growth, increased anoikis sensitization, and decreased three-dimensional tumor spheroid invasion. These in vivo data further implicate tumor-NQO1 expression in a protumor survival role, because its depletion suppressed cell proliferation and decreased lung tumor xenograft growth. Finally, these data reveal an exploitable link between tumor-NQO1 expression and the survival of lung tumors because NQO1 depletion significantly decreased the percentage of ALDH((high)) cancer cells within the tumor population. Loss of tumor-NQO1 expression inhibits tumor growth and suggests that novel therapeutics directed at tumor-NQO1 may have clinical benefit. ©2015 American Association for Cancer Research.

  13. NQO1-mediated tumor-selective lethality and radiosensitization for head and neck cancer

    PubMed Central

    Li, Long-Shan; Reddy, Srilakshmi; Lin, Zhen-Hua; Liu, Shuangping; Park, Hyunsil; Chun, Stephen G.; Bornmann, William G.; Thibodeaux, Joel; Yan, Jingsheng; Chakrabarti, Gaurab; Xie, Xian-Jin; Sumer, Baran D.; Boothman, David A.; Yordy, John S.

    2016-01-01

    Ionizing radiation (IR) is a key therapeutic regimen for many head and neck cancers (HNCs). However, the 5-year overall survival rate for locally-advanced HNCs is ∼50% and better therapeutic efficacy is needed. NAD(P)H:quinone oxidoreductase 1 (NQO1) is over-expressed in many cancers, and β-lapachone (β-lap), an unique NQO1 bioactivatable drug, exploits this enzyme to release massive reactive oxygen species (ROS) levels that synergizes with IR to kill by programmed necrosis. β-Lap represents a novel therapeutic opportunity in HNC leading to tumor-selective lethality that will enhance the efficacy of ionizing radiation. Immunohistochemical staining and western blot assays were used to assess the expression levels of NQO1 in HNC cells and tumors. Forty-five percent of endogenous HNCs express elevated NQO1 levels. In addition, multiple HNC cell lines and tumors demonstrated elevated levels of NQO1 expression and activity and were tested for anticancer lethality and radiosensitization by β-lap using long-term survival assays. The combination of nontoxic β-lap doses and IR significantly enhanced NQO1-dependenttumor cell lethality, increased ROS, TUNEL positive cells, DNA damage, NAD+ and adenosine triphosphate (ATP) consumption, and resulted in significantantitumor efficacy and prolonged survival in two xenograft murine HNC models, demonstrating β-Lap radiosensitization of HNCs through a NQO1-dependent mechanism. This translational study offers a potential biomarker-driven strategy using NQO1 expression to select tumors susceptible to β-lap-induced radiosensitization. PMID:27196777

  14. Depleting tumor-NQO1 Potentiates Anoikis and Inhibits Growth of NSCLC

    PubMed Central

    Chakrabarti, Gaurab; Boothman, David A.; Bey, Erik A.

    2015-01-01

    The fundamental role that NAD(P)H/quinone oxidoreductase 1 (NQO1) plays, in normal cells, as a cyto-protective enzyme guarding against stress induced by reactive oxygen species (ROS) is well documented. However, what is not known is whether the observed overexpression of NQO1 in neoplastic cells contributes to their survival. The current study discovered that depleting NQO1 expression in A549 and H292 lung adenocarcinoma cells caused an increase in ROS formation, inhibited anchorage-independent growth, increased anoikis sensitization and decreased 3-D tumor-spheroid invasion. These in vivo data further implicate tumor-NQO1 expression in a pro-tumor survival role, since its depletion suppressed cell proliferation and decreased lung tumor xenograft growth. Finally, these data reveal an exploitable link between tumor-NQO1 expression and the survival of lung tumors since NQO1 depletion significantly decreased the percentage of ALDH(high) cancer cells within the tumor population. PMID:26553038

  15. NQO1 gene rs1800566 variant is not associated with risk for multiple sclerosis

    PubMed Central

    2014-01-01

    Background A possible role of oxidative stress in the pathogenesis of multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis has been suggested. The detoxification enzyme NAD(P)H dehydrogenase, quinone 1 (NQO1) has been found up-regulated in MS lesions. A previous report described an association between the SNP rs1800566 in the NQO1 gene and the risk for MS in the Greek population. The aim of this study was to replicate a possible influence of the. SNP rs1800566 in the NQO1 gene in the risk for MS in the Spanish Caucasian population. Methods We analyzed allelic and genotypic frequency of NQO1 rs1800566 in 290 patients with MS and 310 healthy controls, using TaqMan Assays. Results NQO1 rs1800566 allelic and genotypic frequencies did not differ significantly between MS patients and controls, and were unrelated with age of onset of MS, gender, and clinical type of MS. Conclusions Our results indicate that NQO1 rs1800566 does not have an effect on MS disease risk. PMID:24755231

  16. NQO1 suppresses NF-κB-p300 interaction to regulate inflammatory mediators associated with prostate tumorigenesis.

    PubMed

    Thapa, Dinesh; Meng, Peng; Bedolla, Roble G; Reddick, Robert L; Kumar, Addanki P; Ghosh, Rita

    2014-10-01

    NADPH reductase quinone oxidoreductase 1 (NQO1) is needed to maintain a cellular pool of antioxidants, and this enzyme may contribute to tumorigenesis on the basis of studies in NQO1-deficient mice. In this work, we sought deeper insights into how NQO1 contributes to prostate carcinogenesis, a setting in which oxidative stress and inflammation are established contributors to disease development and progression. In the TRAMP mouse model of prostate cancer, NQO1 was highly expressed in tumor cells. NQO1 silencing in prostate cancer cells increased levels of nuclear IKKα and NF-κB while decreasing the levels of p53, leading to interactions between NF-κB and p300 that reinforce survival signaling. Gene expression analysis revealed upregulation of a set of immune-associated transcripts associated with inflammation and tumorigenesis in cells in which NQO1 was attenuated, with IL8 confirmed functionally in cell culture as one key NQO1-supported cytokine. Notably, NQO1-silenced prostate cancer cells were more resistant to androgen deprivation. Furthermore, NQO1 inhibition increased migration, including under conditions of androgen deprivation. These results reveal a molecular link between NQO1 expression and proinflammatory cytokine signaling in prostate cancer. Furthermore, our results suggest that altering redox homeostasis through NQO1 inhibition might promote androgen-independent cell survival via opposing effects on NF-κB and p53 function. ©2014 American Association for Cancer Research.

  17. Higher activity of polymorphic NAD(P)H:quinone oxidoreductase in liver cytosols from blacks compared to whites.

    PubMed

    Covarrubias, Vanessa Gonzalez; Lakhman, Sukhwinder S; Forrest, Alan; Relling, Mary V; Blanco, Javier G

    2006-07-14

    In human liver, the two-electron reduction of quinone compounds, such as menadione is catalyzed by cytosolic carbonyl reductase (CBR) and NAD(P)H:quinone oxidoreductase (NQO1) activities. We assessed the relative contributions of CBR and NQO1 activities to the total menadione reducing capacity in liver cytosols from black (n=31) and white donors (n=63). Maximal menadione reductase activities did not differ between black (13.0+/-5.0 nmol/min mg), and white donors (11.4+/-6.6 nmol/min mg; p=0.208). In addition, both groups presented similar levels of CBR activities (CBR(blacks)=10.9+/-4.1 nmol/min mg) versus CBR(whites)=10.5+/-5.8 nmol/min mg; p=0.708). In contrast, blacks showed higher NQO1 activities (two-fold) than whites (NQO1(blacks)=2.1+/-3.0 nmol/min mg versus NQO1(whites)=0.9+/-1.6 nmol/min mg, p<0.01). To further explore this disparity, we tested whether NQO1 activity was associated with the common NQO1(*)2 genetic polymorphism by using paired DNA samples for genotyping. Cytosolic NQO1 activities differed significantly by NQO1 genotype status in whites (NQO1(whites[NQO1*1/*1])=1.3+/-1.7 nmol/min mg versus NQO1(whites[NQO1*1/*2+NQO1*2/*2])=0.5+/-0.7 nmol/min mg, p<0.01), but not in blacks (NQO1(blacks[NQO1*1/*1])=2.6+/-3.4 nmol/min mg versus NQO1(blacks[NQO1*1/*2])=1.1+/-1.2 nmol/min mg, p=0.134). Our findings pinpoint the presence of significant interethnic differences in polymorphic hepatic NQO1 activity.

  18. Protection of hydroquinone-induced apoptosis by downregulation of Fau is mediated by NQO1.

    PubMed

    Siew, E L; Chan, K M; Williams, G T; Ross, D; Inayat-Hussain, S H

    2012-10-15

    The Fau gene (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV)-associated ubiquitously expressed gene) was identified as a potential tumor suppressor gene using a forward genetics approach. Downregulation of Fau by overexpression of its reverse sequence has been shown to inhibit apoptosis induced by DNA-damaging agents. To address a potential role of Fau in benzene toxicity, we investigated the apoptotic effects of hydroquinone (HQ), a major benzene metabolite, in W7.2 mouse thymoma cells transfected with either a plasmid construct expressing the antisense sequence of Fau (rfau) or the empty vector (pcDNA3.1) as a control. HQ induced apoptosis via increased production of reactive oxygen species and DNA damage, measured using dihydroethidine (HE) staining and alkaline Comet assay, respectively, in W7.2 pcDNA3.1 cells. In contrast, when Fau was downregulated by the antisense sequence in W7.2 rfau cells, HQ treatment did not cause DNA damage and oxidative stress and these cells were markedly more resistant to HQ-induced apoptosis. Further investigation revealed that there was an upregulation of NAD(P)H: quinone oxidoreductase 1 (NQO1), a detoxification enzyme for benzene-derived quinones, in W7.2 rfau cells. Compromising cellular NQO1 by use of a specific mechanism-based inhibitor (MAC 220) and NQO1 siRNA resensitized W7.2 rfau cells to HQ-induced apoptosis. Silencing of Fau in W7.2 wild-type cells resulted in increased levels of NQO1, confirming that downregulation of Fau results in NQO1 upregulation which protects against HQ-induced apoptosis. Copyright © 2012 Elsevier Inc. All rights reserved.

  19. Tumor-Selective, Futile Redox Cycle-Induced Bystander Effects Elicited by NQO1 Bioactivatable Radiosensitizing Drugs in Triple-Negative Breast Cancers

    PubMed Central

    Cao, Lifen; Li, Long Shan; Spruell, Christopher; Xiao, Ling; Chakrabarti, Gaurab; Bey, Erik A.; Reinicke, Kathryn E.; Srougi, Melissa C.; Moore, Zachary; Dong, Ying; Vo, Peggy; Kabbani, Wareef; Yang, Chin-Rang; Wang, Xiaoyu; Fattah, Farjana; Morales, Julio C.; Motea, Edward A.; Bornmann, William G.

    2014-01-01

    Abstract Aims: β-Lapachone (β-lap), a novel radiosensitizer with potent antitumor efficacy alone, selectively kills solid cancers that over-express NAD(P)H:quinone oxidoreductase 1 (NQO1). Since breast or other solid cancers have heterogeneous NQO1 expression, therapies that reduce the resistance (e.g., NQO1low) of tumor cells will have significant clinical advantages. We tested whether NQO1-proficient (NQO1+) cells generated sufficient hydrogen peroxide (H2O2) after β-lap treatment to elicit bystander effects, DNA damage, and cell death in neighboring NQO1low cells. Results: β-Lap showed NQO1-dependent efficacy against two triple-negative breast cancer (TNBC) xenografts. NQO1 expression variations in human breast cancer patient samples were noted, where ∼60% cancers over-expressed NQO1, with little or no expression in associated normal tissue. Differential DNA damage and lethality were noted in NQO1+ versus NQO1-deficient (NQO1−) TNBC cells and xenografts after β-lap treatment. β-Lap-treated NQO1+ cells died by programmed necrosis, whereas co-cultured NQO1− TNBC cells exhibited DNA damage and caspase-dependent apoptosis. NQO1 inhibition (dicoumarol) or H2O2 scavenging (catalase [CAT]) blocked all responses. Only NQO1− cells neighboring NQO1+ TNBC cells responded to β-lap in vitro, and bystander effects correlated well with H2O2 diffusion. Bystander effects in NQO1− cells in vivo within mixed 50:50 co-cultured xenografts were dramatic and depended on NQO1+ cells. However, normal human cells in vitro or in vivo did not show bystander effects, due to elevated endogenous CAT levels. Innovation and Conclusions: NQO1-dependent bystander effects elicited by NQO1 bioactivatable drugs (β-lap or deoxynyboquinone [DNQ]) likely contribute to their efficacies, killing NQO1+ solid cancer cells and eliminating surrounding heterogeneous NQO1low cancer cells. Normal cells/tissue are protected by low NQO1:CAT ratios. Antioxid. Redox Signal. 21, 237–250. PMID

  20. β-Lapachone-containing PEG-PLA Polymer Micelles as Novel Nanotherapeutics against NQO1-Overexpressing Tumor Cells

    PubMed Central

    Blanco, Elvin; Bey, Erik A.; Dong, Ying; Weinberg, Brent D.; Sutton, Damon M.; Boothman, David A.; Gao, Jinming

    2007-01-01

    β-Lapachone (β-lap) is a novel anticancer agent that is bioactivated by NADP(H): quinone oxidoreductase 1 (NQO1), an enzyme overexpressed in a variety of tumors. Despite its therapeutic promise, the poor aqueous solubility of β-lap hinders its preclinical evaluation and clinical translation. Our objective was to develop β-lap-containing poly(ethylene glycol)-block-poly(D,L-lactide) (PEG-PLA) polymer micelles for the treatment of NQO1-overexpressing tumors. Several micelle fabrication strategies were examined to maximize drug loading. A film sonication method yielded β-lap micelles with relatively high loading density (4.7 ± 1.0% to 6.5 ± 1.0%) and optimal size (29.6 ± 1.5 nm). Release studies in phosphate-buffered saline (pH 7.4) showed the time (t1/2) for 50% of drug release at 18 h. In vitro cytotoxicity assays were performed in NQO1-overexpressing (NQO1+) and NQO1-null (NQO1-) H596 lung, DU-145 prostate, and MDA-MB-231 breast cancer cells. Cytotoxicity data showed that after a 2 h incubation with β-lap micelles, a marked increase in toxicity was shown in NQO1+ cells over NQO1- cells, resembling free drug both in efficacy and mechanism of cell death. In summary, these data demonstrate the potential of β-lap micelles as an effective therapeutic strategy against NQO1-overexpressing tumor cells. PMID:17574288

  1. An NQO1 Substrate with Potent Antitumor Activity That Selectively Kills by PARP1-Induced Programmed Necrosis

    PubMed Central

    Huang, Xiumei; Dong, Ying; Bey, Erik A.; Kilgore, Jessica A.; Bair, Joseph S.; Li, Long-Shan; Patel, Malina; Parkinson, Elizabeth I.; Wang, Yiguang; Williams, Noelle S.; Gao, Jinming; Hergenrother, Paul J.; Boothman, David A.

    2016-01-01

    Agents, such as β-lapachone, that target the redox enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1), to induce programmed necrosis in solid tumors have shown great promise, but more potent tumor-selective compounds are needed. Here, we report that deoxynyboquinone kills a wide spectrum of cancer cells in an NQO1-dependent manner with greater potency than β-lapachone. Deoxynyboquinone lethality relies on NQO1-dependent futile redox cycling that consumes oxygen and generates extensive reactive oxygen species (ROS). Elevated ROS levels cause extensive DNA lesions, PARP1 hyperactivation, and severe NAD+/ATP depletion that stimulate Ca2+–dependent programmed necrosis, unique to this new class of NQO1 "bioactivated" drugs. Short-term exposure of NQO1+ cells to deoxynyboquinone was sufficient to trigger cell death, although genetically matched NQO1− cells were unaffected. Moreover, siRNA-mediated NQO1 or PARP1 knockdown spared NQO1+ cells from short-term lethality. Pretreatment of cells with BAPTA-AM (a cytosolic Ca2+ chelator) or catalase (enzymatic H2O2 scavenger) was sufficient to rescue deoxynyboquinone-induced lethality, as noted with β-lapachone. Investigations in vivo showed equivalent antitumor efficacy of deoxynyboquinone to β-lapachone, but at a 6-fold greater potency. PARP1 hyperactivation and dramatic ATP loss were noted in the tumor, but not in the associated normal lung tissue. Our findings offer preclinical proof-of-concept for deoxynyboquinone as a potent chemotherapeutic agent for treatment of a wide spectrum of therapeutically challenging solid tumors, such as pancreatic and lung cancers. PMID:22532167

  2. Discovery of quinone-directed antitumor agents selectively bioactivated by NQO1 over CPR with improved safety profile.

    PubMed

    Bian, Jinlei; Li, Xiang; Wang, Nan; Wu, Xingsen; You, Qidong; Zhang, Xiaojin

    2017-03-31

    In this work, we mainly focused on discovering compounds with good selectivity for NQO1 over CPR. The NQO1-mediated two-electron reduction of compounds would kill cancer cells selectively, while CPR-mediated one-electron reduction would induce potential hepatotoxicity. Several novel quinone-directed antitumor agents were discovered as specific NQO1 substrates through structure-activity relationship studies. Among them, compound 3,7,8-trimethylnaphtho[1,2-b]furan-4,5-dione (12b) emerged as the most specific substrate of the two-electron oxidoreductase NQO1 and could hardly be reduced by CPR. It afforded the highest selectivity between NQO1/CPR (selectivity ratio = 6.37), much higher than the control β-lapachone (selectivity ratio = 1.36), indicated 12b may possess superior safety profile. The electrochemical studies provided a reasonable explanation to the good selectivity toward NQO1. Molecular docking studies supported that 12b was capable of forming additional C-H … π interactions with Trp105 and Phe178 residues compared to the control β-lap. In addition, compound 12b was shown to kill cancer cells efficiently both in vitro and in vivo model. This work gave us a promising and novel scaffold for further investigation.

  3. High-Throughput Library Screening Identifies Two Novel NQO1 Inducers in Human Lung Cells

    PubMed Central

    Marquardt, Gaby; Massimi, Aldo B.; Shi, Miao; Han, Weiguo; Spivack, Simon D.

    2012-01-01

    Many phytochemicals possess antioxidant and cancer-preventive properties, some putatively through antioxidant response element–mediated phase II metabolism, entailing mutagen/oxidant quenching. In our recent studies, however, most candidate phytochemical agents were not potent in inducing phase II genes in normal human lung cells. In this study, we applied a messenger RNA (mRNA)–specific gene expression–based high throughput in vitro screening approach to discover new, potent plant-derived phase II inducing chemopreventive agents. Primary normal human bronchial epithelial (NHBE) cells and immortalized human bronchial epithelial cells (HBECs) were exposed to 800 individual compounds in the MicroSource Natural Products Library. At a level achievable in humans by diet (1.0 μM), 2,3-dihydroxy-4-methoxy-4′-ethoxybenzophenone (DMEBP), triacetylresveratrol (TRES), ivermectin, sanguinarine sulfate, and daunorubicin induced reduced nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1 (NQO1) mRNA and protein expression in NHBE cells. DMEBP and TRES were the most attractive agents as coupling potency and low toxicity for induction of NQO1 (mRNA level, ≥3- to 10.8-fold that of control; protein level, ≥ two- to fourfold that of control). Induction of glutathione S-transferase pi mRNA expression was modest, and none was apparent for glutathione S-transferase pi protein expression. Measurements of reactive oxygen species and glutathione/oxidized glutathione ratio showed an antioxidant effect for DMEBP, but no definite effect was found for TRES in NHBE cells. Exposure of NHBE cells to H2O2 induced nuclear translocation of nuclear factor erythroid 2–related factor 2, but this translocation was not significantly inhibited by TRES and DMEBP. These studies show that potency and low toxicity may align for two potential NQO1-inducing agents, DMEBP and TRES. PMID:22021338

  4. High-throughput library screening identifies two novel NQO1 inducers in human lung cells.

    PubMed

    Tan, Xiang-Lin; Marquardt, Gaby; Massimi, Aldo B; Shi, Miao; Han, Weiguo; Spivack, Simon D

    2012-03-01

    Many phytochemicals possess antioxidant and cancer-preventive properties, some putatively through antioxidant response element-mediated phase II metabolism, entailing mutagen/oxidant quenching. In our recent studies, however, most candidate phytochemical agents were not potent in inducing phase II genes in normal human lung cells. In this study, we applied a messenger RNA (mRNA)-specific gene expression-based high throughput in vitro screening approach to discover new, potent plant-derived phase II inducing chemopreventive agents. Primary normal human bronchial epithelial (NHBE) cells and immortalized human bronchial epithelial cells (HBECs) were exposed to 800 individual compounds in the MicroSource Natural Products Library. At a level achievable in humans by diet (1.0 μM), 2,3-dihydroxy-4-methoxy-4'-ethoxybenzophenone (DMEBP), triacetylresveratrol (TRES), ivermectin, sanguinarine sulfate, and daunorubicin induced reduced nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1 (NQO1) mRNA and protein expression in NHBE cells. DMEBP and TRES were the most attractive agents as coupling potency and low toxicity for induction of NQO1 (mRNA level, ≥3- to 10.8-fold that of control; protein level, ≥ two- to fourfold that of control). Induction of glutathione S-transferase pi mRNA expression was modest, and none was apparent for glutathione S-transferase pi protein expression. Measurements of reactive oxygen species and glutathione/oxidized glutathione ratio showed an antioxidant effect for DMEBP, but no definite effect was found for TRES in NHBE cells. Exposure of NHBE cells to H(2)O(2) induced nuclear translocation of nuclear factor erythroid 2-related factor 2, but this translocation was not significantly inhibited by TRES and DMEBP. These studies show that potency and low toxicity may align for two potential NQO1-inducing agents, DMEBP and TRES.

  5. A physiological threshold for protection against menadione toxicity by human NAD(P)H:quinone oxidoreductase (NQO1) in Chinese hamster ovary (CHO) cells.

    PubMed

    De Haan, Laura H J; Boerboom, Anne Marie J F; Rietjens, Ivonne M C M; van Capelle, Daniëlla; De Ruijter, Annemieke J M; Jaiswal, Anil K; Aarts, Jac M M J G

    2002-12-01

    NAD(P)H:quinone oxidoreductase 1 (NQO1) has often been suggested to be involved in cancer prevention by means of detoxification of electrophilic quinones. In the present study, a series of Chinese hamster ovary (CHO) cell lines expressing various elevated levels of human NQO1 were generated by stable transfection. The level of NQO1 over-expression ranged from 14 to 29 times the NQO1 activity in the wild-type CHO cells. This panel of cell lines, allowed investigation of the protective role of NQO1 in quinone cytotoxicity. It could be demonstrated that menadione toxicity was significantly reduced in all NQO1-transfected CHO clones compared to the wild-type cells, but the clones did not show differences in their level of protection against menadione. This observation pointed at a critical threshold concentration of NQO1 above which a further increase does not provide further protection against quinone cytotoxicity. Additional studies in which the NQO1 activity was inhibited by dicoumarol showed that only dicoumarol concentrations of about five times the EC(50) for NQO1 inhibition were able to reduce NQO1 levels below the apparent threshold, making the cells more sensitive. The level of this threshold was estimated to be in the range of base line NQO1 activities observed in several tissues and species. Thus, the results of the present study indicate that beneficial effects of NQO1 induction by, for example, cruciferous vegetables might be absent or present depending on the NQO1 activity threshold for optimal protection and the basal level of NQO1 expression in the tissue and species of interest.

  6. Low expression of NQO1 predicts pathological complete response to neoadjuvant chemotherapy in breast cancer patients treated with TAC regimen.

    PubMed

    Grim, J; Jandík, P; Slánská, I; Doležalová-Brčáková, E; Fuksa, L; Ryška, A; Knížek, J; Petera, J; Mičuda, S; Hornychová, H

    2012-01-01

    The aim of this study was to evaluate preoperative tumour expression of NAD(P)H:quinone oxidoreductase 1 (NQO1) along with other biological markers as potential predictors of pathological complete response (pCR) to neoadjuvant docetaxel, doxorubicin, and cyclophosphamide-containing (TAC) chemotherapy in patients with primary breast cancer. Sixty-one patients who received neoadjuvant chemotherapy (NCT) with TAC regimen were enrolled in this prospective study. The pre- and post- NCT expression of oestrogen receptor (ER), progesterone receptor (PR), epidermal growth factor receptor 1 and 2 (EGFR and HER2), NQO1, Ki-67 proliferation index, multidrug resistance protein 1 (MDR1), p53 and BCL2 were evaluated by immunohistochemistry. The pCR was reached in 14 patients (23 % of the study group). Multivariate analysis demonstrated that patients with ER-, PR-, NQO1- negative, and Ki-67-positive tumours had a significantly higher chance to achieve pCR. Within the biological subtypes, the highest pCR rate (50 %) was seen in triple-negative (i.e. ER-, PR-, HER2-) tumours. Post-operative evaluation showed that in comparison to pre-operative tissue samples, NQO1 expression was significantly increased, while Ki-67 and HER2 decreased, in the residual tissue after NCT. In conclusion, the present data suggests that NQO1 expression may be a novel diagnostic biomarker for the prediction of positive response to NCT in patients with breast cancer.

  7. Inhibition of colon carcinogenesis by post-initiation induction of NQO1 in Sprague-Dawley rats.

    PubMed

    Begleiter, Asher; Sivananthan, Kosala; Lefas, Georgia M; Maksymiuk, Andrew W; Bird, Ranjana P

    2009-06-01

    Inducers of phase II detoxifying enzymes have been studied as chemopreventive agents for a variety of cancers. Phase II detoxifying enzymes may play a significant role in preventing carcinogen-induced colon cancer at the initiation and post-initiation stage, but the contribution of NAD(P) H:quinone oxidoreductase 1 (NQO1) to this effect remains unclear. Using the carcinogen-induced colon cancer Sprague-Dawley rat model, we previously showed that oltipraz selectively induces NQO1 in the colons of these rats without inducing other phase II detoxifying enzymes. We demonstrated that selective induction of NQO1 in the rat colon prior to treatment with a carcinogen significantly inhibited the formation of aberrant crypt foci (ACF). Using the same rat model, we found that rats fed oltipraz containing diet following treatment with the colon carcinogen, azoxymethane (AOM), had 60% fewer ACF after 12 weeks compared with rats fed a control diet. In addition, rats fed oltipraz containing diet after AOM treatment developed 40% fewer colon adenomas and fewer colon tumors than rats fed a control diet. There was also a 60% increase in the percentage of apoptotic cells in ACF from oltipraz fed rats compared with ACF from control fed rats. Together, these results suggest that NQO1 can contribute to inhibition of colon carcinogenesis at the post-initiation stage. A possible mechanism for this effect may be that induction of NQO1 increases apoptosis in carcinogen initiated colonic epithelial cells that prevents these cells from progressing to a neoplastic state. Thus, NQO1 may be an important target for chemoprevention of colon cancer.

  8. Candidate dietary phytochemicals modulate expression of phase II enzymes GSTP1 and NQO1 in human lung cells.

    PubMed

    Tan, Xiang-Lin; Shi, Miao; Tang, Hui; Han, Weiguo; Spivack, Simon D

    2010-08-01

    Many phytochemicals possess cancer-preventive properties, some putatively through phase II metabolism-mediated mutagen/oxidant quenching. We applied human lung cells in vitro to investigate the effects of several candidate phytopreventive agents, including green tea extracts (GTE), broccoli sprout extracts (BSE), epigallocatechin gallate (EGCG), sulforaphane (SFN), phenethyl isothiocyanate (PEITC), and benzyl isothiocyanate (BITC), on inducing phase II enzymes glutathione S-transferase P1 (GSTP1) and NAD(P)H:quinone oxidoreductase 1 (NQO1) at mRNA and protein levels. Primary normal human bronchial epithelial cells (NHBE), immortalized human bronchial epithelial cells (HBEC), and lung adenocarcinoma cells (A549) were exposed to diet-achievable levels of GTE and BSE (0.5, 1.0, 2.0 mg/L), or individual index components EGCG, SFN, PEITC, BITC (0.5, 1.0, 2.0 micromol/L) for 24 h, 48 h, and 6 d, respectively. mRNA assays employed RNA-specific quantitative RT-PCR and protein assays employed Western blotting. We found that in NHBE cells, while GSTP1 mRNA levels were slightly but significantly increased after exposure to GTE or BSE, NQO1 mRNA increased to 2- to 4-fold that of control when exposed to GTE, BSE, or SFN. Effects on NQO1 mRNA expression in HBEC cells were similar. NQO1 protein expression increased up to 11.8-fold in SFN-treated NHBE cells. Both GSTP1 and NQO1 protein expression in A549 cells were constitutively high but not induced under any condition. Our results suggest that NQO1 is more responsive to the studied chemopreventive agents than GSTP1 in human lung cells and there is discordance between single agent and complex mixture effects. We conclude that modulation of lung cell phase II metabolism by chemopreventive agents requires cell- and agent-specific discovery and testing.

  9. Catalase abrogates β-lapachone-induced PARP1 hyperactivation-directed programmed necrosis in NQO1-positive breast cancers

    PubMed Central

    Bey, Erik A.; Reinicke, Kathryn E.; Srougi, Melissa C.; Varnes, Marie; Anderson, Vernon; Pink, John J.; Li, Long Shan; Patel, Malina; Cao, Lifen; Moore, Zachary; Rommel, Amy; Boatman, Michael; Lewis, Cheryl; Euhus, David M.; Bornmann, William G.; Buchsbaum, Donald J.; Spitz, Douglas R.; Gao, Jinming; Boothman, David A.

    2013-01-01

    Improving patient outcome by personalized therapy involves a thorough understanding of an agent’s mechanism of action. β-Lapachone (clinical forms, Arq501/Arq761) has been developed to exploit dramatic cancer-specific elevations in the phase II detoxifying enzyme, NAD(P)H:quinone oxidoreductase (NQO1). NQO1 is dramatically elevated in solid cancers, including primary and metastatic (e.g., triple-negative (ER-, PR-, Her2/Neu-)) breast cancers. To define cellular factors that influence the efficacy of β-lapachone using knowledge of its mechanism of action, we confirmed that NQO1 was required for lethality and mediated a futile redox cycle where ~120 moles of superoxide were formed per mole of β-lapachone in 5 min. β-Lapachone induced reactive oxygen species (ROS), stimulated DNA single strand break-dependent PARP1 hyperactivation, caused dramatic loss of essential nucleotides (NAD+/ATP) and elicited programmed necrosis in breast cancer cells. While PARP1 hyperactivation and NQO1 expression were major determinants of β-lapachone-induced lethality, alterations in catalase expression, including treatment with exogenous enzyme, caused marked cytoprotection. Thus, catalase is an important resistance factor, and highlights H2O2 as an obligate ROS for cell death from this agent. Exogenous superoxide dismutase (SOD) enhanced catalase-induced cytoprotection. β-Lapachone-induced cell death included AIF translocation from mitochondria to nuclei, TUNEL+ staining, atypical PARP1 cleavage, and GAPDH S-nitrosylation, which were abrogated by catalase. We predict that the ratio of NQO1:catalase activities in breast cancer versus associated normal tissue are likely to be the major determinants affecting the therapeutic window of β-lapachone and other NQO1 bioactivatable drugs. PMID:23883585

  10. Catalase abrogates β-lapachone-induced PARP1 hyperactivation-directed programmed necrosis in NQO1-positive breast cancers.

    PubMed

    Bey, Erik A; Reinicke, Kathryn E; Srougi, Melissa C; Varnes, Marie; Anderson, Vernon E; Pink, John J; Li, Long Shan; Patel, Malina; Cao, Lifen; Moore, Zachary; Rommel, Amy; Boatman, Michael; Lewis, Cheryl; Euhus, David M; Bornmann, William G; Buchsbaum, Donald J; Spitz, Douglas R; Gao, Jinming; Boothman, David A

    2013-10-01

    Improving patient outcome by personalized therapy involves a thorough understanding of an agent's mechanism of action. β-Lapachone (clinical forms, Arq501/Arq761) has been developed to exploit dramatic cancer-specific elevations in the phase II detoxifying enzyme NAD(P)H:quinone oxidoreductase (NQO1). NQO1 is dramatically elevated in solid cancers, including primary and metastatic [e.g., triple-negative (ER-, PR-, Her2/Neu-)] breast cancers. To define cellular factors that influence the efficacy of β-lapachone using knowledge of its mechanism of action, we confirmed that NQO1 was required for lethality and mediated a futile redox cycle where ∼120 moles of superoxide were formed per mole of β-lapachone in 2 minutes. β-Lapachone induced reactive oxygen species (ROS), stimulated DNA single-strand break-dependent poly(ADP-ribose) polymerase-1 (PARP1) hyperactivation, caused dramatic loss of essential nucleotides (NAD(+)/ATP), and elicited programmed necrosis in breast cancer cells. Although PARP1 hyperactivation and NQO1 expression were major determinants of β-lapachone-induced lethality, alterations in catalase expression, including treatment with exogenous enzyme, caused marked cytoprotection. Thus, catalase is an important resistance factor and highlights H2O2 as an obligate ROS for cell death from this agent. Exogenous superoxide dismutase enhanced catalase-induced cytoprotection. β-Lapachone-induced cell death included apoptosis-inducing factor (AIF) translocation from mitochondria to nuclei, TUNEL+ staining, atypical PARP1 cleavage, and glyceraldehyde 3-phosphate dehydrogenase S-nitrosylation, which were abrogated by catalase. We predict that the ratio of NQO1:catalase activities in breast cancer versus associated normal tissue are likely to be the major determinants affecting the therapeutic window of β-lapachone and other NQO1 bioactivatable drugs. ©2013 AACR.

  11. Plasma membrane electron transport in pancreatic β-cells is mediated in part by NQO1

    PubMed Central

    Gray, Joshua P.; Eisen, Timothy; Cline, Gary W.; Smith, Peter J. S.

    2011-01-01

    Plasma membrane electron transport (PMET), a cytosolic/plasma membrane analog of mitochondrial electron transport, is a ubiquitous system of cytosolic and plasma membrane oxidoreductases that oxidizes cytosolic NADH and NADPH and passes electrons to extracellular targets. While PMET has been shown to play an important role in a variety of cell types, no studies exist to evaluate its function in insulin-secreting cells. Here we demonstrate the presence of robust PMET activity in primary islets and clonal β-cells, as assessed by the reduction of the plasma membrane-impermeable dyes WST-1 and ferricyanide. Because the degree of metabolic function of β-cells (reflected by the level of insulin output) increases in a glucose-dependent manner between 4 and 10 mM glucose, PMET was evaluated under these conditions. PMET activity was present at 4 mM glucose and was further stimulated at 10 mM glucose. PMET activity at 10 mM glucose was inhibited by the application of the flavoprotein inhibitor diphenylene iodonium and various antioxidants. Overexpression of cytosolic NAD(P)H-quinone oxidoreductase (NQO1) increased PMET activity in the presence of 10 mM glucose while inhibition of NQO1 by its inhibitor dicoumarol abolished this activity. Mitochondrial inhibitors rotenone, antimycin A, and potassium cyanide elevated PMET activity. Regardless of glucose levels, PMET activity was greatly enhanced by the application of aminooxyacetate, an inhibitor of the malate-aspartate shuttle. We propose a model for the role of PMET as a regulator of glycolytic flux and an important component of the metabolic machinery in β-cells. PMID:21505151

  12. Esterase-activatable β-lapachone prodrug micelles for NQO1-targeted lung cancer therapy

    PubMed Central

    Ma, Xinpeng; Huang, Xiumei; Moore, Zachary; Huang, Gang; Kilgore, Jessica A.; Wang, Yiguang; Hammer, Suntrea; Williams, Noelle S.; Boothman, David A.; Gao, Jinming

    2016-01-01

    Lung cancer is one of the most lethal forms of cancer and current chemotherapeutic strategies lack broad specificity and efficacy. Recently, β-lapachone (β-lap) was shown to be highly efficacious in killing non-small cell lung cancer (NSCLC) cells regardless of their p53, cell cycle and caspase status. Pre-clinical and clinical use of β-lap (clinical form, ARQ501 or 761) is hampered by poor pharmacokinetics and toxicity due to hemolytic anemia. Here, we report the development and preclinical evaluation of β-lap prodrug nanotherapeutics consisting of diester derivatives of β-lap encapsulated in biocompatible and biodegradable poly(ethylene glycol)-b-poly(d,l-lactic acid) (PEG-b-PLA) micelles. Compared to the parent drug, diester derivatives of β-lap showed higher drug loading densities inside PEG-b-PLA micelles. After esterase treatment, micelle-delivered β-lap-dC3 and -dC6 prodrugs were converted to β-lap. Cytotoxicity assays using A549 and H596 lung cancer cells showed that both micelle formulations maintained NAD(P)H:quinone oxidoreductase 1 (NQO1)-dependent cytotoxicity. However, antitumor efficacy study of β-lap-dC3 micelles against orthotopic A549 NSCLC xenograft-bearing mice showed significantly greater long-term survival over β-lap-dC6 micelles or β-lap-HPβCD complexes. Improved therapeutic efficacy of β-lap-dC3 micelles correlated with higher area under the concentration-time curves of β-lap in tumors, and enhanced pharmacodynamic endpoints (e.g., PARP1 hyperactivation, γH2AX, and ATP depletion). β-Lap-dC3 prodrug micelles provide a promising strategy for NQO1-targeted therapy of lung cancer with improved safety and antitumor efficacy. PMID:25542645

  13. The Protein Level of PGC-1α, a Key Metabolic Regulator, Is Controlled by NADH-NQO1

    PubMed Central

    Adamovich, Yaarit; Shlomai, Amir; Tsvetkov, Peter; Umansky, Kfir B.; Reuven, Nina; Estall, Jennifer L.; Spiegelman, Bruce M.

    2013-01-01

    PGC-1α is a key transcription coactivator regulating energy metabolism in a tissue-specific manner. PGC-1α expression is tightly regulated, it is a highly labile protein, and it interacts with various proteins—the known attributes of intrinsically disordered proteins (IDPs). In this study, we characterize PGC-1α as an IDP and demonstrate that it is susceptible to 20S proteasomal degradation by default. We further demonstrate that PGC-1α degradation is inhibited by NQO1, a 20S gatekeeper protein. NQO1 binds and protects PGC-1α from degradation in an NADH-dependent manner. Using different cellular physiological settings, we also demonstrate that NQO1-mediated PGC-1α protection plays an important role in controlling both basal and physiologically induced PGC-1α protein level and activity. Our findings link NQO1, a cellular redox sensor, to the metabolite-sensing network that tunes PGC-1α expression and activity in regulating energy metabolism. PMID:23648480

  14. Augmentation of NAD+ by NQO1 attenuates cisplatin-mediated hearing impairment

    PubMed Central

    Kim, H-J; Oh, G-S; Shen, A; Lee, S-B; Choe, S-K; Kwon, K-B; Lee, S; Seo, K-S; Kwak, T H; Park, R; So, H-S

    2014-01-01

    Cisplatin (cis-diaminedichloroplatinum-II) is an extensively used chemotherapeutic agent, and one of its most adverse effects is ototoxicity. A number of studies have demonstrated that these effects are related to oxidative stress and DNA damage. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. The cofactor nicotinamide adenine dinucleotide (NAD+) has emerged as a key regulator of cellular energy metabolism and homeostasis. Here, we demonstrate for the first time that, in cisplatin-mediated ototoxicity, the levels and activities of SIRT1 are suppressed by the reduction of intracellular NAD+ levels. We provide evidence that the decrease in SIRT1 activity and expression facilitated by increasing poly(ADP-ribose) transferase (PARP)-1 activation and microRNA-34a through p53 activation aggravates cisplatin-mediated ototoxicity. Moreover, we show that the induction of cellular NAD+ levels using β-lapachone (β-Lap), whose intracellular target is NQO1, prevents the toxic effects of cisplatin through the regulation of PARP-1 and SIRT1 activity. These results suggest that direct modulation of cellular NAD+ levels by pharmacological agents could be a promising therapeutic approach for protection from cisplatin-induced ototoxicity. PMID:24922076

  15. Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors.

    PubMed

    Huang, Xiumei; Motea, Edward A; Moore, Zachary R; Yao, Jun; Dong, Ying; Chakrabarti, Gaurab; Kilgore, Jessica A; Silvers, Molly A; Patidar, Praveen L; Cholka, Agnieszka; Fattah, Farjana; Cha, Yoonjeong; Anderson, Glenda G; Kusko, Rebecca; Peyton, Michael; Yan, Jingsheng; Xie, Xian-Jin; Sarode, Venetia; Williams, Noelle S; Minna, John D; Beg, Muhammad; Gerber, David E; Bey, Erik A; Boothman, David A

    2016-12-12

    Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and β-lapachone are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen-consumption-rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1(+) cancers, such as non-small-cell lung, pancreatic, and breast cancers, cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with β-lapachone monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and β-lapachone. Synergistic antitumor efficacy and prolonged survival were noted in human orthotopic pancreatic and non-small-cell lung xenograft models, expanding use and efficacy of PARP inhibitors for human cancer therapy. Published by Elsevier Inc.

  16. Hydrogen sulfide attenuates calcification of vascular smooth muscle cells via KEAP1/NRF2/NQO1 activation.

    PubMed

    Aghagolzadeh, Parisa; Radpour, Ramin; Bachtler, Matthias; van Goor, Harry; Smith, Edward R; Lister, Adam; Odermatt, Alex; Feelisch, Martin; Pasch, Andreas

    2017-10-01

    Vascular calcification is a common health problem related to oxidative stress, inflammation, and circulating calciprotein particles (CPP). Hydrogen sulfide is an endogenous signaling molecule with antioxidant properties and potential for drug development targeting redox signaling. Yet, its molecular mechanisms of action in vascular smooth muscle cell (VSMC) calcification have not been delineated. We therefore sought to identify key pathways involved in the calcification-inhibitory properties of sulfide employing our recently developed CPP-induced VSMC calcification model. Using next-generation sequencing, we investigated the transcriptomic changes of sodium hydrosulfide-treated versus non-treated calcifying VSMCs. The potential role of candidate genes and/or regulatory pathways in prevention of calcification was investigated by small interfering RNA (siRNA). CPP led to a pronounced accumulation of cell-associated calcium, which was decreased by sulfide in a concentration-dependent manner. Both, CPP-induced hydrogen peroxide production and enhanced pro-inflammatory/oxidative stress-related gene expression signatures were attenuated by sulfide-treatment. Gene ontology enrichment and in silico pathway analysis of our transcriptome data suggested NAD(P)H dehydrogenase [quinone] 1 (NQO1) as potential mediator. Corroborating these findings, silencing of Kelch-like ECH-associated protein 1 (KEAP1), an inhibitor of nuclear factor (erythroid-derived 2)-like 2 (NRF2) nuclear activity, enhanced NQO1 expression, whereas NRF2 silencing reduced the expression of NQO1 and abrogated the calcification-suppressing activity of sulfide. Moreover, immunofluorescence microscopy and Western blot analysis confirmed nuclear translocation of NRF2 by sulfide in VSMC. Sulfide attenuates CPP-induced VSMC calcification in vitro via the KEAP1-NRF2 redox sensing/stress response system by enhancing NQO1 expression. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Protective effects of Tat-NQO1 against oxidative stress-induced HT-22 cell damage, and ischemic injury in animals

    PubMed Central

    Jo, Hyo Sang; Kim, Duk-Soo; Ahn, Eun Hee; Kim, Dae Won; Shin, Min Jea; Cho, Su Bin; Park, Jung Hwan; Lee, Chi Hern; Yeo, Eun Ji; Choi, Yeon Joo; Yeo, Hyeon Ji; Chung, Christine Seok Young; Cho, Sung-Woo; Han, Kyu Hyung; Park, Jinseu; Eum, Won Sik; Choi, Soo Young

    2016-01-01

    Oxidative stress is closely associated with various diseases and is considered to be a major factor in ischemia. NAD(P)H: quinone oxidoreductase 1 (NQO1) protein is a known antioxidant protein that plays a protective role in various cells against oxidative stress. We therefore investigated the effects of cell permeable Tat-NQO1 protein on hippocampal HT-22 cells, and in an animal ischemia model. The Tat-NQO1 protein transduced into HT-22 cells, and significantly inhibited against hydrogen peroxide (H2O2)-induced cell death and cellular toxicities. Tat-NQO1 protein inhibited the Akt and mitogen activated protein kinases (MAPK) activation as well as caspase-3 expression levels, in H2O2 exposed HT-22 cells. Moreover, Tat-NQO1 protein transduced into the CA1 region of the hippocampus of the animal brain and drastically protected against ischemic injury. Our results indicate that Tat-NQO1 protein exerts protection against neuronal cell death induced by oxidative stress, suggesting that Tat-NQO1 protein may potentially provide a therapeutic agent for neuronal diseases. PMID:27616357

  18. Mechanistic studies of cancer cell mitochondria- and NQO1-mediated redox activation of beta-lapachone, a potentially novel anticancer agent

    SciTech Connect

    Li, Jason Z.; Ke, Yuebin; Misra, Hara P.; Trush, Michael A.; Li, Y. Robert; Zhu, Hong; Jia, Zhenquan

    2014-12-15

    Beta-lapachone (beta-Lp) derived from the Lapacho tree is a potentially novel anticancer agent currently under clinical trials. Previous studies suggested that redox activation of beta-Lp catalyzed by NAD(P)H:quinone oxidoreductase 1 (NQO1) accounted for its killing of cancer cells. However, the exact mechanisms of this effect remain largely unknown. Using chemiluminescence and electron paramagnetic resonance (EPR) spin-trapping techniques, this study for the first time demonstrated the real-time formation of ROS in the redox activation of beta-lapachone from cancer cells mediated by mitochondria and NQO1 in melanoma B16–F10 and hepatocellular carcinoma HepG2 cancer cells. ES936, a highly selective NQO1 inhibitor, and rotenone, a selective inhibitor of mitochondrial electron transport chain (METC) complex I were found to significantly block beta-Lp meditated redox activation in B16–F10 cells. In HepG2 cells ES936 inhibited beta-Lp-mediated oxygen radical formation by ∼ 80% while rotenone exerted no significant effect. These results revealed the differential contribution of METC and NQO1 to beta-lapachone-induced ROS formation and cancer cell killing. In melanoma B16–F10 cells that do not express high NQO1 activity, both NOQ1 and METC play a critical role in beta-Lp redox activation. In contrast, in hepatocellular carcinoma HepG2 cells expressing extremely high NQO1 activity, redox activation of beta-Lp is primarily mediated by NQO1 (METC plays a minor role). These findings will contribute to our understanding of how cancer cells are selectively killed by beta-lapachone and increase our ability to devise strategies to enhance the anticancer efficacy of this potentially novel drug while minimizing its possible adverse effects on normal cells. - Highlights: • Both isolated mitochondria and purified NQO1 are able to generate ROS by beta-Lp. • The differential roles of mitochondria and NQO1 in mediating redox activation of beta-Lp • In cancer cells with

  19. JNK–NQO1 axis drives TAp73-mediated tumor suppression upon oxidative and proteasomal stress

    PubMed Central

    Kostecka, A; Sznarkowska, A; Meller, K; Acedo, P; Shi, Y; Mohammad Sakil, H A; Kawiak, A; Lion, M; Królicka, A; Wilhelm, M; Inga, A; Zawacka-Pankau, J

    2014-01-01

    Hyperproliferating cancer cells produce energy mainly from aerobic glycolysis, which results in elevated ROS levels. Thus aggressive tumors often possess enhanced anti-oxidant capacity that impedes many current anti-cancer therapies. Additionally, in ROS-compromised cancer cells ubiquitin proteasome system (UPS) is often deregulated for timely removal of oxidized proteins, thus enabling cell survival. Taken that UPS maintains the turnover of factors controlling cell cycle and apoptosis – such as p53 or p73, it represents a promising target for pharmaceutical intervention. Enhancing oxidative insult in already ROS-compromised cancer cells appears as an attractive anti-tumor scenario. TAp73 is a bona fide tumor suppressor that drives the chemosensitivity of some cancers to cisplatin or γ-radiation. It is an important drug target in tumors where p53 is lost or mutated. Here we discovered a novel synergistic mechanism leading to potent p73 activation and cancer cell death by oxidative stress and inhibition of 20S proteasomes. Using a small-molecule inhibitor of 20S proteasome and ROS-inducer – withaferin A (WA), we found that WA-induced ROS activates JNK kinase and stabilizes phase II anti-oxidant response effector NF-E2-related transcription factor (NRF2). This results in activation of Nrf2 target – NQO1 (NADPH quinone oxidoreductase), and TAp73 protein stabilization. The observed effect was ablated by the ROS scavenger – NAC. Concurrently, stress-activated JNK phosphorylates TAp73 at multiple serine and threonine residues, which is crucial to ablate TAp73/MDM2 complex and to promote TAp73 transcriptional function and induction of robust apoptosis. Taken together our data demonstrate that ROS insult in combination with the inhibition of 20S proteasome and TAp73 activation endows synthetic lethality in cancer cells. Thus, our results may enable the establishment of a novel pharmacological strategy to exploit the enhanced sensitivity of tumors to elevated ROS

  20. An NQO1- and PARP-1-mediated cell death pathway induced in non-small-cell lung cancer cells by beta-lapachone.

    PubMed

    Bey, Erik A; Bentle, Melissa S; Reinicke, Kathryn E; Dong, Ying; Yang, Chin-Rang; Girard, Luc; Minna, John D; Bornmann, William G; Gao, Jinming; Boothman, David A

    2007-07-10

    Lung cancer is the number one cause of cancer-related deaths in the world. Patients treated with current chemotherapies for non-small-cell lung cancers (NSCLCs) have a survival rate of approximately 15% after 5 years. Novel approaches are needed to treat this disease. We show elevated NAD(P)H:quinone oxidoreductase-1 (NQO1) levels in tumors from NSCLC patients. beta-Lapachone, an effective chemotherapeutic and radiosensitizing agent, selectively killed NSCLC cells that expressed high levels of NQO1. Isogenic H596 NSCLC cells that lacked or expressed NQO1 along with A549 NSCLC cells treated with or without dicoumarol, were used to elucidate the mechanism of action and optimal therapeutic window of beta-lapachone. NSCLC cells were killed in an NQO1-dependent manner by beta-lapachone (LD50, approximately 4 microM) with a minimum 2-h exposure. Kinetically, beta-lapachone-induced cell death was characterized by the following: (i) dramatic reactive oxygen species (ROS) formation, eliciting extensive DNA damage; (ii) hyperactivation of poly(ADP-ribose)polymerase-1 (PARP-1); (iii) depletion of NAD+/ATP levels; and (iv) proteolytic cleavage of p53/PARP-1, indicating mu-calpain activation and apoptosis. Beta-lapachone-induced PARP-1 hyperactivation, nucleotide depletion, and apoptosis were blocked by 3-aminobenzamide, a PARP-1 inhibitor, and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM), a Ca2+ chelator. NQO1- cells (H596, IMR-90) or dicoumarol-exposed NQO1+ A549 cells were resistant (LD50, >40 microM) to ROS formation and all cytotoxic effects of beta-lapachone. Our data indicate that the most efficacious strategy using beta-lapachone in chemotherapy was to deliver the drug in short pulses, greatly reducing cytotoxicity to NQO1- "normal" cells. beta-Lapachone killed cells in a tumorselective manner and is indicated for use against NQO1+ NSCLC cancers.

  1. Novel high throughput pooled shRNA screening identifies NQO1 as a potential drug target for host directed therapy for tuberculosis

    PubMed Central

    Li, Qing; Karim, Ahmad F.; Ding, Xuedong; Das, Biswajit; Dobrowolski, Curtis; Gibson, Richard M.; Quiñones-Mateu, Miguel E.; Karn, Jonathan; Rojas, Roxana E.

    2016-01-01

    Chemical regulation of macrophage function is one key strategy for developing host-directed adjuvant therapies for tuberculosis (TB). A critical step to develop these therapies is the identification and characterization of specific macrophage molecules and pathways with a high potential to serve as drug targets. Using a barcoded lentivirus-based pooled short-hairpin RNA (shRNA) library combined with next generation sequencing, we identified 205 silenced host genes highly enriched in mycobacteria-resistant macrophages. Twenty-one of these “hits” belonged to the oxidoreductase functional category. NAD(P)H:quinone oxidoreductase 1 (NQO1) was the top oxidoreductase “hit”. NQO1 expression was increased after mycobacterial infection, and NQO1 knockdown increased macrophage differentiation, NF-κB activation, and the secretion of pro-inflammatory cytokines TNF-α and IL-1β in response to infection. This suggests that mycobacteria hijacks NQO1 to down-regulate pro-inflammatory and anti-bacterial functions. The competitive inhibitor of NQO1 dicoumarol synergized with rifampin to promote intracellular killing of mycobacteria. Thus, NQO1 is a new host target in mycobacterial infection that could potentially be exploited to increase antibiotic efficacy in vivo. Our findings also suggest that pooled shRNA libraries could be valuable tools for genome-wide screening in the search for novel druggable host targets for adjunctive TB therapies. PMID:27297123

  2. Neophobia, NQO1 and SIRT1 as premorbid and prodromal indicators of AD in 3xTg-AD mice.

    PubMed

    Torres-Lista, Virginia; Parrado-Fernández, Cristina; Alvarez-Montón, Ismael; Frontiñán-Rubio, Javier; Durán-Prado, Mario; Peinado, Juan Ramón; Johansson, Björn; Alcaín, Francisco Javier; Giménez-Llort, Lydia

    2014-09-01

    Increased oxidative stress seems to be a key factor underlying natural processes of aging, but also to occur prior to neuropathological hallmarks of neurodegenerative diseases. The present work studied the temporal variation of three key antioxidant enzymes in cortex and hippocampus during the development of behavioral and cognitive symptoms in 3xTg-AD mice, and as compared to age-matched controls. At 2 months of age, when no intraneuronal Aβ immunoreactivity has been reported, increased neophobia shown as a delayed and reduced rearing, evidenced the onset of BPSD-like symptoms at premorbid stages of disease. In these animals, NQO1 was found increased in both the hippocampus (800%) and cortex (400%) and progressively diminished at older ages. SOD1 was increased in the hippocampus at 4 months of age, when neuronal Aβ accumulation has been established. These hippocampal increases of antioxidants before the prodromal emergence of cognitive symptoms support their role as defense mechanisms. SIRT1 levels showed opposite age-dependent changes in cortex (increase) and hippocampus (decrease) relative to controls. Prodromal cognitive deficits emerged at 6 months of age, concomitantly to cortical overexpression of SIRT1 but down-regulation of NQO1 and SIRT1 in the hippocampus, suggesting inadequate antioxidative protection to prevent or delay the subjacent neuronal damage. The present data further support the link between oxidative status and the anxious profile. Their crosstalk may underline AD-pathological mechanisms that may lead to deranged physiology and selective neuronal degeneration. It also points out increased neophobia and high expression of NQO1 among the first indicators of disease in the 3xTg-AD mice. Copyright © 2014. Published by Elsevier B.V.

  3. 2-Substituted 3-methylnaphtho[1,2-b]furan-4,5-diones as novel L-shaped ortho-quinone substrates for NAD(P)H:quinone oxidoreductase (NQO1).

    PubMed

    Bian, Jinlei; Deng, Bang; Xu, Lili; Xu, Xiaoli; Wang, Nan; Hu, Tianhan; Yao, Zeyu; Du, Jianyao; Yang, Li; Lei, Yonghua; Li, Xiang; Sun, Haopeng; Zhang, Xiaojin; You, Qidong

    2014-07-23

    A series of L-shaped ortho-quinone analogs were designed by analyzing the binding mode with NQO1. Metabolic studies demonstrated that compounds 2m, 2n and 2q exhibited higher metabolic rates than β-lapachone. The docking studies, which supported the rationalization of the metabolic studies, constituted a prospective rational basis for the development of optimized ortho-quinone analogs. Besides, good substrates (2m, 2n and 2r) for NQO1 showed higher selective toxicity than β-lapachone toward A549 (NQO1-rich) cancer cells versus H596 (NQO1-deficient) cells. Determination of superoxide (O2(•-)) production and in vitro cytotoxicity evaluation in the presence of the NQO1 inhibitor dicoumarol confirmed that the ortho-quinones exerted their antitumor activity through NQO1-mediated ROS production by redox cycling. It was suggested that the L-shaped quinone substrates for NQO1 possessed better specificity and safety than β-lapachone.

  4. Dual effects of N-acetyl-L-cysteine dependent on NQO1 activity: Suppressive or promotive of 9,10-phenanthrenequinone-induced toxicity

    SciTech Connect

    Toyooka, Tatsushi; Shinmen, Takuya; Aarts, Jac M.M.J.G.; Ibuki, Yuko

    2012-11-01

    A typical antioxidant, N-acetyl-L-cysteine (NAC) generally protects cells from oxidative damage induced by reactive oxygen species (ROS). 9,10-Phenanthrenequinone (9,10-PQ), a major quinone in diesel exhaust particles, produces ROS in redox cycling following two-electron reduction by NAD(P)H:quinone oxidoreductase 1 (NQO1), which has been considered as a cause of its cyto- and genotoxicity. In this study, we show that NAC unexpectedly augments the toxicity of 9,10-PQ in cells with low NQO1 activity. In four human skin cell lines, the expression and the activity of NQO1 were lower than in human adenocarcinoma cell lines, A549 and MCF7. In the skin cells, the cytotoxicity of 9,10-PQ was significantly enhanced by addition of NAC. The formation of DNA double strand breaks accompanying phosphorylation of histone H2AX, was also remarkably augmented. On the other hand, the cyto- and genotoxicity were suppressed by addition of NAC in the adenocarcinoma cells. Two contrasting experiments: overexpression of NQO1 in CHO-K1 cells which originally expressed low NQO1 levels, and knock‐down of NQO1 in the adenocarcinoma cell line A549 by transfection of RNAi, also showed that NAC suppressed 9,10-PQ-induced toxicity in cell lines expressing high NQO1 activity and enhanced it in cell lines with low NQO1 activity. The results suggested that dual effects of NAC on the cyto- and genotoxicity of 9,10-PQ were dependent on tissue-specific NQO1 activity. -- Highlights: ► NAC augmented the cytotoxicity of 9,10-PQ in skin cell lines. ► 9,10-PQ-induced DSBs accompanying γ-H2AX were also augmented by NAC. ► NAC suppressed the cyto- and genotoxicity of 9,10-PQ in adenocarcinoma cell lines. ► The dual effects of NAC on toxicity of 9,10-PQ were dependent on NQO1 activity.

  5. Candidate Dietary Phytochemicals Modulate Expression of Phase II Enzymes GSTP1 and NQO1 in Human Lung Cells1–3

    PubMed Central

    Tan, Xiang-Lin; Shi, Miao; Tang, Hui; Han, Weiguo; Spivack, Simon D.

    2010-01-01

    Many phytochemicals possess cancer-preventive properties, some putatively through phase II metabolism-mediated mutagen/oxidant quenching. We applied human lung cells in vitro to investigate the effects of several candidate phytopreventive agents, including green tea extracts (GTE), broccoli sprout extracts (BSE), epigallocatechin gallate (EGCG), sulforaphane (SFN), phenethyl isothiocyanate (PEITC), and benzyl isothiocyanate (BITC), on inducing phase II enzymes glutathione S-transferase P1 (GSTP1) and NAD(P)H:quinone oxidoreductase 1 (NQO1) at mRNA and protein levels. Primary normal human bronchial epithelial cells (NHBE), immortalized human bronchial epithelial cells (HBEC), and lung adenocarcinoma cells (A549) were exposed to diet-achievable levels of GTE and BSE (0.5, 1.0, 2.0 mg/L), or individual index components EGCG, SFN, PEITC, BITC (0.5, 1.0, 2.0 μmol/L) for 24 h, 48 h, and 6 d, respectively. mRNA assays employed RNA-specific quantitative RT-PCR and protein assays employed Western blotting. We found that in NHBE cells, while GSTP1 mRNA levels were slightly but significantly increased after exposure to GTE or BSE, NQO1 mRNA increased to 2- to 4-fold that of control when exposed to GTE, BSE, or SFN. Effects on NQO1 mRNA expression in HBEC cells were similar. NQO1 protein expression increased up to 11.8-fold in SFN-treated NHBE cells. Both GSTP1 and NQO1 protein expression in A549 cells were constitutively high but not induced under any condition. Our results suggest that NQO1 is more responsive to the studied chemopreventive agents than GSTP1 in human lung cells and there is discordance between single agent and complex mixture effects. We conclude that modulation of lung cell phase II metabolism by chemopreventive agents requires cell- and agent-specific discovery and testing. PMID:20554899

  6. Increased Cellular NAD+ Level through NQO1 Enzymatic Action Has Protective Effects on Bleomycin-Induced Lung Fibrosis in Mice

    PubMed Central

    Oh, Gi-Su; Lee, Su-Bin; Karna, Anjani; Kim, Hyung-Jin; Shen, AiHua; Pandit, Arpana; Lee, SeungHoon

    2016-01-01

    Background Idiopathic pulmonary fibrosis is a common interstitial lung disease; it is a chronic, progressive, and fatal lung disease of unknown etiology. Over the last two decades, knowledge about the underlying mechanisms of pulmonary fibrosis has improved markedly and facilitated the identification of potential targets for novel therapies. However, despite the large number of antifibrotic drugs being described in experimental pre-clinical studies, the translation of these findings into clinical practices has not been accomplished yet. NADH:quinone oxidoreductase 1 (NQO1) is a homodimeric enzyme that catalyzes the oxidation of NADH to NAD+ by various quinones and thereby elevates the intracellular NAD+ levels. In this study, we examined the effect of increase in cellular NAD+ levels on bleomycin-induced lung fibrosis in mice. Methods C57BL/6 mice were treated with intratracheal instillation of bleomycin. The mice were orally administered with β-lapachone from 3 days before exposure to bleomycin to 1-3 weeks after exposure to bleomycin. Bronchoalveolar lavage fluid (BALF) was collected for analyzing the infiltration of immune cells. In vitro, A549 cells were treated with transforming growth factor β1 (TGF-β1) and β-lapachone to analyze the extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT). Results β-Lapachone strongly attenuated bleomycin-induced lung inflammation and fibrosis, characterized by histological staining, infiltrated immune cells in BALF, inflammatory cytokines, fibrotic score, and TGF-β1, α-smooth muscle actin accumulation. In addition, β-lapachone showed a protective role in TGF-β1–induced ECM expression and EMT in A549 cells. Conclusion Our results suggest that β-lapachone can protect against bleomycin-induced lung inflammation and fibrosis in mice and TGF-β1–induced EMT in vitro, by elevating the NAD+/NADH ratio through NQO1 activation. PMID:27790277

  7. Effect of NQO1 and CYP4F2 genotypes on warfarin dose requirements in Hispanic–Americans and African–Americans

    PubMed Central

    Bress, Adam; Patel, Shitalben R; Perera, Minoli A; Campbell, Richard T; Kittles, Rick A; Cavallari, Larisa H

    2013-01-01

    Aim The objective of this study was to determine the additional contribution of NQO1 and CYP4F2 genotypes to warfarin dose requirements across two racial groups after accounting for known clinical and genetic predictors. Patients & methods The following were assessed in a cohort of 260 African–Americans and 53 Hispanic–Americans: clinical data; NQO1 p.P187S (*1/*2); CYP2C9*2, *3, *5, *6, *8 and *11; CYP4F2 p.V433M; and VKORC1 c.-1639G>A genotypes. Results Both the CYP4F2 433M (0.23 vs 0.06; p < 0.05) and NQO1*2 (0.27 vs. 0.18; p < 0.05) allele frequencies were higher in Hispanic–Americans compared with African–Americans. Multiple regression analysis in the Hispanic–American cohort revealed that each CYP4F2 433M allele was associated with a 22% increase in warfarin maintenance dose (p = 0.019). Possession of the NQO1*2 allele was associated with a 34% increase in warfarin maintenance dose (p = 0.004), while adjusting for associated genetic (CYP2C9, CYP4F2 and VKORC1) and clinical factors. In this population, the inclusion of CYP4F2 and NQO1*2 genotypes improved the dose variability explained by the model from 0.58 to 0.68 (p = 0.001), a 17% relative improvement. By contrast, there was no association between CYP4F2 or NQO1*2 genotype and therapeutic warfarin dose in African–Americans after adjusting for known genetic and clinical predictors. Conclusion In our cohort of inner-city Hispanic–Americans, the CYP4F2 and NQO1*2 genotypes significantly contributed to warfarin dose requirements. If our findings are confirmed, they would suggest that inclusion of the CYP4F2 and NQO1*2 genotypes in warfarin dose prediction algorithms may improve the predictive ability of such algorithms in Hispanic–Americans. PMID:23215885

  8. Effect of NQO1 and CYP4F2 genotypes on warfarin dose requirements in Hispanic-Americans and African-Americans.

    PubMed

    Bress, Adam; Patel, Shitalben R; Perera, Minoli A; Campbell, Richard T; Kittles, Rick A; Cavallari, Larisa H

    2012-12-01

    The objective of this study was to determine the additional contribution of NQO1 and CYP4F2 genotypes to warfarin dose requirements across two racial groups after accounting for known clinical and genetic predictors. The following were assessed in a cohort of 260 African-Americans and 53 Hispanic-Americans: clinical data; NQO1 p.P187S (*1/*2); CYP2C9*2, *3, *5, *6, *8 and *11; CYP4F2 p.V433M; and VKORC1 c.-1639G>A genotypes. Both the CYP4F2 433M (0.23 vs 0.06; p < 0.05) and NQO1*2 (0.27 vs 0.18; p < 0.05) allele frequencies were higher in Hispanic-Americans compared with African-Americans. Multiple regression analysis in the Hispanic-American cohort revealed that each CYP4F2 433M allele was associated with a 22% increase in warfarin maintenance dose (p = 0.019). Possession of the NQO1*2 allele was associated with a 34% increase in warfarin maintenance dose (p = 0.004), while adjusting for associated genetic (CYP2C9, CYP4F2 and VKORC1) and clinical factors. In this population, the inclusion of CYP4F2 and NQO1*2 genotypes improved the dose variability explained by the model from 0.58 to 0.68 (p = 0.001), a 17% relative improvement. By contrast, there was no association between CYP4F2 or NQO1*2 genotype and therapeutic warfarin dose in African-Americans after adjusting for known genetic and clinical predictors. In our cohort of inner-city Hispanic-Americans, the CYP4F2 and NQO1*2 genotypes significantly contributed to warfarin dose requirements. If our findings are confirmed, they would suggest that inclusion of the CYP4F2 and NQO1*2 genotypes in warfarin dose prediction algorithms may improve the predictive ability of such algorithms in Hispanic-Americans.

  9. An NQO1- and PARP-1-mediated cell death pathway induced in non-small-cell lung cancer cells by β-lapachone

    PubMed Central

    Bey, Erik A.; Bentle, Melissa S.; Reinicke, Kathryn E.; Dong, Ying; Yang, Chin-Rang; Girard, Luc; Minna, John D.; Bornmann, William G.; Gao, Jinming; Boothman, David A.

    2007-01-01

    Lung cancer is the number one cause of cancer-related deaths in the world. Patients treated with current chemotherapies for non-small-cell lung cancers (NSCLCs) have a survival rate of ≈15% after 5 years. Novel approaches are needed to treat this disease. We show elevated NAD(P)H:quinone oxidoreductase-1 (NQO1) levels in tumors from NSCLC patients. β-Lapachone, an effective chemotherapeutic and radiosensitizing agent, selectively killed NSCLC cells that expressed high levels of NQO1. Isogenic H596 NSCLC cells that lacked or expressed NQO1 along with A549 NSCLC cells treated with or without dicoumarol, were used to elucidate the mechanism of action and optimal therapeutic window of β-lapachone. NSCLC cells were killed in an NQO1-dependent manner by β-lapachone (LD50, ≈4 μM) with a minimum 2-h exposure. Kinetically, β-lapachone-induced cell death was characterized by the following: (i) dramatic reactive oxygen species (ROS) formation, eliciting extensive DNA damage; (ii) hyperactivation of poly(ADP-ribose)polymerase-1 (PARP-1); (iii) depletion of NAD+/ATP levels; and (iv) proteolytic cleavage of p53/PARP-1, indicating μ-calpain activation and apoptosis. β-Lapachone-induced PARP-1 hyperactivation, nucleotide depletion, and apoptosis were blocked by 3-aminobenzamide, a PARP-1 inhibitor, and 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid acetoxymethyl ester (BAPTA-AM), a Ca2+ chelator. NQO1− cells (H596, IMR-90) or dicoumarol-exposed NQO1+ A549 cells were resistant (LD50, >40 μM) to ROS formation and all cytotoxic effects of β-lapachone. Our data indicate that the most efficacious strategy using β-lapachone in chemotherapy was to deliver the drug in short pulses, greatly reducing cytotoxicity to NQO1− “normal” cells. β-Lapachone killed cells in a tumorselective manner and is indicated for use against NQO1+ NSCLC cancers. PMID:17609380

  10. Protection of chlorophyllin against oxidative damage by inducing HO-1 and NQO1 expression mediated by PI3K/Akt and Nrf2.

    PubMed

    Zhang, Yanlin; Guan, Li; Wang, Xifu; Wen, Tao; Xing, Junjie; Zhao, Jinyuan

    2008-04-01

    Green vegetables are thought to have a chemoprotective effect on the basis of epidemiologic evidence. This study investigated whether chlorophyllin (CHL) could induce antioxidant enzymes and confer protection against oxidative damage. The results showed that CHL could induce HO-1 and NQO1 expression in human umbilical vein endothelial cell (HUVEC) in a time- and dose-dependent manner and protect them against hydrogen peroxide caused oxidative damage. The induction of HO-1 and NQO1 by CHL was accompanied with the accumulation of transcription factor Nrf2 in nucleus and the activation of PI3K/Akt signalling pathway. Additionally, the specific inhibitor of PI3K/Akt could obviously decrease not only the induced expression of HO-1 and NQO1 but also the antioxidant effect of CHL. In conclusion, this study proved that CHL exerts antioxidant effect by inducing HO-1 and NQO1 expression mediated by PI3K/Akt and Nrf2. One thinks CHL may have promise to be prophylactic pharmaceuticals without adverse effects.

  11. Tumor-selective use of DNA base excision repair inhibition in pancreatic cancer using the NQO1 bioactivatable drug, β-lapachone

    PubMed Central

    Chakrabarti, Gaurab; Silvers, Molly A.; Ilcheva, Mariya; Liu, Yuliang; Moore, Zachary R.; Luo, Xiuquan; Gao, Jinming; Anderson, Glenda; Liu, Lili; Sarode, Venetia; Gerber, David E.; Burma, Sandeep; DeBerardinis, Ralph J.; Gerson, Stanton L.; Boothman, David A.

    2015-01-01

    Base excision repair (BER) is an essential pathway for pancreatic ductal adenocarcinoma (PDA) survival. Attempts to target this repair pathway have failed due to lack of tumor-selectivity and very limited efficacy. The NAD(P)H:Quinone Oxidoreductase 1 (NQO1) bioactivatable drug, ß-lapachone (ARQ761 in clinical form), can provide tumor-selective and enhanced synergy with BER inhibition. ß-Lapachone undergoes NQO1-dependent futile redox cycling, generating massive intracellular hydrogen peroxide levels and oxidative DNA lesions that stimulate poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation. Rapid NAD+/ATP depletion and programmed necrosis results. To identify BER modulators essential for repair of ß-lapachone-induced DNA base damage, a focused synthetic lethal RNAi screen demonstrated that silencing the BER scaffolding protein, XRCC1, sensitized PDA cells. In contrast, depleting OGG1 N-glycosylase spared cells from ß-lap-induced lethality and blunted PARP1 hyperactivation. Combining ß-lapachone with XRCC1 knockdown or methoxyamine (MeOX), an apyrimidinic/apurinic (AP)-modifying agent, led to NQO1-dependent synergistic killing in PDA, NSCLC, breast and head and neck cancers. OGG1 knockdown, dicoumarol-treatment or NQO1- cancer cells were spared. MeOX + ß-lapachone exposure resulted in elevated DNA double-strand breaks, PARP1 hyperactivation and TUNEL+ programmed necrosis. Combination treatment caused dramatic antitumor activity, enhanced PARP1-hyperactivation in tumor tissue, and improved survival of mice bearing MiaPaca2-derived xenografts, with 33% apparent cures. Significance: Targeting base excision repair (BER) alone has limited therapeutic potential for pancreatic or other cancers due to a general lack of tumor-selectivity. Here, we present a treatment strategy that makes BER inhibition tumor-selective and NQO1-dependent for therapy of most solid neoplasms, particularly for pancreatic cancer. PMID:26602448

  12. NAD(P)H-dependent quinone oxidoreductase 1 (NQO1) and cytochrome P450 oxidoreductase (CYP450OR) differentially regulate menadione-mediated alterations in redox status, survival and metabolism in pancreatic β-cells.

    PubMed

    Gray, Joshua P; Karandrea, Shpetim; Burgos, Delaine Zayasbazan; Jaiswal, Anil A; Heart, Emma A

    2016-11-16

    NQO1 (NAD(P)H-quinone oxidoreductase 1) reduces quinones and xenobiotics to less-reactive compounds via 2-electron reduction, one feature responsible for the role of NQO1 in antioxidant defense in several tissues. In contrast, NADPH cytochrome P450 oxidoreductase (CYP450OR), catalyzes the 1-electron reduction of quinones and xenobiotics, resulting in enhanced superoxide formation. However, to date, the roles of NQO1 and CYP450OR in pancreatic β-cell metabolism under basal conditions and oxidant challenge have not been characterized. Using NQO1 inhibition, over-expression and knock out, we have demonstrated that, in addition to protection of β-cells from toxic concentrations of the redox cycling quinone menadione, NQO1 also regulates the basal level of reduced-to-oxidized nucleotides, suggesting other role(s) beside that of an antioxidant enzyme. In contrast, over-expression of NADPH cytochrome P450 oxidoreductase (CYP450OR) resulted in enhanced redox cycling activity and decreased cellular viability, consistent with the enhanced generation of superoxide and H2O2. Basal expression of NQO1 and CYP450OR was comparable in isolated islets and liver. However, NQO1, but not CYP450OR, was strongly induced in β-cells exposed to menadione. NQO1 and CYP450OR exhibited a reciprocal preference for reducing equivalents in β-cells: while CYP450OR preferentially utilized NADPH, NQO1 primarily utilized NADH. Together, these results demonstrate that NQO1 and CYP450OR reciprocally regulate oxidant metabolism in pancreatic β-cells.

  13. Microarray-based detection of CYP1A1, CYP2C9, CYP2C19, CYP2D6, GSTT1, GSTM1, MTHFR, MTRR, NQO1, NAT2, HLA-DQA1, and AB0 allele frequencies in native Russians.

    PubMed

    Gra, Olga; Mityaeva, Olga; Berdichevets, Iryna; Kozhekbaeva, Zhanna; Fesenko, Denis; Kurbatova, Olga; Goldenkova-Pavlova, Irina; Nasedkina, Tatyana

    2010-06-01

    Xenobiotic-metabolizing genes (e.g., Cytochromes P450, GST, NAT2, and NQO1), folate metabolism genes (e.g., MTHFR and MTRR), and major histocompatibility complex genes (e.g., HLA-DQA1) play multiple roles in the organism functioning. In addition, AB0 is the most clinically significant high-polymorphic gene in transfusion and transplantation medicine. Epidemiological data show that allele frequencies of these genes exhibit ethnic and geographic diversity. Besides, little is known about frequency distribution of the major polymorphic variants in native Russians. We developed biological microchips that allow us to analyze a spectrum of allelic variants in 12 different genes: CYP1A1, CYP2D6, CYP2C9, CYP2C19, GSTT1, GSTM1, MTHFR, MTRR, NQO1, NAT2, HLA-DQA1, and AB0. Using this composite methodological platform we have studied 352 DNA samples from healthy native Russian volunteers. The allelic frequencies of gene polymorphisms obtained are close to allelic frequencies observed in some European populations, as published earlier. These data were used in comparative studies to determine predisposition to tuberculosis, lymphoma, and leukemia in adults and to childhood acute leukemia. The HLA-DQA1 and AB0 allele frequencies were used to estimate forensic population parameters for these loci.

  14. Induction of NAD(P)H:quinone oxidoreductase 1 (NQO1) by Glycyrrhiza species used for women's health: differential effects of the Michael acceptors isoliquiritigenin and licochalcone A

    PubMed Central

    Hajirahimkhan, Atieh; Simmler, Charlotte; Dong, Huali; Lantvit, Daniel D.; Li, Guannan; Chen, Shao-Nong; Nikolić, Dejan; Pauli, Guido F.; van Breemen, Richard B.; Dietz, Birgit M.; Bolton, Judy L.

    2016-01-01

    For the alleviation of menopausal symptoms, women frequently turn to botanical dietary supplements, such as licorice and hops. In addition to estrogenic properties, these botanicals could also have chemopreventive effects. We have previously shown that hops and its Michael acceptor xanthohumol (XH) induced the chemoprevention enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1), in vitro and in vivo. Licorice species could also induce NQO1, as they contain the Michael acceptors isoliquiritigenin (LigC) found in Glycyrrhiza glabra (GG), G. uralensis (GU), and G. inflata (GI) and licochalcone A (LicA) which is only found in GI. These licorice species and hops induced NQO1 activity in murine hepatoma (Hepa1c1c7) cells; hops >> GI > GG ≅ GU. Similar to the known chemopreventive compounds curcumin (turmeric), sulforaphane (broccoli), and XH, LigC and LicA were active dose-dependently; sulforaphane >> XH > LigC > LicA ≅ curcumin >> LigF. Induction of the antioxidant response element-luciferase in human hepatoma (Hep-G2-ARE-C8) cells suggested involvement of the Keap1-Nrf2 pathway. GG, GU, and LigC also induced NQO1 in non-tumorigenic breast epithelial MCF-10A cells. In female Sprague-Dawley rats treated with GG and GU, LigC and LigF were detected in the liver and mammary gland. GG weakly enhanced NQO1 activity in the mammary tissue but not in the liver. Treatment with LigC alone did not induce NQO1 in vivo most likely due to its conversion to LigF, extensive metabolism, and its low bioavailability in vivo. These data show the chemopreventive potential of licorice species in vitro could be due to LigC and LicA and emphasize the importance of chemical and biological standardization of botanicals used as dietary supplements. Although the in vivo effects in the rat model after four day treatment are minimal, it must be emphasized that menopausal women take these supplements for extended periods of time and long-term beneficial effects are quite possible. PMID:26473469

  15. Short-term Exposure to 50-Hz Electromagnetic Field and Alterations in NQO1 and NQO2 Expression in MCF-7 Cells

    PubMed Central

    Mahmoudinasab, Hamideh; Saadat, Mostafa

    2016-01-01

    AIM: Extremely low-frequency electromagnetic fields (ELF-EMFs) have some genotoxic effects and it may alter the mRNA levels of antioxidant genes. The NAD(P)H: quinone oxidoreductase-1 (NQO1) and NQO2 are ubiquitously expressed. Considering that there is no published data on the effect(s) of ELF-EMF (50-Hz) exposure and expression levels of NQO1 and NQO2 in the human MCF-7 cells, the present study was carried out. METHODS: The ELF-EMF (0.25 and 0.50 mT) exposure patterns were: 5 min field-on/5 min filed-off, 15 min field-on/15 min field-off, and 30 min field-on continuously. In all exposure conditions, total exposure time were 30 minutes. The RNA extraction was done at two times; immediately post exposure and two hours post exposure. The effect of ELF-EMF on gene expression was assessed by real-time PCR. RESULTS: The NQO1 mRNA level (at 0h) decreased in the cells exposed to 5 min field-on/5 min filed-off condition at 0.25 mT EMF when compared with the unexposed cells. The NQO2 mRNA level (at 0h and 2h) increased in the cells exposed to 5 min field-on/5 min filed-off condition at 0.50 mT EMF when compared with the unexposed cells. CONCLUSIONS: Alterations in the NQO1 and NQO2 mRNA levels seem at the “5 min field-on/5 min field-off” condition. PMID:28028389

  16. De-novo NAD+ synthesis regulates SIRT1-FOXO1 apoptotic pathway in response to NQO1 substrates in lung cancer cells

    PubMed Central

    Cheng, Xuefang; Li, Qingran; Liu, Fang; Ye, Hui; Zhao, Min; Wang, Hong; Wang, Guangji; Hao, Haiping

    2016-01-01

    Tryptophan metabolism is essential in diverse kinds of tumors via regulating tumor immunology. However, the direct role of tryptophan metabolism and its signaling pathway in cancer cells remain largely elusive. Here, we establish a mechanistic link from L-type amino acid transporter 1 (LAT1) mediated transport of tryptophan and the subsequent de-novo NAD+ synthesis to SIRT1-FOXO1 regulated apoptotic signaling in A549 cells in response to NQO1 activation. In response to NQO1 activation, SIRT1 is repressed leading to the increased cellular accumulation of acetylated FOXO1 that transcriptionally activates apoptotic signaling. Decreased uptake of tryptophan due to the downregulation of LAT1 coordinates with PARP-1 hyperactivation to induce rapid depletion of NAD+ pool. Particularly, the LAT1-NAD+-SIRT1 signaling is activated in tumor tissues of patients with non-small cell lung cancer. Because NQO1 activation is characterized with oxidative challenge induced DNA damage, these results suggest that LAT1 and de-novo NAD+ synthesis in NSCLC cells may play essential roles in sensing excessive oxidative stress. PMID:27566573

  17. Novel naphtho[2,1-d]oxazole-4,5-diones as NQO1 substrates with improved aqueous solubility: Design, synthesis, and in vivo antitumor evaluation.

    PubMed

    Li, Xiang; Bian, Jinlei; Wang, Nan; Qian, Xue; Gu, Jing; Mu, Tong; Fan, Jun; Yang, Xiuwen; Li, Shangzhen; Yang, Tingting; Sun, Haopeng; You, Qidong; Zhang, Xiaojin

    2016-03-01

    A new series of ortho-naphthoquinone analogs of β-lapachone were designed, synthesized and evaluated. The biological results indicated that most of our compounds were efficient substrates for NQO1. The new scaffold with water-soluble side chain resulted in greater solubility under acidic condition compared to β-lapachone. Thus avoiding the use of hydroxylpropyl β-cyclodextrin which would finally cause the rapid drug clearance from the blood and dose-limiting toxicity in the form of hemolytic anemia. The most soluble and promising compound in this series was 2-((4-benzylpiperazin-1-yl)methyl)naphtho[2,1-d]oxazole-4,5-dione (3k), which inhibited cancer cell (NQO1-rich A549 cell line) growth at IC50 values of 4.6±1.0μmol·L(-1). Furthermore, compound 3k had in vivo antitumor activity in an A549 tumor xenografts mouse model comparable to the activity obtained with β-lapachone. The results indicated that these ortho-naphthoquinones could serve as promising leads for further optimization as novel substrates for NQO1. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. An NAD(P)H:quinone oxidoreductase 1 (NQO1) enzyme responsive nanocarrier based on mesoporous silica nanoparticles for tumor targeted drug delivery in vitro and in vivo

    NASA Astrophysics Data System (ADS)

    Gayam, Srivardhan Reddy; Venkatesan, Parthiban; Sung, Yi-Ming; Sung, Shuo-Yuan; Hu, Shang-Hsiu; Hsu, Hsin-Yun; Wu, Shu-Pao

    2016-06-01

    The synthesis and characterization of an NAD(P)H:quinone oxidoreductase 1 (NQO1) enzyme responsive nanocarrier based on mesoporous silica nanoparticles (MSNPs) for on-command delivery applications has been described in this paper. Gatekeeping of MSNPs is achieved by the integration of mechanically interlocked rotaxane nanovalves on the surface of MSNPs. The rotaxane nanovalve system is composed of a linear stalk anchoring on the surface of MSNPs, an α-cyclodextrin ring that encircles it and locks the payload ``cargo'' molecules in the mesopores, and a benzoquinone stopper incorporated at the end of the stalk. The gate opening and controlled release of the cargo are triggered by cleavage of the benzoquinone stopper using an endogenous NQO1 enzyme. In addition to having efficient drug loading and controlled release mechanisms, this smart biocompatible carrier system showed obvious uptake and consequent release of the drug in tumor cells, could selectively induce the tumor cell death and enhance the capability of inhibition of tumor growth in vivo. The controlled drug delivery system demonstrated its use as a potential theranostic material.The synthesis and characterization of an NAD(P)H:quinone oxidoreductase 1 (NQO1) enzyme responsive nanocarrier based on mesoporous silica nanoparticles (MSNPs) for on-command delivery applications has been described in this paper. Gatekeeping of MSNPs is achieved by the integration of mechanically interlocked rotaxane nanovalves on the surface of MSNPs. The rotaxane nanovalve system is composed of a linear stalk anchoring on the surface of MSNPs, an α-cyclodextrin ring that encircles it and locks the payload ``cargo'' molecules in the mesopores, and a benzoquinone stopper incorporated at the end of the stalk. The gate opening and controlled release of the cargo are triggered by cleavage of the benzoquinone stopper using an endogenous NQO1 enzyme. In addition to having efficient drug loading and controlled release mechanisms, this

  19. Urinary isothiocyanate excretion, brassica consumption, and gene polymorphisms among women living in Shanghai, China.

    PubMed

    Fowke, Jay H; Shu, Xiao-Ou; Dai, Qi; Shintani, Ayumi; Conaway, C Clifford; Chung, Fung-Lung; Cai, Qiuyin; Gao, Yu-Tang; Zheng, Wei

    2003-12-01

    Alternative measures of Brassica vegetable consumption (e.g., cabbage) may clarify the association between Brassica and cancer risk. Brassica isothiocyanates (ITCs) are excreted in urine and may provide a sensitive and food-specific dietary biomarker. However, the persistence of ITCs in the body may be brief and dependent on the activity of several Phase II enzymes, raising questions about the relationship between a single ITC measure and habitual dietary patterns. This study investigates the association between urinary ITC excretion and habitual Brassica consumption, estimated by a food frequency questionnaire, among healthy Chinese women enrolled in the Shanghai Breast Cancer Study. Participants (n = 347) completed a validated food frequency questionnaire querying habitual dietary intake during the prior 5 years and provided a fasting first-morning urine specimen. Genetic deletion of glutathione S-transferases (GSTM1/GSTT1), and single nucleotide substitutions in GSTP1 (A313G) and NAD(P)H:quinone oxidoreductase 1 (NQO1: C609T), were identified from blood DNA. Urinary ITC excretion levels were marginally higher with the GSTT1-null or GSTP1-G/G genotypes (P = 0.07, P = 0.05, respectively). Mean habitual Brassica intake was 98.3 g/day, primarily as bok choy, and Brassica intake significantly increased across quartile categories of ITC levels. The association between habitual Brassica intake and urinary ITC levels was stronger among women with GSTT1-null or GSTP1-A/A genotypes, or NQO1 T-allele, and the interaction was statistically significant across GSTP1 genotype. In conclusion, a single urinary ITC measure, in conjunction with markers of Phase II enzyme activity, provides a complementary measure of habitual Brassica intake among Shanghai women.

  20. The cytoprotective effects of ethanol extract of Ecklonia cava against oxidative stress are associated with upregulation of Nrf2-mediated HO-1 and NQO-1 expression through activation of the MAPK pathway.

    PubMed

    Choi, Yung Hyun

    2016-01-01

    The aim of the present study was to examine the cytoprotective effect of Ecklonia cava against oxidative stress in C2C12 myoblasts. The ethanol extract of E. cava (EEEC) prevented hydrogen peroxide (H₂O₂)-induced inhibition of the growth of C2C12 myoblasts and exhibited scavenging activity against intracellular reactive oxygen species (ROS) induced by H₂O₂. EEEC treatment attenuated H2O2-induced comet tail formation and phospho-histone γH2A.X expression. Furthermore, EEEC treatment enhanced the level of the phosphorylated form of nuclear factor erythroid 2- related factor 2 (Nrf2) and its nuclear translocation, which was associated with the induction of heme oxygenase-1 (HO-1) and NADPH-quinone oxidoreductase 1 (NQO-1). Zinc protoporphyrin IX, a HO-1 competitive inhibitor, significantly abolished the protective effects of EEEC against H₂O₂-induced ROS generation and growth inhibition in C2C12 myoblasts. Transient transfection with Nrf2-specific small interfering RNA restored the elevated HO-1 and NQO-1 expression and the phosphorylation of Nrf2 to near normal levels. The EEEC treatment also induced the activation of mitogen-activated protein kinases (MAPKs), and specific inhibitors of MAPKs abolished upregulated HO-1 and NQO-1, as well as the phosphorylation of Nrf2. Taken together, these data suggest that EEEC attenuates oxidative stress by activating Nrf2-mediated HO-1 and inducing NQO-1 via the activation of MAPK signaling pathways.

  1. β-Lapachone and Paclitaxel Combination Micelles with Improved Drug Encapsulation and Therapeutic Synergy as Novel Nanotherapeutics for NQO1-Targeted Cancer Therapy.

    PubMed

    Zhang, Ling; Chen, Zhen; Yang, Kuan; Liu, Chun; Gao, Jinming; Qian, Feng

    2015-11-02

    β-Lapachone (LPC) is a novel cytotoxic agent that is bioactivated by NADP(H): quinone oxidoreductase 1 (NQO1), an enzyme elevated in a variety of tumors, such as non-small cell lung cancer (NSCLC), pancreatic cancer, liver cancer, and breast cancer. Despite its unique mechanism of action, its clinical evaluation has been largely hindered by low water solubility, short blood half-life, and narrow therapeutic window. Although encapsulation into poly(ethylene glycol)-b-poly(D,L-lactic acid) (PEG-PLA) micelles could modestly improve its solubility and prolong its half-life, the extremely fast intrinsic crystallization tendency of LPC prevents drug loading higher than ∼2 wt %. The physical stability of the LPC-loaded micelles is also far from satisfactory for further development. In this study, we demonstrate that paclitaxel (PTX), a front-line drug for many cancers, can provide two functions when coencapsulated together with LPC in the PEG-PLA micelles; first, as a strong crystallization inhibitor for LPC, thus to significantly increase the LPC encapsulation efficiency in the micelle from 11.7 ± 2.4% to 100.7 ± 2.2%. The total drug loading efficiency of both PTX and LPC in the combination polymeric micelle reached 100.3 ± 3.0%, and the drug loading density reached 33.2 ± 1.0%. Second, the combination of LPC/PTX demonstrates strong synergistic cytotoxicity effect against the NQO1 overexpressing cancer cells, including A549 NSCLC cells, and several pancreatic cancer cells (combination index <1). In vitro drug release study showed that LPC was released faster than PTX either in phosphate-buffered saline (PH = 7.4) or in 1 M sodium salicylate, which agrees with the desired dosing sequence of the two drugs to exert synergistic pharmacologic effect at different cell checkpoints. The PEG-PLA micelles coloaded with LPC and PTX offer a novel nanotherapeutic, with high drug loading, sufficient physical stability, and biological synergy to increase drug delivery efficiency

  2. Caffeinated coffee, decaffeinated coffee, and the phenolic phytochemical chlorogenic acid up-regulate NQO1 expression and prevent H₂O₂-induced apoptosis in primary cortical neurons.

    PubMed

    Kim, Jiyoung; Lee, Siyoung; Shim, Jaesung; Kim, Hyo Won; Kim, Jaekyoon; Jang, Young Jin; Yang, Hee; Park, Jiman; Choi, Seung Hwan; Yoon, Ji Hye; Lee, Ki Won; Lee, Hyong Joo

    2012-04-01

    Neurodegenerative disorders are strongly associated with oxidative stress, which is induced by reactive oxygen species including hydrogen peroxide (H₂O₂). Epidemiological studies have suggested that coffee may be neuroprotective, but the molecular mechanisms underlying this effect have not been clarified. In this study, we investigated the protective effects of caffeinated coffee, decaffeinated coffee, and the phenolic phytochemical chlorogenic acid (5-O-caffeoylquinic acid), which is present in both caffeinated and decaffeinated coffee, against oxidative neuronal death. H₂O₂-induced apoptotic nuclear condensation in neuronal cells was strongly inhibited by pretreatment with caffeinated coffee, decaffeinated coffee, or chlorogenic acid. Pretreatment with caffeinated coffee, decaffeinated coffee, or chlorogenic acid inhibited the H₂O₂-induced down-regulation of anti-apoptotic proteins Bcl-2 and Bcl-X(L) while blocking H₂O₂-induced pro-apoptotic cleavage of caspase-3 and pro-poly(ADP-ribose) polymerase. We also found that caffeinated coffee, decaffeinated coffee, and chlorogenic acid induced the expression of NADPH:quinine oxidoreductase 1 (NQO1) in neuronal cells, suggesting that these substances protect neurons from H₂O₂-induced apoptosis by up-regulation of this antioxidant enzyme. The neuroprotective efficacy of caffeinated coffee was similar to that of decaffeinated coffee, indicating that active compounds present in both caffeinated and decaffeinated coffee, such as chlorogenic acid, may drive the effects. Copyright © 2012 Elsevier Ltd. All rights reserved.

  3. Cross-species microarray analysis with the OSCAR system suggests an INSR->Pax6->NQO1 neuro-protective pathway in aging and Alzheimer's disease

    PubMed Central

    Lu, Yue; He, Xin; Zhong, Sheng

    2007-01-01

    OSCAR is a web platform for cluster and cross-species analysis of microarray data. It provides a comprehensive but friendly environment to both users and algorithm developers. For users, OSCAR provides cluster tools for both single and multiple species data, together with interactive analysis features. For single species data, OSCAR currently provides Hierarchical Clustering, K-means, partition around medoids (PAM), Self-Organizing Map (SOM), Tight Clustering and a novel algorithm called ‘Consensus Tight-clustering’. The new Consensus Tight-clustering algorithm delivers robust gene clusters and its result is more resistant to false positives than other state-of-the-art algorithms. For cross-species data analysis, OSCAR provides two novel computational tools: ‘coherentCluster’, ‘coherentSubset’ and a novel visualization tool: ‘comparative heatmap’. Applying the coherentCluster algorithm to human and fly aging data, we identified several coherent clusters of genes, which share co-regulation patterns that are highly correlated with the aging process in both of the two species. One coherent cluster suggests insulin receptor (INSR) may regulate Pax6 in both species and across different tissues. Further analysis with human brain expression and pathological data suggests an INSR->Pax6->quinone oxidoreductase (NQO1)->detoxification neuro-protective pathway might be present in aging or diseased brain. For algorithm developers, OSCAR is a plug-and-play platform. With little effort, developers can plug their own algorithms into the OSCAR server without revealing the source codes, which will equip their command line executables with user-friendly interface and interactive analysis capability. In summary, OSCAR initiates an open platform for development and application of clustering and cross-species analysis programs. OSCAR stands for an open system for cluster analysis of microarray data. It is available at: http://biocomp.bioen.uiuc.edu/oscar PMID:17545194

  4. Effect of 3-(3'-tert-butyl-4'-hydroxyphenyl)propyl thiosulfonate sodium on expression of GSTP1 and NQO1 genes and protein transcription factors in BALB/c mouse liver.

    PubMed

    Shintyapina, A B; Safronova, O G; Vavilin, V A; Kandalintseva, N V; Prosenko, A E; Lyakhovich, V V

    2014-08-01

    The study examined dynamics of the effect of novel phenol antioxidant preparation 3-(3'-tertbutyl- 4'-hydroxyphenyl)propyl thiosulfonate sodium (TS-13) on expression of antioxidant protection enzymes genes GSTP1 and NQO1 and on the content of protein transcription factors NF-κB and ATF-2 in mouse liver. Expression of GSTP1 gene decreased significantly on days 4 and 7 after per os administration of TS-13 (100 mg/kg), but increased on post-administration day 14. On days 7 and 14 post-administration, expression of NQO1 gene was significantly increased. On day 7, the hepatic content of the phosphorylated form of ATF-2 and two subunits of nuclear factor NF-κB (p50, p65) decreased significantly.

  5. Camel Milk Modulates the Expression of Aryl Hydrocarbon Receptor-Regulated Genes, Cyp1a1, Nqo1, and Gsta1, in Murine hepatoma Hepa 1c1c7 Cells

    PubMed Central

    Korashy, Hesham M.; El Gendy, Mohamed A. M.; Alhaider, Abdulqader A.; El-Kadi, Ayman O.

    2012-01-01

    There is a traditional belief in the Middle East that camel milk may aid in prevention and treatment of numerous cases of cancer yet, the exact mechanism was not investigated. Therefore, we examined the ability of camel milk to modulate the expression of a well-known cancer-activating gene, Cytochrome P450 1a1 (Cyp1a1), and cancer-protective genes, NAD(P)H:quinone oxidoreductase 1 (Nqo1) and glutathione S-transferase a1 (Gsta1), in murine hepatoma Hepa 1c1c7 cell line. Our results showed that camel milk significantly inhibited the induction of Cyp1a1 gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent Cyp1a1 inducer and known carcinogenic chemical, at mRNA, protein, and activity levels in a concentration-dependent manner. In addition, camel milk significantly decreased the xenobiotic responsive element (XRE)-dependent luciferase activity, suggesting a transcriptional mechanism is involved. Furthermore, this inhibitory effect of camel milk was associated with a proportional increase in heme oxygenase 1. On the other hand, camel milk significantly induced Nqo1 and Gsta1 mRNA expression level in a concentration-dependent fashion. The RNA synthesis inhibitor, actinomycin D, completely blocked the induction of Nqo1 mRNA by camel milk suggesting the requirement of de novo RNA synthesis through a transcriptional mechanism. In conclusion, camel milk modulates the expression of Cyp1a1, Nqo1, and Gsta1 at the transcriptional and posttranscriptional levels. PMID:22570534

  6. Pharmacokinetics and derivation of an anticancer dosing regimen for the novel anti-cancer agent isobutyl-deoxynyboquinone (IB-DNQ), a NQO1 bioactivatable molecule, in the domestic felid species.

    PubMed

    Lundberg, Alycen P; Francis, Joshua M; Pajak, Malgorzata; Parkinson, Elizabeth I; Wycislo, Kathryn L; Rosol, Thomas J; Brown, Megan E; London, Cheryl A; Dirikolu, Levent; Hergenrother, Paul J; Fan, Timothy M

    2016-12-14

    Isobutyl-deoxynyboquinone (IB-DNQ) is a selective substrate for NAD(P)H:quinone oxidoreductase (NQO1), an enzyme overexpressed in many solid tumors. Following activation by NQO1, IB-DNQ participates in a catalytic futile reduction/reoxidation cycle with consequent toxic reactive oxygen species generation within the tumor microenvironment. To elucidate the potential of IB-DNQ to serve as a novel anticancer agent, in vitro studies coupled with in vivo pharmacokinetic and toxicologic investigations in the domestic felid species were conducted to investigate the tractability of IB-DNQ as a translationally applicable anticancer agent. First, using feline oral squamous cell carcinoma (OSCC) as a comparative cancer model, expressions of NQO1 were characterized in not only human, but also feline OSCC tissue microarrays. Second, IB-DNQ mediated cytotoxicity in three immortalized feline OSCC cell lines were studied under dose-dependent and sequential exposure conditions. Third, the feasibility of administering IB-DNQ at doses predicted to achieve cytotoxic plasma concentrations and biologically relevant durations of exposure were investigated through pharmacokinetic and tolerability studies in healthy research felines. Intravenous administration of IB-DNQ at 1.0-2.0 mg/kg achieved peak plasma concentrations and durations of exposure reaching or exceeding predicted in vitro cytotoxic concentrations. Clinical adverse side effects including ptyalism and tachypnea exhibited during and post-IV infusion of IB-DNQ were transient and tolerable. Additionally, IB-DNQ administration did not produce acute or delayed-onset unacceptable hematologic, non-hematologic, or off-target oxidative toxicities. Collectively, the findings reported here within provide important safety and pharmacokinetic data to support the continued development of IB-DNQ as a novel anticancer strategy for NQO1 expressing cancers.

  7. Camel milk modulates the expression of aryl hydrocarbon receptor-regulated genes, Cyp1a1, Nqo1, and Gsta1, in murine hepatoma Hepa 1c1c7 cells.

    PubMed

    Korashy, Hesham M; El Gendy, Mohamed A M; Alhaider, Abdulqader A; El-Kadi, Ayman O

    2012-01-01

    There is a traditional belief in the Middle East that camel milk may aid in prevention and treatment of numerous cases of cancer yet, the exact mechanism was not investigated. Therefore, we examined the ability of camel milk to modulate the expression of a well-known cancer-activating gene, Cytochrome P450 1a1 (Cyp1a1), and cancer-protective genes, NAD(P)H:quinone oxidoreductase 1 (Nqo1) and glutathione S-transferase a1 (Gsta1), in murine hepatoma Hepa 1c1c7 cell line. Our results showed that camel milk significantly inhibited the induction of Cyp1a1 gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent Cyp1a1 inducer and known carcinogenic chemical, at mRNA, protein, and activity levels in a concentration-dependent manner. In addition, camel milk significantly decreased the xenobiotic responsive element (XRE)-dependent luciferase activity, suggesting a transcriptional mechanism is involved. Furthermore, this inhibitory effect of camel milk was associated with a proportional increase in heme oxygenase 1. On the other hand, camel milk significantly induced Nqo1 and Gsta1 mRNA expression level in a concentration-dependent fashion. The RNA synthesis inhibitor, actinomycin D, completely blocked the induction of Nqo1 mRNA by camel milk suggesting the requirement of de novo RNA synthesis through a transcriptional mechanism. In conclusion, camel milk modulates the expression of Cyp1a1, Nqo1, and Gsta1 at the transcriptional and posttranscriptional levels.

  8. Resveratrol pretreatment attenuates injury and promotes proliferation of neural stem cells following oxygen-glucose deprivation/reoxygenation by upregulating the expression of Nrf2, HO-1 and NQO1 in vitro

    PubMed Central

    Shen, Changbo; Cheng, Wei; Yu, Pingping; Wang, Li; Zhou, Lulin; Zeng, Li; Yang, Qin

    2016-01-01

    There is considerable interest in the use of drugs and other methods for protecting implanted neural stem cells (NSCs) from the adverse environment of injured tissue for successful cell therapy. Resveratrol can modify cardiac stem cells to enhance their survival and differentiation, however, its effect and the mechanism underlying its neuroprotective effect on NSCs following stroke remain to be fully elucidated. Nuclear factor erythroid 2-related factor 2 (Nrf-2) signaling is important in antioxidative stress, and the role of Nrf-2 signaling in the enhanced neuroprotection of NSCs by resveratrol following stroke also remains to be elucidated. In the present study, NSCs were pretreated with resveratrol prior to oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro. The survival, apoptosis and proliferation of the NSCs were assessed using an MTT assay, Hoechst 33258 staining of nuclei and flow cytometry, respectively. In addition, the activity of superoxide dismutase (SOD), level of malondiadehyde (MDA) and content of glutathione (GSH) were determined. The protein expressions levels of Nrf-2, NAD(P)H:quinone oxidoreductase 1 (NQO-1), and heme oxygenase 1 (HO-1) were detected using western blot analysis. It was found that resveratrol markedly enhanced NSC survival and proliferation, decreased apoptosis and the levels of MDA, and increased the activity of SOD and content of GSH in a concentration-dependent manner following OGD/R injury in vitro. In addition, the protein expression levels of Nrf2, HO-1 and NQO1 were significantly upregulated. These findings suggested that resveratrol attenuated injury and promoted proliferation of the NSCs, at least in part, by upregulating the expression of Nrf2, HO-1 and NQO1 following OGD/R injury in vitro. PMID:27573874

  9. Pesticide, Gene Polymorphisms and Bladder Cancer among Egyptian Agricultural Workers

    PubMed Central

    Amr, Sania; Dawson, Rebecca; Saleh, Doa’a A.; Magder, Laurence S.; St. George, Diane Marie; El-Daly, Mai; Squibb, Katherine; Mikhail, Nabiel N.; Abdel-Hamid, Mohamed; Khaled, Hussein; Loffredo, Christopher A.

    2013-01-01

    We examined the associations between pesticide exposure, genetic polymorphisms for NAD(P)H:quinone oxidoreductase I (NQO1) and superoxide dismutase 2 (SOD2), and urinary bladder cancer risk among male agricultural workers in Egypt. We used logistic regression to analyze data from a multi-center case-control study and estimate adjusted odds ratio (OR) and 95% CI (confidence interval) Exposure to pesticides was associated with increased bladder cancer risk (1.68 (1.23–2.29)) in a dose-dependent manner. The association was slightly stronger for urothelial (1.79 (1.25–2.56) than for squamous cell carcinoma (1.55 (1.03–2.31)), and among participants with combined genotypes for low NQO1 and high SOD2 (2.14 (1.19–3.85) activities as compared to those with high NQO1 and low SOD2 genotypes (1.53 (0.73–3.25)). In conclusion, among male agricultural workers in Egypt, pesticide exposure is associated with bladder cancer risk and possibly modulated by genetic polymorphism. PMID:24219772

  10. NAD(P)H:quinone oxidoreductase 1 Arg139Trp and Pro187Ser polymorphisms imbalance estrogen metabolism towards DNA adduct formation in human mammary epithelial cells.

    PubMed

    Singh, Seema; Zahid, Muhammad; Saeed, Muhammad; Gaikwad, Nilesh W; Meza, Jane L; Cavalieri, Ercole L; Rogan, Eleanor G; Chakravarti, Dhrubajyoti

    2009-10-01

    Estrogens (estrone, E(1); estradiol, E(2)) are oxidized in the breast first to catechols and then to form two ortho-quinones (E(1/2)-3,4-Q) that react with DNA to form depurinating adducts, which lead to mutations associated with breast cancer. NAD(P)H:quinone oxidoreductase 1 (NQO1) reduces these quinones back to catechols, and thus may protect against this mechanism. We examined whether the inheritance of two polymorphic variants of NQO1 (Pro187Ser or Arg139Trp) would result in poor reduction of E(1/2)-3,4-Q in normal human mammary epithelial cells (MCF-10F) and increased depurinating adduct formation. An isogenic set of stably transfected normal human breast epithelial cells (MCF-10F) that express a truncated (135Stop), the wild-type, the 139Trp variant or the 187Ser variant of human NQO1 cDNA was constructed. MCF-10F cells showed a low endogenous NQO1 activity. NQO1 expression was examined by RT-PCR and Western blotting, and catalytic activity of reducing E(2)-3,4-Q to 4-hydroxyE(1/2) and associated changes in the levels of quinone conjugates (4-methoxyE(1/2), 4-OHE(1/2)-2-glutathione, 4-OHE(1/2)-2-Cys and 4-OHE(1/2)-2-N-acetylcysteine) and depurinating DNA adducts (4-OHE(1/2)-1-N3Ade and 4-OHE(1/2)-1-N7Gua) were examined by HPLC with electrochemical detection, as well as by ultra-performance liquid chromatography with tandem mass spectrometry. The polymorphic variants transcribed comparably to the wild-type NQO1, but produced approximately 2-fold lower levels of the protein, suggesting that the variant proteins may become degraded. E(1/2)-3,4-Q toxicity to MCF-10F cells (IC50=24.74 microM) was increased (IC50=3.7 microM) by Ro41-0960 (3 microM), a catechol-O-methyltransferase inhibitor. Cells expressing polymorphic NQO1 treated with E(2)-3,4-Q with or without added Ro41-0960, showed lower ability to reduce the quinone ( approximately 50% lower levels of the free catechols and approximately 3-fold lower levels of methylated catechols) compared to the wild

  11. Induction of heme oxygenase-1 (HO-1) and NAD[P]H: quinone oxidoreductase 1 (NQO1) by a phenolic antioxidant, butylated hydroxyanisole (BHA) and its metabolite, tert-butylhydroquinone (tBHQ) in primary-cultured human and rat hepatocytes.

    PubMed

    Keum, Young-Sam; Han, Yong-Hae; Liew, Celine; Kim, Jung-Hwan; Xu, Changjiang; Yuan, Xiaoling; Shakarjian, Michael P; Chong, Saeho; Kong, Ah-Ng

    2006-11-01

    This study was aimed to investigate the effects of a phenolic antioxidant, butylated hydroxyanisole (BHA) and its metabolite, tert-butylhydroquinone (tBHQ) on the induction of HO-1, NQO1 and Nrf2 proteins and their regulatory mechanisms in primary-cultured hepatocytes. After exposure of BHA and tBHQ to primary-cultured rat and human hepatocytes and mouse neonatal fibroblasts (MFs), Western blot, semi-quantitative RT-PCR and microarray analysis were conducted. Induction of HO-1, NQO1 and Nrf2 proteins and activation of ERK1/2 and JNK1/2 were observed after BHA and tBHQ treatments in primary-cultured rat and human hepatocytes. Semi-quantitative RT-PCR study and microarray analysis revealed that HO-1 and NQO1 were transcriptionally activated in primary-cultured rat hepatocytes and a substantial transcriptional activation, including HO-1 occurred in primary-cultured human hepatocytes after BHA treatment. Whereas BHA failed to induce HO-1 in wild-type and Nrf2 knock-out MFs, tBHQ strongly induced HO-1 in wild-type, but not in Nrf2 knock-out MFs. Our data demonstrate that both BHA and tBHQ are strong chemical inducers of HO-1, NQO1 and Nrf2 proteins in primary-cultured human and rat hepatocytes with the activation of MAPK ERK1/2 and JNK1/2. However, in MFs, BHA failed to induce HO-1, whereas tBHQ strongly induced HO-1 in Nrf2 wild-type but not in Nrf2 knock-out, suggesting that Nrf2 is indispensable for tBHQ-induced HO-1 in MF.

  12. Unique Familial MLL(KMT2A)-Rearranged Precursor B-Cell Infant Acute Lymphoblastic Leukemia in Non-twin Siblings.

    PubMed

    Urtishak, Karen A; Robinson, Blaine W; Rappaport, Eric F; Sarezky, Margaret D; Biegel, Jaclyn A; Nichols, Kim E; Wilmoth, Donna M; Wang, Li-San; Stern, Julie W; Felix, Carolyn A

    2016-07-01

    Infant acute lymphoblastic leukemia (ALL) has never occurred in families except for the ∼100% concordant cases in monozygous twins attributed to twin-to-twin metastases. We report the first kindred with infant ALL in non-twin siblings. The siblings were diagnosed with MLL-rearranged (MLL-R) ALL 26 months apart. The second affected sibling had an unaffected dichorionic monozygous co-twin. Both had fatal outcomes. Translocations were characterized by karyotype, FISH, multiplex FISH, and MLL breakpoint cluster region (bcr) Southern blot analysis. Breakpoint junctions and fusion transcripts were cloned by PCR. TP53 mutation and NADPH quinone oxidorecuctase 1 (NQO1) C609T analyses were performed, and pedigree history and parental occupations were ascertained. The likelihood of chance occurrence of infant ALL in non-twin siblings was computed based on a binomial distribution. Zygosity was determined by single nucleotide polymorphism (SNP) array. The translocations were not related or vertically transmitted. The complex karyotype of the proband's ALL had chromosome 2, 3, 4, and 11 abnormalities causing a 5'-MLL-AFF1-3' fusion and a non-productive rearrangement of 3'MLL with a chromosome 3q intergenic region. The affected twin's ALL exhibited a simple t(4;11). The complex karyotype of the proband's ALL suggested a genotoxic insult, but no exposure was identified. There was no germline TP53 mutation. The NQO1 C609T risk allele was absent. The likelihood of infant ALL occurring in non-twin siblings by chance alone is one in 1.198 × 10(9) families. Whether because of a deleterious transplacental exposure, novel predisposition syndrome, or exceedingly rare chance occurrence, MLL-R infant ALL can occur in non-twin siblings. The discordant occurrence of infant ALL in the monozygous twins was likely because they were dichorionic. © 2016 Wiley Periodicals, Inc.

  13. Association of cytochrome P4502E1 and NAD(P)H:quinone oxidoreductase 1 genetic polymorphisms with susceptibility to large artery atherosclerotic ischemic stroke: a case-control study in the Turkish population.

    PubMed

    Türkanoğlu Özçelik, Aysun; Can Demirdöğen, Birsen; Demirkaya, Şeref; Adalı, Orhan

    2017-06-01

    Stroke, a major cause of death and disability, is described as interruption or severe reduction of blood flow in cerebral arteries. Oxidative stress plays an important role in the pathogenesis of atherosclerosis and carotid atherosclerosis is a risk factor for stroke. Combination of multiple environmental and genetic risk factors is thought to increase stroke. Therefore, investigation of the polymorphisms of enzymes is of crucial importance to determine the molecular etiology of the disease. To test this hypothesis, we performed a case-control study in which we compared the distribution of CYP2E1 and NQO1 genotypes between 245 large artery atherosclerotic ischemic stroke patients and 145 controls, using PCR-RFLP. A significant difference was observed between stroke patients and controls with respect to the CYP2E1*5B genotype (odds ratio; OR 8.069, P = 0.011) and allele (OR 7.876, P = 0.011) distribution. However, this polymorphism was not a significant predictor of disease status in logistic regression analysis. NQO1*2 polymorphism genotype distribution was significantly different between patients and controls (P = 0.027) and heterozygote *1*2 genotype was found to be a protective factor against large artery atherosclerotic ischemic stroke in logistic regression analysis (OR 0.562, P = 0.018). This is the first study conducted regarding the association of CYP2E1 and NQO1 genetic polymorphisms and large artery atherosclerotic ischemic stroke risk in Turkish population.

  14. Novel non invasive diagnostic strategies in bladder cancer

    PubMed Central

    TRUTA, ANAMARIA; POPON, TUDOR ADRIAN HODOR; SARACI, GEORGE; GHERVAN, LIVIU; POP, IOAN VICTOR

    2016-01-01

    Bladder cancer is one of the most commonly diagnosed malignancies worldwide, derived from the urothelium of the urinary bladder and defined by long asymptomatic and atypical clinical picture. Its complex etiopathogenesis is dependent on numerous risk factors that can be divided into three distinct categories: genetic and molecular abnormalities, chemical or environmental exposure and previous genitourinary disorders and family history of different malignancies. Various genetic polymorphisms and microRNA might represent useful diagnostic or prognostic biomarkers. Genetic and molecular abnormalities - risk factors are represented by miRNA or genetic polymorphisms proved to be part of bladder carcinogenesis such as: genetic mutations of oncogenes TP53, Ras, Rb1 or p21 oncoproteins, cyclin D or genetic polymorhisms of XPD,ERCC1, CYP1B1, NQO1C609T, MDM2SNP309, CHEK2, ERCC6, NRF2, NQO1Pro187Ser polymorphism and microRNA (miR-143, −145, −222, −210, −10b, 576-3p). The aim of our article is to highlight the most recent acquisitions via molecular biomarkers (miRNAs and genetic polymorphisms) involved in bladder cancer in order to provide early diagnosis, precise therapy according to the molecular profile of bladder tumors, as well as to improve clinical outcome, survival rates and life quality of oncological patients. These molecular biomarkers play a key role in bladder carcinogenesis, clinical evolution, prognosis and therapeutic response and explain the molecular mechanisms involved in bladder carcinogenesis; they can also be selected as therapeutic targets in developing novel therapeutic strategies in bladder malignancies. Moreover, the purpose in defining these molecular non invasive biomarkers is also to develop non invasive screening programs in bladder malignancies with the result of decreasing bladder cancer incidence in risk population. PMID:27152066

  15. Novel non invasive diagnostic strategies in bladder cancer.

    PubMed

    Truta, Anamaria; Popon, Tudor Adrian Hodor; Saraci, George; Ghervan, Liviu; Pop, Ioan Victor

    2016-01-01

    Bladder cancer is one of the most commonly diagnosed malignancies worldwide, derived from the urothelium of the urinary bladder and defined by long asymptomatic and atypical clinical picture. Its complex etiopathogenesis is dependent on numerous risk factors that can be divided into three distinct categories: genetic and molecular abnormalities, chemical or environmental exposure and previous genitourinary disorders and family history of different malignancies. Various genetic polymorphisms and microRNA might represent useful diagnostic or prognostic biomarkers. Genetic and molecular abnormalities - risk factors are represented by miRNA or genetic polymorphisms proved to be part of bladder carcinogenesis such as: genetic mutations of oncogenes TP53, Ras, Rb1 or p21 oncoproteins, cyclin D or genetic polymorhisms of XPD,ERCC1, CYP1B1, NQO1C609T, MDM2SNP309, CHEK2, ERCC6, NRF2, NQO1Pro187Ser polymorphism and microRNA (miR-143, -145, -222, -210, -10b, 576-3p). The aim of our article is to highlight the most recent acquisitions via molecular biomarkers (miRNAs and genetic polymorphisms) involved in bladder cancer in order to provide early diagnosis, precise therapy according to the molecular profile of bladder tumors, as well as to improve clinical outcome, survival rates and life quality of oncological patients. These molecular biomarkers play a key role in bladder carcinogenesis, clinical evolution, prognosis and therapeutic response and explain the molecular mechanisms involved in bladder carcinogenesis; they can also be selected as therapeutic targets in developing novel therapeutic strategies in bladder malignancies. Moreover, the purpose in defining these molecular non invasive biomarkers is also to develop non invasive screening programs in bladder malignancies with the result of decreasing bladder cancer incidence in risk population.

  16. Melatonin enhances mitochondrial ATP synthesis, reduces reactive oxygen species formation, and mediates translocation of the nuclear erythroid 2-related factor 2 resulting in activation of phase-2 antioxidant enzymes (γ-GCS, HO-1, NQO1) in ultraviolet radiation-treated normal human epidermal keratinocytes (NHEK).

    PubMed

    Kleszczyński, Konrad; Zillikens, Detlef; Fischer, Tobias W

    2016-09-01

    Melatonin is an ubiquitous molecule with a variety of functions including potent antioxidative properties. Due to its lipophilic character, it easily crosses cellular and intracellular membranes and reaches all subcellular organelles. Because of its ability to scavenge free radicals, melatonin protects against oxidative stress, for example, induced by ultraviolet radiation (UVR). Here, we investigated, in a dose-dependent (0, 10, 25, and 50 mJ/cm(2) ) and time-dependent (0, 4, 24, 48 hr post-UVR) manner, whether melatonin prevents the UVR-mediated alterations in ATP synthesis and the generation of reactive oxygen species (ROS) in normal human epidermal keratinocytes (NHEK). Additionally, we evaluated the molecular mechanism of action of melatonin with regard to activation of phase-2 antioxidative enzymes via nuclear erythroid 2-related factor (Nrf2). We found that (i) melatonin counteracted UVR-induced alterations in the ATP synthesis and reduced free radical formation; (ii) melatonin induced the translocation of Nrf2 transcription factor from the cytosol into the nucleus resulting in, (iii) melatonin enhanced gene expression of phase-2 antioxidative enzymes including γ-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), and NADPH: quinone dehydrogenase-1 (NQO1) representing an elevated antioxidative response of keratinocytes. These results suggest that melatonin not only directly scavenges ROS, but also significantly induces the activation of phase-2 antioxidative enzymes via the Nrf2 pathway uncovering a new action mechanism that supports the ability of keratinocytes to protect themselves from UVR-mediated oxidative stress. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Genetic Predisposition for Dermal Problems in Hexavalent Chromium Exposed Population

    PubMed Central

    Sharma, Priti; Bihari, Vipin; Agarwal, Sudhir K.; Goel, Sudhir K.

    2012-01-01

    We studied the effect of genetic susceptibility on hexavalent chromium induced dermal adversities. The health status of population was examined from the areas of Kanpur (India) having the elevated hexavalent chromium levels in groundwater. Blood samples were collected for DNA isolation to conduct polymorphic determination of genes, namely: NQO1 (C609T), hOGG1 (C1245G), GSTT1, and GSTM1 (deletion). Symptomatic exposed subjects (n = 38) were compared with asymptomatic exposed subjects (n = 108) along with asymptomatic controls (n = 148) from a non contaminated reference community. Exposed symptomatic group consisted of 36.8% subjects who were GSTM1 null genotyped as compared to asymptomatic where only 19.4% subjects were null. The exposed subjects with GSTM1 null genotype were more susceptible to dermal adversities in comparison with wild genotyped subjects (OR = 2.42; 95% CI = 1.071–5.451). Age, smoking, gender or duration of residence were not found to have any confounding effect towards this association. Association with other genes was not statistically significant, nonetheless, possible contribution by these genes cannot be ruled out. In conclusion, variation in the polymorphic status of GSTM1 gene may influence dermal outcomes among residents from Cr(VI) contaminated areas. Further studies are therefore, needed to examine these observations among different population groups. PMID:22919465

  18. Effects of antioxidant enzyme polymorphisms on ozone-induced lung function changes

    PubMed Central

    Chen, C.; Arjomandi, M.; Tager, I.B.; Holland, N.; Balmes, J.R.

    2012-01-01

    Chronic exposure to ozone (O3) can cause changes in lung function that may reflect remodelling of small airways. It is likely that antioxidant enzyme function affects susceptibility to O3. The aim of the present study was to determine whether polymorphisms in antioxidant enzyme (GSTM1, GSTP1 and NQO1) genes affect the risk of lung function changes related to chronic exposure to O3. In total, 210 young adults who participated in a previous study, which showed a relationship between lifetime exposure to O3 and decreased lung function, were genotyped. Multivariable linear regression was used to model sex-specific associations between genotypes and O3-related lung function changes, adjusting for height, weight, lifetime exposure to nitrogen dioxide and particles with a 50% cut-off aerodynamic diameter of 10 μm, and self-identified race/ethnicity. The GSTM1-null/NQO1 Pro187Pro-combination genotype was significantly associated with increased risk of an O3-related decrease in mean forced expiratory flow between 25–75% of forced vital capacity in females (parameter estimate ± SE −75 ± 35 mL·s−1), while the GSTP1 Val105 variant genotypes were significantly associated with greater risk of an O3-related decrease in mean forced expiratory flow at 75% of forced vital capacity in males (−81 ± 31 mL·s−1). GSTM1-null status was not significantly associated with any O3-related changes in lung function in either sex. The current authors conclude that the effects of antioxidant enzyme gene polymorphisms on the risk of decreased lung function related to chronic exposure to ozone may be modified by sex-specific factors. PMID:17652311

  19. Xenobiotic and folate pathway gene polymorphisms and risk of childhood acute lymphoblastic leukaemia in Javanese children.

    PubMed

    Chan, Jason Yong-Sheng; Ugrasena, Dewa G; Lum, Danny Wai-Kiong; Lu, Yi; Yeoh, Allen Eng-Juh

    2011-09-01

    Xenobiotic and folate metabolic pathways are important for the maintenance of genetic stability and may influence susceptibility to the development of childhood acute lymphoblastic leukaemia (ALL). In this study, we investigated 10 polymorphisms in 6 genes (GSTM1-present/null, GSTT1-present/null, GSTP1 1578A > G, NQO1 609C > T, MTHFR 677C > T, MTHFR 1298A > C, MTHFD1 1958G > A, 3'-TYMS 1494 6bp-deletion/insertion, 5'-TYMS 28bp-tandem repeats, and SLC19A1 80G > A) in a cohort of 185 Javanese children with ALL and 177 healthy controls. In ALL patients, none of the polymorphisms demonstrated a statistically significant association with ALL after correcting for multiple comparisons. Gender-stratified analysis showed that in girls, GSTT1-null genotype was associated with increased ALL risk (OR = 2.20; p = 0.027), while GSTP1 1578AG genotype was associated with reduced risk (OR = 0.43; p = 0.031). Strong linkage disequilibrium between the MTHFR 677C > T and 1298A > C polymorphisms was observed (D' = 1.0; r(2) = 0.072). The haplotypes 677C-1298C and 677T-1298A were associated with a reduced risk of ALL (OR = 0.68 and 0.64, respectively; gender-adjusted global p = 0.028). Classification and regression tree (CART) analysis was employed to identify potential high-order gene-gene interactions and cluster subjects into susceptibility groups. SLC19A1 80G > A emerged as the predominant polymorphism associated with risk of ALL. Individuals simultaneously carrying MTHFR 1298AA, 3'-TYMS 6bp deletion(s) and SLC19A1 80A-allele(s) were at higher disease risk (OR = 2.21; p < 0.001). On the contrary, simultaneous possession of MTHFR 1298CC, 3'-TYMS 6bp homozygosity and SLC19A1 80A-allele(s) conferred lower risk (OR = 0.25; p = 0.004). Carriage of NQO1 609C-allele amongst SLC19A1 80GG genotype was associated with lower risk (OR = 0.47; p = 0.003). In conclusion, our study has demonstrated the importance of gender and gene-gene interaction within the xenobiotic and folate pathways in

  20. Candidate gene association studies and risk of childhood acute lymphoblastic leukemia: a systematic review and meta-analysis

    PubMed Central

    Vijayakrishnan, Jayaram; Houlston, Richard S.

    2010-01-01

    To evaluate the contribution of candidate gene association studies to the understanding of genetic susceptibility to childhood acute lymphoblastic leukemia we conducted a systematic review and meta-analysis of published studies (January 1996–July 2009). Studies had to meet the following criteria: be case-control design, be studied by two or more studies, not be focused on HLA antigen genetic markers and be published in English. We identified 47 studies of polymorphic variation in 16 genes and acute lymphoblastic leukemia risk. To clarify the impact of individual polymorphisms on risk, pooled analyses were performed. Of the 25 polymorphic variants studied, significant associations (P<0.05) were seen in pooled analyses for eight variants: GSTM1 (OR =1.16; 95%CI: 1.04–1.30), MTRR A66G (OR=0.73, 95%CI:0.59–0.91), SHMT1 C1420T (OR=0.79, 95%CI: 0.65–0.98), RFC1 G80A (OR=1.37, 95%CI: 1.11–1.69), CYP1A1*2A (OR=1.36, 95%CI:1.11–1.66), CYP2E1*5B (OR=1.99, 95%CI:1.32–3.00) NQO1 C609T (OR=1.24, 95%CI:1.02–1.50) and XRCC1 G28152A (OR=1.78, 95%CI:1.32–2.42). These findings should, however, be interpreted with caution as the estimated false-positive report probabilities (FPRP) for each association were not noteworthy (i.e. FPRP>0.2). While candidate gene analyses are complementary to genome-wide association studies, future analyses should be based on sample sizes commensurate with the detection of small effects and attention needs to be paid to study design. PMID:20511665

  1. Association of Nuclear Factor-Erythroid 2-Related Factor 2, Thioredoxin Interacting Protein, and Heme Oxygenase-1 Gene Polymorphisms with Diabetes and Obesity in Mexican Patients

    PubMed Central

    Jiménez-Osorio, Angélica Saraí; González-Reyes, Susana; García-Niño, Wylly Ramsés; Moreno-Macías, Hortensia; Rodríguez-Arellano, Martha Eunice; Vargas-Alarcón, Gilberto; Zúñiga, Joaquín; Barquera, Rodrigo; Pedraza-Chaverri, José

    2016-01-01

    The nuclear factor-erythroid 2- (NF-E2-) related factor 2 (Nrf2) is abated and its ability to reduce oxidative stress is impaired in type 2 diabetes and obesity. Thus, the aim of this study was to explore if polymorphisms in Nrf2 and target genes are associated with diabetes and obesity in Mexican mestizo subjects. The rs1800566 of NAD(P)H:quinone oxidoreductase 1 (NQO1) gene, rs7211 of thioredoxin interacting protein (TXNIP) gene, rs2071749 of heme oxygenase-1 (HMOX1) gene, and the rs6721961 and the rs2364723 from Nrf2 gene were genotyped in 627 diabetic subjects and 1020 controls. The results showed that the rs7211 polymorphism is a protective factor against obesity in nondiabetic subjects (CC + CT versus TT, OR = 0.40, P = 0.005) and in women (CC versus CT + TT, OR = 0.7, P = 0.016). TT carriers had lower high-density lipoprotein cholesterol levels and lower body mass index. The rs2071749 was positively associated with obesity (AA versus AG + GG, OR = 1.25, P = 0.026). Finally, the rs6721961 was negatively associated with diabetes in men (CC versus CA + AA, OR = 0.62, P = 0.003). AA carriers showed lower glucose concentrations. No association was found for rs1800566 and rs2364723 polymorphisms. In conclusion, the presence of Nrf2 and related genes polymorphisms are associated with diabetes and obesity in Mexican patients. PMID:27274779

  2. Association of Nuclear Factor-Erythroid 2-Related Factor 2, Thioredoxin Interacting Protein, and Heme Oxygenase-1 Gene Polymorphisms with Diabetes and Obesity in Mexican Patients.

    PubMed

    Jiménez-Osorio, Angélica Saraí; González-Reyes, Susana; García-Niño, Wylly Ramsés; Moreno-Macías, Hortensia; Rodríguez-Arellano, Martha Eunice; Vargas-Alarcón, Gilberto; Zúñiga, Joaquín; Barquera, Rodrigo; Pedraza-Chaverri, José

    2016-01-01

    The nuclear factor-erythroid 2- (NF-E2-) related factor 2 (Nrf2) is abated and its ability to reduce oxidative stress is impaired in type 2 diabetes and obesity. Thus, the aim of this study was to explore if polymorphisms in Nrf2 and target genes are associated with diabetes and obesity in Mexican mestizo subjects. The rs1800566 of quinone oxidoreductase 1 (NQO1) gene, rs7211 of thioredoxin interacting protein (TXNIP) gene, rs2071749 of heme oxygenase-1 (HMOX1) gene, and the rs6721961 and the rs2364723 from Nrf2 gene were genotyped in 627 diabetic subjects and 1020 controls. The results showed that the rs7211 polymorphism is a protective factor against obesity in nondiabetic subjects (CC + CT versus TT, OR = 0.40, P = 0.005) and in women (CC versus CT + TT, OR = 0.7, P = 0.016). TT carriers had lower high-density lipoprotein cholesterol levels and lower body mass index. The rs2071749 was positively associated with obesity (AA versus AG + GG, OR = 1.25, P = 0.026). Finally, the rs6721961 was negatively associated with diabetes in men (CC versus CA + AA, OR = 0.62, P = 0.003). AA carriers showed lower glucose concentrations. No association was found for rs1800566 and rs2364723 polymorphisms. In conclusion, the presence of Nrf2 and related genes polymorphisms are associated with diabetes and obesity in Mexican patients.

  3. Polymorphous light eruption

    MedlinePlus

    Polymorphous light eruption (PMLE) is a common skin reaction in people who are sensitive to sunlight (ultraviolet light). ... Polymorphic light eruption; Photodermatosis; PMLE; Benign summer light eruption

  4. Metabolic Polymorphisms and Clinical Findings Related to Benzene Poisoning Detected in Exposed Brazilian Gas-Station Workers.

    PubMed

    Mitri, Simone; Fonseca, Antônio Sérgio Almeida; Otero, Ubirani Barros; Tabalipa, Marianne Medeiros; Moreira, Josino Costa; Sarcinelli, Paula de Novaes

    2015-07-21

    Benzene is a ubiquitous environmental pollutant and an important industrial chemical present in both gasoline and motor vehicle emissions. Occupational human exposure to benzene occurs in the petrochemical and petroleum refining industries as well as in gas-station workers, where it can lead to benzene poisoning (BP), but the mechanisms of BP are not completely understood. In Brazil, a significant number of gas-station service workers are employed. The aim of the present study was to evaluate alterations related to BP and metabolic polymorphisms in gas-station service workers exposed to benzene in the city of Rio de Janeiro, Brazil. Occupational exposure was based on clinical findings related to BP, and metabolic polymorphisms in 114 Brazilian gas-station attendants. These workers were divided into No Clinical Findings (NCF) and Clinical Findings (CF) groups. Neutrophil and Mean Corpuscular Volume (MCV) showed a significant difference between the two study groups, and neutrophil has the greatest impact on the alterations suggestive of BP. The clinical findings revealed higher frequencies of symptoms in the CF group, although not all members presented statistical significance. The frequencies of alleles related to risk were higher in the CF group for GSTM1, GSTT1, CYP2E1 7632T > A, but lower for NQO1 and CYP2E1 1053C > T genotypes. Moreover, an association was found between GSTM1 null and alterations related to BP, but we did not observe any effects of other polymorphisms. Variations in benzene metabolizing genes may modify benzene toxicity and should be taken into consideration during risk assessment evaluations.

  5. Metabolic Polymorphisms and Clinical Findings Related to Benzene Poisoning Detected in Exposed Brazilian Gas-Station Workers

    PubMed Central

    Mitri, Simone; Fonseca, Antônio Sérgio Almeida; Otero, Ubirani Barros; Tabalipa, Marianne Medeiros; Moreira, Josino Costa; Sarcinelli, Paula de Novaes

    2015-01-01

    Benzene is a ubiquitous environmental pollutant and an important industrial chemical present in both gasoline and motor vehicle emissions. Occupational human exposure to benzene occurs in the petrochemical and petroleum refining industries as well as in gas-station workers, where it can lead to benzene poisoning (BP), but the mechanisms of BP are not completely understood. In Brazil, a significant number of gas-station service workers are employed. The aim of the present study was to evaluate alterations related to BP and metabolic polymorphisms in gas-station service workers exposed to benzene in the city of Rio de Janeiro, Brazil. Occupational exposure was based on clinical findings related to BP, and metabolic polymorphisms in 114 Brazilian gas-station attendants. These workers were divided into No Clinical Findings (NCF) and Clinical Findings (CF) groups. Neutrophil and Mean Corpuscular Volume (MCV) showed a significant difference between the two study groups, and neutrophil has the greatest impact on the alterations suggestive of BP. The clinical findings revealed higher frequencies of symptoms in the CF group, although not all members presented statistical significance. The frequencies of alleles related to risk were higher in the CF group for GSTM1, GSTT1, CYP2E1 7632T > A, but lower for NQO1 and CYP2E1 1053C > T genotypes. Moreover, an association was found between GSTM1 null and alterations related to BP, but we did not observe any effects of other polymorphisms. Variations in benzene metabolizing genes may modify benzene toxicity and should be taken into consideration during risk assessment evaluations. PMID:26197327

  6. Exposure assessment of benzene in Thai workers, DNA-repair capacity and influence of genetic polymorphisms.

    PubMed

    Chanvaivit, Sirirat; Navasumrit, Panida; Hunsonti, Potchanee; Autrup, Herman; Ruchirawat, Mathuros

    2007-01-10

    Exposure to benzene can cause DNA damage and the subsequent development of cancer. In this study, study subjects were 31 laboratory workers at a petrochemical factory and 31 gasoline service attendants. Control subjects were 34 workers from a mail sorting service center. Occupational exposures to benzene were assessed using biomarkers of exposure in blood and urine. Induction of DNA-repair capacity was assessed as a biomarker of early effect. The effects of polymorphisms in a metabolizing gene (CYP2E1), in detoxification genes (NQO1 and GSTT1), and in a DNA-repair gene (XRCC1, codon 399) on biomarker levels were evaluated. The mean individual benzene exposure of laboratory workers (24.40+/-5.82 ppb) and that of gasoline service attendants (112.41+/-13.92 ppb) were significantly higher than in controls (1.39+/-0.17 ppb, p<0.001). Blood benzene levels of laboratory workers (169.12+/-30.60 ppt) and gasoline service attendants (483.46+/-59.62 ppt) were significantly higher than those of the controls (43.30+/-4.89 ppt, p<0.001). Trans,trans-muconic acid levels in post-shift urine samples collected from laboratory workers (0.14+/-0.02 mg/g creatinine) and gasoline service attendants (0.20+/-0.02 mg/g creatinine) were significantly higher than in urine samples of controls (0.04+/-0.01 mg/g creatinine, p<0.001). The level of benzene exposure was correlated with blood benzene levels (R2=0.65, p<0.01) and post-shift urinary trans,trans-muconic acid concentrations (R2=0.49, p<0.01). As a biomarker of early effect, DNA-repair capacity was assessed by use of the cytogenetic challenge assay, i.e., chromosomal aberrations in peripheral lymphocytes were assessed after challenging blood cultures with 1 Gy gamma radiation. A significantly lower DNA-repair capacity--determined as dicentrics in laboratory workers (0.17 per metaphase cell) and in gasoline service attendants (0.19 per metaphase cell) compared with controls (0.12 per metaphase cell, p<0.001)--was observed. The frequency

  7. [Effect of genetic polymorphisms of microsomal epoxide hydrolase on urinary 1-hydroxypyrene levels in coke oven workers].

    PubMed

    Leng, Shu-Guang; Zheng, Yu-Xin; Huang, Chuan-Feng; Dai, Yu-Fei; Li, Xiao-Hua; Niu, Yong; Pan, Zu-Fei; Li, Tao; He, Feng-Sheng

    2004-08-01

    To investigate the associations of polymorphisms of metabolic enzyme genes with urinary 1-hydroxypyrene levels in coke oven workers. One hundred and forty-eight workers from a coke oven plant and 69 controls without occupational PAHs exposure were selected in this study. Urinary 1-hydroxypyrene was detected by high performance liquid chromatography with florescence detector. The genotypes at I462V site in exon 7 of CYP1A1 gene, GSTM1, GSTT1, I105V site in GSTP1gene, Pst1 and Dra1 sites in CYP2E1 gene, P187S site in NQO1 gene, Kpn1, BamH1 and Taq1 sites in NAT2 gene, and H113Y, R139H sites in mEH gene were determined by PCR-based methods. Personal information including occupational exposure history, age, sex, smoking and drinking status was collected by the questionnaire. The level of urinary 1-hydroxypyrene in coke oven workers [(5.61 +/- 1.04) mol/mol Cr] was higher than that in control [(0.74 +/- 0.32) micro mol/mol Cr]. After adjusting external occupational exposure category and smoking, coke oven workers with variant homozygotes at H113Y site of mEH gene had significantly higher urinary 1-hydroxypyrene concentrations than those with heterozygotes, and wild homozygotes (6.41 +/- 1.09 vs. 6.24 +/- 1.08, and 4.62 +/- 0.95 micro mol/mol Cr, P < 0.05), and gene-gene interaction was found between CYP1A1 and mEH. Genetic polymorphism of mEH gene could be a susceptible biomarker in coke oven workers which was involved in the individual susceptibility on metabolism of PAHs.

  8. Metabolic polymorphisms and biomarkers of effect in the biomonitoring of occupational exposure to low-levels of benzene: state of the art.

    PubMed

    De Palma, G; Manno, M

    2014-12-01

    Current levels of occupational exposure to benzene, a genotoxic human carcinogen, in Western countries are reduced by two-three orders of magnitude (from ppm to ppb) as compared to the past. However, as benzene toxicity is strongly dependent on biotransformation and recent evidence underlines a higher efficiency of bio-activation pathways at lower levels of exposure, toxic effects at low doses could be higher than expected, particularly in susceptible individuals. Currently, biological monitoring can allow accurate exposure assessment, relying on sensitive and specific enough biomarkers of internal dose. The availability of similarly reliable biomarkers of early effect or susceptibility could greatly improve the risk assessment process to such an extent that risk could even be assessed at the individual level. As to susceptibility biomarkers, functional genetic polymorphisms of relevant biotransformation enzymes may modulate the risk of adverse effects (NQO1) and the levels of biomarkers of internal dose, in particular S-phenylmercapturic acid (GSTM1, GSTT1, GSTA1). Among biomarkers of early effect, genotoxicity indicators, although sensitive in some cases, are too aspecific for routine use in occupational health surveillance programmes. Currently only the periodical blood cell count seems suitable enough to be applied in the longitudinal monitoring of effects from benzene exposure. Novel biomarkers of early effect are expected from higher collaboration among toxicologists and clinicians, also using advanced "omics" techniques.

  9. Polymorphous computing fabric

    DOEpatents

    Wolinski, Christophe Czeslaw [Los Alamos, NM; Gokhale, Maya B [Los Alamos, NM; McCabe, Kevin Peter [Los Alamos, NM

    2011-01-18

    Fabric-based computing systems and methods are disclosed. A fabric-based computing system can include a polymorphous computing fabric that can be customized on a per application basis and a host processor in communication with said polymorphous computing fabric. The polymorphous computing fabric includes a cellular architecture that can be highly parameterized to enable a customized synthesis of fabric instances for a variety of enhanced application performances thereof. A global memory concept can also be included that provides the host processor random access to all variables and instructions associated with the polymorphous computing fabric.

  10. Tobacco and estrogen metabolic polymorphisms and risk of non-small cell lung cancer in women

    PubMed Central

    Cote, Michele L.; Yoo, Wonsuk; Wenzlaff, Angela S.; Prysak, Geoffrey M.; Santer, Susan K.; Claeys, Gina B.; Van Dyke, Alison L.; Land, Susan J.; Schwartz, Ann G.

    2009-01-01

    To explore the potential role for estrogen in lung cancer susceptibility, candidate single-nucleotide polymorphism (SNPs) in tobacco and estrogen metabolism genes were evaluated. Population-based cases (n = 504) included women aged 18–74, diagnosed with NSCLC in metropolitan Detroit between November 2001 and October 2005. Population-based controls (n = 527) were identified through random digit dialing and matched on race and age. Eleven SNPs in 10 different genes were examined in relation to risk: CYP1A1 Msp1, CYP1A1 Ile462Val, CYP1B1 Leu432Val, CYP17, CYP19A1, XRCC1 Gln399Arg, COMT Val158Met, NQO1 Pro187Ser, GSTM1, GSTT1 and GSTP1 Ile105Val. Lung cancer risk associated with individual SNPs was seen for GSTP1 [A allele; odds ratio (OR) = 1.85; 95% confidence interval (CI), 1.04–3.27] and XRCC1 (A/A genotype; OR = 1.68; 95% CI, 1.01–2.79) in white women and CYP1B1 (G allele; OR = 11.1; 95% CI, 1.18–104) in black women smokers. White women smokers carrying two risk genotypes at the following loci were at increased risk of lung cancer compared with individuals not carrying risk alleles at these loci: CYP17 and GSTM1, COMT and GSTM1, CYP17 and GSTT1, XRCC1 and GSTP1, CYP1B1 and XRCC1 and COMT and XRCC1. The most parsimonious model of lung cancer risk in white smoking women included age, family history of lung cancer, history of chronic lung disease, pack-years, body mass index, XRCC1 A/A genotype, GSTM1 null and COMT A/G or G/G genotype. These findings support the need for continued study of estrogen in relation to lung cancer risk. Polymorphisms in the tobacco metabolism, estrogen metabolism and DNA repair pathways will be useful in developing more predictive models of individual risk. PMID:19174490

  11. Polymorphism and solvatomorphism 2008.

    PubMed

    Brittain, Harry G

    2010-09-01

    Papers and patents that deal with polymorphism and solvatomorphism have been summarized in an annual review. The review is divided into sections that cover articles of general interest, computational and theoretical studies, preparative and isolation methods, structural characterization and properties of polymorphic and solvatomorphic systems, studies of phase transformations, effects associated with secondary processing, and United States patents issued during 2008.

  12. Polymorphism in Carbamazepine Cocrystals

    PubMed Central

    Porter, William W.; Elie, Sophia C.; Matzger, Adam J.

    2009-01-01

    Cocrystals of carbamazepine with nicotinamide and saccharin are shown to be polymorphic. Two polymorphs of carbamazepine-nicotinamide (CBZ-NCT) cocrystals and two polymorphs of carbamazepine-saccharin (CBZ-SAC) cocrystals were grown from solution in the presence of polymer heteronuclei. The two CBZ-NCT polymorphs, CBZ-NCT I and a polymer nucleated (PN) form of CBZ-NCT, were characterized by Raman spectroscopy and powder X-ray diffraction. CBZ-SAC II, a new polymorph, was found to be in the monoclinic space group C2/c with a = 35.72 Å, b = 6.84 Å, c = 16.11 Å, and β = 98.03°. The unique feature of CBZ-SAC II is the formation of a heterosynthon between the carbamazepine and saccharin. These results are notable because CBZ-NCT and CBZ-SAC are among the most widely studied pharmaceutical cocrystals. PMID:19367342

  13. Exploiting Novel Calcium-Mediated Apoptotic Processes for the Treatment of Human Breast Cancers with Elevated Nqo1 Levels

    DTIC Science & Technology

    2008-03-01

    886-895, 2000. 13. Allalunis-Turner, M. J., Barron , G. M., Day, R. S., 3rd, Dobler, K. D., and Mirzayans, R. Isolation of two cell lines from a human...Mol Cell Biol 2003;23:5836–48. 34. Allalunis-Turner MJ, Barron GM, Day RS III, Dobler KD, Mirzayans R. Isolation of two cell lines from a human...essential for DNA-pkcs phosphorylations at T2609 cluster upon DNA double strand break. J Biol Chem 2006;282:6582–7. 48. Michel B, Ehrlich SD, Uzest M. DNA

  14. Exploiting Novel-Calcium-Mediated Apoptotic Processes for the Treatment of Human Breast Cancers with Elevated NQO1 Levels

    DTIC Science & Technology

    2007-03-01

    catalytic subunit is required for rejoining of DNA double-strand breaks. Genes Dev, 16: 2333-2338, 2002. 18. Allalunis-Turner, M. J., Barron , G. M., Day...1998. 22 23. Lees-Miller, S. P., Godbout, R., Chan, D. W., Weinfeld, M., Day, R. S., 3rd, Barron , G. M., and Allalunis-Turner, J. Absence of p350...Allalunis-Turner, M. J., Barron , G. M., Day, R. S., 3rd, Dobler, K. D., and Mirzayans, R. Isolation of two cell lines from a human malignant glioma

  15. Fetal Genotype for the Xenobiotic Metabolizing Enzyme "NQO1" Influences Intrauterine Growth among Infants Whose Mothers Smoked during Pregnancy

    ERIC Educational Resources Information Center

    Price, Thomas S.; Grosser, Tilo; Plomin, Robert; Jaffee, Sara R.

    2010-01-01

    Maternal smoking during pregnancy retards fetal growth and depresses infant birth weight. The magnitude of these effects may be moderated by fetal genotype. The current study investigated maternal smoking, fetal genotype, and fetal growth in a large population sample of dizygotic twins. Maternal smoking retarded fetal growth in a dose-dependent…

  16. Fetal Genotype for the Xenobiotic Metabolizing Enzyme "NQO1" Influences Intrauterine Growth among Infants Whose Mothers Smoked during Pregnancy

    ERIC Educational Resources Information Center

    Price, Thomas S.; Grosser, Tilo; Plomin, Robert; Jaffee, Sara R.

    2010-01-01

    Maternal smoking during pregnancy retards fetal growth and depresses infant birth weight. The magnitude of these effects may be moderated by fetal genotype. The current study investigated maternal smoking, fetal genotype, and fetal growth in a large population sample of dizygotic twins. Maternal smoking retarded fetal growth in a dose-dependent…

  17. Disappearing Polymorphs Revisited

    PubMed Central

    Bučar, Dejan-Krešimir; Lancaster, Robert W; Bernstein, Joel

    2015-01-01

    Nearly twenty years ago, Dunitz and Bernstein described a selection of intriguing cases of polymorphs that disappear. The inability to obtain a crystal form that has previously been prepared is indeed a frustrating and potentially serious problem for solid-state scientists. This Review discusses recent occurrences and examples of disappearing polymorphs (as well as the emergence of elusive crystal forms) to demonstrate the enduring relevance of this troublesome, but always captivating, phenomenon in solid-state research. A number of these instances have been central issues in patent litigations. This Review, therefore, also highlights the complex relationship between crystal chemistry and the law. PMID:26031248

  18. Polymorphism of sorbitol

    NASA Astrophysics Data System (ADS)

    Nezzal, Amale; Aerts, Luc; Verspaille, Marleen; Henderickx, Geert; Redl, Andreas

    2009-07-01

    The polymorphism of sorbitol was investigated, confirming the existence of four anhydrous crystalline phases plus the hydrate. The crystallised melt (CM), the alpha form, and the gamma form were obtained via a dry route. The CM was confirmed to be a crystalline state with a spherulite morphology. The alpha form was obtained via direct conversion from the CM, in contrast to more complicated routes previously reported, and was found to have a very high crystallinity. Gamma crystals were obtained by seeding the melt at high temperature; however, crystallinity was clearly less than for alpha crystals. Despite its lower crystallinity, the gamma polymorph was found to be the most stable of the anhydrous crystalline forms; this was confirmed by its high melting point and low hygroscopicity. In contrast, the alpha polymorph has a relatively high melting point but lacks moisture stability at high relative humidity. The hydrate form has the same resistance to moisture as the gamma form, but melts at a lower temperature. The combination of both a high melting point and high stability in the presence of water makes the gamma polymorph best suited for confectionary applications.

  19. Polymorphous Perversity in Texts

    ERIC Educational Resources Information Center

    Johnson-Eilola, Johndan

    2012-01-01

    Here's the tricky part: If we teach ourselves and our students that texts are made to be broken apart, remixed, remade, do we lose the polymorphous perversity that brought us pleasure in the first place? Does the pleasure of transgression evaporate when the borders are opened?

  20. Enzyme polymorphisms in Canarium

    USDA-ARS?s Scientific Manuscript database

    Fifty-two accessions of Canarium involving seven species, C. ovatum, C. album, C. megalanthum, C. harveyi, C. indicum, C. mehenbethene, and C. odontophyllum were studied for isozyme polymorphisms. Starch gel electrophoresis with a histidine-citrate buffer system (pH 6.5) was employed to assay six en...

  1. Investigation of Uranium Polymorphs

    SciTech Connect

    Sweet, Lucas E.; Henager, Charles H.; Hu, Shenyang Y.; Johnson, Timothy J.; Meier, David E.; Peper, Shane M.; Schwantes, Jon M.

    2011-08-01

    The UO3-water system is complex and has not been fully characterized, even though these species are common throughout the nuclear fuel cycle. As an example, most production schemes for UO3 result in a mixture of up to six or more different polymorphic phases, and small differences in these conditions will affect phase genesis that ultimately result in measureable changes to the end product. As a result, this feature of the UO3-water system may be useful as a means for determining process history. This research effort attempts to better characterize the UO3-water system with a variety of optical techniques for the purpose of developing some predictive capability for estimating process history in polymorphic phases of unknown origin. Three commercially relevant preparation methods for the production of UO3 were explored. Previously unreported low temperature routes to β- and γ-UO3 were discovered. Raman and fluorescence spectroscopic libraries were established for pure and mixed polymorphic forms of UO3 in addition to the common hydrolysis products of UO3. An advantage of the sensitivity of optical fluorescence microscopy over XRD has been demonstrated. Preliminary aging studies of the α and γ forms of UO3 have been conducted. In addition, development of a 3-D phase field model used to predict phase genesis of the system was initiated. Thermodynamic and structural constants that will feed the model have been gathered from the literature for most of the UO3 polymorphic phases.

  2. Polymorphism in Energetic Materials

    DTIC Science & Technology

    2008-01-01

    salicylic acid ) was first prepared by Charles Frederic Gerhardt in 1853, a second polymorph of this drug was not discovered until 2005. Studies have...the crystallization conditions post- synthesis were not recorded, reproducing the condi- tions resulting in the analyzed sample was not possible. All

  3. Polymorphism of phosphoric oxide

    USGS Publications Warehouse

    Hill, W.L.; Faust, G.T.; Hendricks, S.B.

    1943-01-01

    The melting points and monotropic relationship of three crystalline forms of phosphoric oxide were determined by the method of quenching. Previous vapor pressure data are discussed and interpreted to establish a pressure-temperature diagram (70 to 600??) for the one-component system. The system involves three triple points, at which solid, liquid and vapor (P4O10) coexist in equilibrium, namely: 420?? and 360 cm., 562?? and 43.7 cm. and 580?? and 55.5 cm., corresponding to the hexagonal, orthorhombic and stable polymorphs, respectively, and at least two distinct liquids, one a stable polymer of the other, which are identified with the melting of the stable form and the hexagonal modification, respectively. Indices of refraction of the polymorphs and glasses were determined. The density and the thermal, hygroscopic and structural properties of the several phases are discussed.

  4. Facts and fictions about polymorphism.

    PubMed

    Cruz-Cabeza, Aurora J; Reutzel-Edens, Susan M; Bernstein, Joel

    2015-12-07

    We present new facts about polymorphism based on (i) crystallographic data from the Cambridge Structural Database (CSD, a database built over 50 years of community effort), (ii) 229 solid form screens conducted at Hoffmann-La Roche and Eli Lilly and Company over the course of 8+ and 15+ years respectively and (iii) a dataset of 446 polymorphic crystals with energies and properties computed with modern DFT-d methods. We found that molecular flexibility or size has no correlation with the ability of a compound to be polymorphic. Chiral molecules, however, were found to be less prone to polymorphism than their achiral counterparts and compounds able to hydrogen bond exhibit only a slightly higher propensity to polymorphism than those which do not. Whilst the energy difference between polymorphs is usually less than 1 kcal mol(-1), conformational polymorphs are capable of differing by larger values (up to 2.5 kcal mol(-1) in our dataset). As overall statistics, we found that one in three compounds in the CSD are polymorphic whilst at least one in two compounds from the Roche and Lilly set display polymorphism with a higher estimate of up to three in four when compounds are screened intensively. Whilst the statistics provide some guidance of expectations, each compound constitutes a new challenge and prediction and realization of targeted polymorphism still remains a holy grail of materials sciences.

  5. Stability of Polymeric Crystalline Polymorphs

    NASA Astrophysics Data System (ADS)

    Sinkovits, Daniel W.; Kumar, Sanat K.

    2014-03-01

    In the search for polymeric materials with novel properties, such as high dielectric constant and low loss, an important attribute of a material is its crystal structure. Most polymers can crystallize into multiple polymorphs whose properties vary. Therefore, the question of which polymorphs are thermodynamically preferred under what conditions is of great importance. We generate polymorphs using atomistic molecular dynamics simulations and tackle the question of stability using a combination of molecular dynamics and Monte Carlo techniques. Multidisciplinary University Research Initiative (MURI).

  6. The Third Ambient Aspirin Polymorph

    DOE PAGES

    Shtukenberg, Alexander G.; Hu, Chunhua T.; Zhu, Qiang; ...

    2017-05-17

    Polymorphism in aspirin (acetylsalicylic acid), one of the most widely consumed medications, was equivocal until the structure of a second polymorph II, similar in structure to the original form I, was reported in 2005. Here, the third ambient polymorph of aspirin is described. Lastly, it was crystallized from the melt and its structure was determined using a combination of X-ray powder diffraction analysis and crystal structure prediction algorithms.

  7. Significant interactions between maternal PAH exposure and single nucleotide polymorphisms in candidate genes on B[a]P-DNA adducts in a cohort of non-smoking Polish mothers and newborns.

    PubMed

    Iyer, Shoba; Wang, Ya; Xiong, Wei; Tang, Deliang; Jedrychowski, Wieslaw; Chanock, Stephen; Wang, Shuang; Stigter, Laura; Mróz, Elzbieta; Perera, Frederica

    2016-08-26

    Polycyclic aromatic hydrocarbons (PAH) are a class of chemicals common in the environment. Certain PAH are carcinogenic, although the degree to which genetic variation influences susceptibility to carcinogenic PAH remains unclear. Also unknown is the influence of genetic variation on the procarcinogenic effect of in utero exposures to PAH. Benzo[a]pyrene (B[a]P) is a well-studied PAH that is classified as a known human carcinogen. Within our Polish cohort, we explored interactions between maternal exposure to airborne PAH during pregnancy and maternal and newborn single nucleotide polymorphisms (SNPs) in plausible B[a]P metabolism genes on B[a]P-DNA adducts in paired cord blood samples. The study subjects included non-smoking women (n = 368) with available data on maternal PAH exposure, paired cord adducts, and genetic data who resided in Krakow, Poland. We selected eight common variants in maternal and newborn candidate genes related to B[a]P metabolism, detoxification, and repair for our analyses: CYP1A1, CYP1A2, CYP1B1, GSTM1, GSTT2, NQO1, and XRCC1 We observed significant interactions between maternal PAH exposure and SNPs on cord B[a]P-DNA adducts in the following genes: maternal CYP1A1 and GSTT2, and newborn CYP1A1 and CYP1B1 These novel findings highlight differences in maternal and newborn genetic contributions to B[a]P-DNA adduct formation and have the potential to identify at-risk subpopulations who are susceptible to the carcinogenic potential of B[a]P.

  8. Polymorphic Electronic Circuits

    NASA Technical Reports Server (NTRS)

    Stoica, Adrian

    2004-01-01

    Polymorphic electronics is a nascent technological discipline that involves, among other things, designing the same circuit to perform different analog and/or digital functions under different conditions. For example, a circuit can be designed to function as an OR gate or an AND gate, depending on the temperature (see figure). Polymorphic electronics can also be considered a subset of polytronics, which is a broader technological discipline in which optical and possibly other information- processing systems could also be designed to perform multiple functions. Polytronics is an outgrowth of evolvable hardware (EHW). The basic concepts and some specific implementations of EHW were described in a number of previous NASA Tech Briefs articles. To recapitulate: The essence of EHW is to design, construct, and test a sequence of populations of circuits that function as incrementally better solutions of a given design problem through the selective, repetitive connection and/or disconnection of capacitors, transistors, amplifiers, inverters, and/or other circuit building blocks. The evolution is guided by a search-and-optimization algorithm (in particular, a genetic algorithm) that operates in the space of possible circuits to find a circuit that exhibits an acceptably close approximation of the desired functionality. The evolved circuits can be tested by computational simulation (in which case the evolution is said to be extrinsic), tested in real hardware (in which case the evolution is said to be intrinsic), or tested in random sequences of computational simulation and real hardware (in which case the evolution is said to be mixtrinsic).

  9. Energetics of kaolin polymorphs

    SciTech Connect

    Ligny, D. de; Navrotsky, A.

    1999-04-01

    The enthalpy of formation of kaolin polymorphs at 298 K has been determined by drop-solution calorimetry into molten lead borate at 975 K. Corrections have been made for impurities in the samples. The standard enthalpy of formation from the elements is: kaolinite {minus}4120.2 {+-} 6.6 kJ/mol, dickite {minus}4107.6 {+-} 5.7 kJ/mol, nacrite {minus}4104.0 {+-} 7.6 kJ/mol, and halloysite {minus}4097.5 {+-} 5.6 kJ/mol. Using entropy data from the literature, the standard free energy of formation from the elements at 298 K is /{minus}3799.4 {+-} 6.4 kJ/mol for kaolinite, {minus}3785.1 {+-} 5.6 kJ/mol for dickite, and {minus}3776.8 {+-} 5.8 kJ/mol for halloysite. The effect of crystallinity (Hinckley index ranging from 1.6 to 0.4) on the enthalpy of formation of kaolinite is smaller than 5 kJ/mol, the experimental error. The relative stability of the polymorphs probably does not change significantly with pressure and temperature over their range of occurrence. Thus the geological occurrence of halloysite, nacrite, and dickite, which are metastable phases, must be interpreted in terms of kinetics or as the result of a specific synthesis path, rather than as resulting from changes in the thermodynamically stable phase assemblage.

  10. Polymorphic Evolutionary Games.

    PubMed

    Fishman, Michael A

    2016-06-07

    In this paper, I present an analytical framework for polymorphic evolutionary games suitable for explicitly modeling evolutionary processes in diploid populations with sexual reproduction. The principal aspect of the proposed approach is adding diploid genetics cum sexual recombination to a traditional evolutionary game, and switching from phenotypes to haplotypes as the new game׳s pure strategies. Here, the relevant pure strategy׳s payoffs derived by summing the payoffs of all the phenotypes capable of producing gametes containing that particular haplotype weighted by the pertinent probabilities. The resulting game is structurally identical to the familiar Evolutionary Games with non-linear pure strategy payoffs (Hofbauer and Sigmund, 1998. Cambridge University Press), and can be analyzed in terms of an established analytical framework for such games. And these results can be translated into the terms of genotypic, and whence, phenotypic evolutionary stability pertinent to the original game.

  11. Gene Polymorphisms in Chronic Periodontitis

    PubMed Central

    Laine, Marja L.; Loos, Bruno G.; Crielaard, W.

    2010-01-01

    We aimed to conduct a review of the literature for gene polymorphisms associated with chronic periodontitis (CP) susceptibility. A comprehensive search of the literature in English was performed using the keywords: periodontitis, periodontal disease, combined with the words genes, mutation, or polymorphism. Candidate gene polymorphism studies with a case-control design and reported genotype frequencies in CP patients were searched and reviewed. There is growing evidence that polymorphisms in the IL1, IL6, IL10, vitamin D receptor, and CD14 genes may be associated with CP in certain populations. However, carriage rates of the rare (R)-allele of any polymorphism varied considerably among studies and most of the studies appeared under-powered and did not correct for other risk factors. Larger cohorts, well-defined phenotypes, control for other risk factors, and analysis of multiple genes and polymorphisms within the same pathway are needed to get a more comprehensive insight into the contribution of gene polymorphisms in CP. PMID:20339487

  12. SOD2 polymorphisms: unmasking the effect of polymorphism on splicing

    PubMed Central

    Shao, Jing; Chen, Lishan; Marrs, Brian; Lee, Lin; Huang, Hai; Manton, Kenneth G; Martin, George M; Oshima, Junko

    2007-01-01

    Background The SOD2 gene encodes an antioxidant enzyme, mitochondrial superoxide dismutase. SOD2 polymorphisms are of interest because of their potential roles in the modulation of free radical-mediated macromolecular damage during aging. Results We identified a new splice variant of SOD2 in human lymphoblastoid cell lines (LCLs). The alternatively spliced product was originally detected by exon trapping of a minigene in order to examine the consequences of an intronic polymorphism found upstream of exon 4 (nucleotide 8136, 10T vs 9T). Examination of the transcripts derived from the endogenous loci in five LCLs with or without the intron 3 polymorphism revealed low levels of an in-frame deletion of exon 4 that were different from those detected by the exon trap assay. This suggested that exon trapping of the minigene unmasked the effect of the 10T vs 9T polymorphism on the splicing of the adjacent exon. We also determined the frequencies of single nucleotide polymorphisms in a sample of US African-Americans and non-African-Americans ages 65 years and older who participated in the 1999 wave of the National Long Term Care Survey (NLTCS). Particularly striking differences between African-Americans and non-African-Americans were found for the frequencies of genotypes at the 10T/9T intron 3 polymorphism. Conclusion Exon trapping can unmask in vitro splicing differences caused by a 10T/9T intron 3 polymorphism. Given the recent evidence that SOD2 is in a region on chromosome 6 linked to susceptibility to hypertension, it will be of interest to investigate possible associations of this polymorphism with cardiovascular disorders. PMID:17331249

  13. Preferential Nucleation during Polymorphic Transformations

    NASA Astrophysics Data System (ADS)

    Sharma, H.; Sietsma, J.; Offerman, S. E.

    2016-08-01

    Polymorphism is the ability of a solid material to exist in more than one phase or crystal structure. Polymorphism may occur in metals, alloys, ceramics, minerals, polymers, and pharmaceutical substances. Unresolved are the conditions for preferential nucleation during polymorphic transformations in which structural relationships or special crystallographic orientation relationships (OR’s) form between the nucleus and surrounding matrix grains. We measured in-situ and simultaneously the nucleation rates of grains that have zero, one, two, three and four special OR’s with the surrounding parent grains. These experiments show a trend in which the activation energy for nucleation becomes smaller - and therefore nucleation more probable - with increasing number of special OR’s. These insights contribute to steering the processing of polymorphic materials with tailored properties, since preferential nucleation affects which crystal structure forms, the average grain size and texture of the material, and thereby - to a large extent - the final properties of the material.

  14. Preferential Nucleation during Polymorphic Transformations

    PubMed Central

    Sharma, H.; Sietsma, J.; Offerman, S. E.

    2016-01-01

    Polymorphism is the ability of a solid material to exist in more than one phase or crystal structure. Polymorphism may occur in metals, alloys, ceramics, minerals, polymers, and pharmaceutical substances. Unresolved are the conditions for preferential nucleation during polymorphic transformations in which structural relationships or special crystallographic orientation relationships (OR’s) form between the nucleus and surrounding matrix grains. We measured in-situ and simultaneously the nucleation rates of grains that have zero, one, two, three and four special OR’s with the surrounding parent grains. These experiments show a trend in which the activation energy for nucleation becomes smaller – and therefore nucleation more probable - with increasing number of special OR’s. These insights contribute to steering the processing of polymorphic materials with tailored properties, since preferential nucleation affects which crystal structure forms, the average grain size and texture of the material, and thereby - to a large extent - the final properties of the material. PMID:27484579

  15. Preferential Nucleation during Polymorphic Transformations.

    PubMed

    Sharma, H; Sietsma, J; Offerman, S E

    2016-08-03

    Polymorphism is the ability of a solid material to exist in more than one phase or crystal structure. Polymorphism may occur in metals, alloys, ceramics, minerals, polymers, and pharmaceutical substances. Unresolved are the conditions for preferential nucleation during polymorphic transformations in which structural relationships or special crystallographic orientation relationships (OR's) form between the nucleus and surrounding matrix grains. We measured in-situ and simultaneously the nucleation rates of grains that have zero, one, two, three and four special OR's with the surrounding parent grains. These experiments show a trend in which the activation energy for nucleation becomes smaller - and therefore nucleation more probable - with increasing number of special OR's. These insights contribute to steering the processing of polymorphic materials with tailored properties, since preferential nucleation affects which crystal structure forms, the average grain size and texture of the material, and thereby - to a large extent - the final properties of the material.

  16. New polymorphous computing fabric.

    SciTech Connect

    Wolinski, C.; Gokhale, M.; McCabe, K. P.

    2002-01-01

    This paper introduces a new polymorphous computing Fabric well suited to DSP and Image Processing and describes its implementation on a Configurable System on a Chip (CSOC). The architecture is highly parameterized and enables customization of the synthesized Fabric to achieve high performance for a specific class of application. For this reason it can be considered to be a generic model for hardware accelerator synthesis from a high level specification. Another important innovation is the Fabric uses a global memory concept, which gives the host processor random access to all the variables and instructions on the Fabric. The Fabric supports different computing models including MIMD, SPMD and systolic flow and permits dynamic reconfiguration. We present a specific implementation of a bank of FIR filters on a Fabric composed of 52 cells on the Altera Excalibur ARM running at 33 MHz. The theoretical performance of this Fabric is 1.8 GMACh. For the FIR application we obtain 1.6 GMAC/s real performance. Some automatic tools have been developed like the tool to provide a host access utility and assembler.

  17. Polymorphous light eruption.

    PubMed

    Hölzle, E; Plewig, G; von Kries, R; Lehmann, P

    1987-03-01

    Polymorphous light eruption (PLE) is a common photodermatosis of unknown etiology. It afflicts mainly fair-skinned patients, with a preponderance of young females. There is, however, no absolute restriction as to age, sex, or race. Clinical variants include the papular, vesiculo-bullous, and hemorrhagic variety, as well as plaque, erythema multiforme-like, and insect bite (strophulus)-like types. Skin lesions appear only in certain exposed areas hours or a few days after intense sunshine, and are nearly always monomorphous in the same patient. The rash subsides spontaneously within several days without leaving scars. The histopathologic picture is characteristic and shows a perivascular lymphocytic infiltrate in the upper and middle corium with subepidermal edema, vacuolization of basal cells, and spongiosis in the lower epidermis. The most important differential diagnoses are solar urticaria, photosensitive erythema multiforme, and lupus erythematosus. The action spectrum of PLE is under debate. Reproduction of skin lesions has been reported with UVB, UVA, and, rarely, visible light, with UVA probably being the most effective part of the spectrum. More important than treatment of PLE is prophylaxis. UVA- and UVB-effective sunscreens are of some help. Phototherapy and especially photochemotherapy (psoralen + UVA; PUVA) offer effective ways to decrease light sensitivity. Systemic treatment with chloroquine or beta-carotene has been disappointing.

  18. [Polymorph transformation of solid drugs].

    PubMed

    Zhang, Qi; Mei, Xue-feng

    2015-05-01

    For the minimized phase transtorming risk, the most stable polymorph is generally considered as the desirable solid form for pharmaceutical applications. However, occasionally, the stable form may have some shortcomings such as low solubility, dissolution rate and bioavailability, etc. In that case, the metastable form which is kinetically stable at room or lower temperature could be selected. Using metastable form may result in polymorph transformation in pharmaceutical manufacture and storage. Hence, the knowledge of the transformation between solid forms is essential to the development of the drug materials. In this paper, we will review the recent studies in the area of crystal conversion of polymorphs and hydrates, to illustrate some cases to introduce the types, conditions and mechanisms of the crystalline solid transformation.

  19. Polymorphic light eruption sine eruption.

    PubMed

    Dover, J S; Hawk, J L

    1988-01-01

    We describe seven patients, four female and three male, who developed intense pruritus on sun-exposed skin without visible change. The clinical features resembled those of polymorphic light eruption (PLE) without rash. Four patients also occasionally developed typical PLE upon sun exposure, but sun-induced pruritus alone occurred most frequently. No patient was taking any drug therapy. One patient developed similar pruritus following solar simulated irradiation, and one following PUVA therapy. All other laboratory investigations were negative. Treatment with low dose UVB phototherapy or PUVA therapy was effective. The condition, which we have called polymorphic light eruption sine eruptione (PLESE), appears to be a variant of PLE not previously reported.

  20. Crystal Polymorphs of Barbital: News about a Classic Polymorphic System

    PubMed Central

    2013-01-01

    Barbital is a hypnotic agent that has been intensely studied for many decades. The aim of this work was to establish a clear and comprehensible picture of its polymorphic system. Four of the six known solid forms of barbital (denoted I0, III, IV, and V) were characterized by various analytical techniques, and the thermodynamic relationships between the polymorph phases were established. The obtained data permitted the construction of the first semischematic energy/temperature diagram for the barbital system. The modifications I0, III, and V are enantiotropically related to one another. Polymorph IV is enantiotropically related to V and monotropically related to the other two forms. The transition points for the pairs I0/III, I0/V, and III/IV lie below 20 °C, and the transition point for IV/V is above 20 °C. At room temperature, the order of thermodynamic stability is I0 > III > V > IV. The metastable modification III is present in commercial samples and has a high kinetic stability. The solid-state NMR spectra provide information on aspects of crystallography (viz., the asymmetric units and the nature of hydrogen bonding). The known correlation between specific N–H···O=C hydrogen bonding motifs of barbiturates and certain IR characteristics was used to predict the H-bonded pattern of polymorph IV. PMID:24283960

  1. Triclinic polymorph of dibenzotetra-thia-fulvalene.

    PubMed

    Mamada, Masashi; Yamashita, Yoshiro

    2009-08-08

    Crystals of the title compound (DBTTF), C(14)H(8)S(4), feature a triclinic polymorph different from two known monoclinic polymorphs. In this form, there are two independent centrosymmetric half-mol-ecules in the asymmetric unit. Although the mol-ecular orientations are relatively similar to one of monoclinic polymorphs, the packing motif is different.

  2. Preferential nucleation during polymorphic transformations

    SciTech Connect

    Sharma, H.; Sietsma, J.; Offerman, S. E.

    2016-08-03

    Polymorphism is the ability of a solid material to exist in more than one phase or crystal structure. Polymorphism may occur in metals, alloys, ceramics, minerals, polymers, and pharmaceutical substances. Unresolved are the conditions for preferential nucleation during polymorphic transformations in which structural relationships or special crystallographic orientation relationships (OR’s) form between the nucleus and surrounding matrix grains. We measured in-situ and simultaneously the nucleation rates of grains that have zero, one, two, three and four special OR’s with the surrounding parent grains. These experiments show a trend in which the activation energy for nucleation becomes smaller – and therefore nucleation more probable - with increasing number of special OR’s. As a result, these insights contribute to steering the processing of polymorphic materials with tailored properties, since preferential nucleation affects which crystal structure forms, the average grain size and texture of the material, and thereby - to a large extent - the final properties of the material.

  3. Preferential nucleation during polymorphic transformations

    DOE PAGES

    Sharma, H.; Sietsma, J.; Offerman, S. E.

    2016-08-03

    Polymorphism is the ability of a solid material to exist in more than one phase or crystal structure. Polymorphism may occur in metals, alloys, ceramics, minerals, polymers, and pharmaceutical substances. Unresolved are the conditions for preferential nucleation during polymorphic transformations in which structural relationships or special crystallographic orientation relationships (OR’s) form between the nucleus and surrounding matrix grains. We measured in-situ and simultaneously the nucleation rates of grains that have zero, one, two, three and four special OR’s with the surrounding parent grains. These experiments show a trend in which the activation energy for nucleation becomes smaller – and thereforemore » nucleation more probable - with increasing number of special OR’s. As a result, these insights contribute to steering the processing of polymorphic materials with tailored properties, since preferential nucleation affects which crystal structure forms, the average grain size and texture of the material, and thereby - to a large extent - the final properties of the material.« less

  4. Polymorphism in regulatory gene sequences

    PubMed Central

    Mitchison, N A

    2001-01-01

    The extensive polymorphism revealed in non-coding gene-regulatory sequences, particularly in the immune system, suggests that this type of genetic variation is functionally and evolutionarily far more important than has been suspected, and provides a lead to new therapeutic strategies. PMID:11178274

  5. Characterization of polymorphic ampicillin forms.

    PubMed

    Baraldi, C; Tinti, A; Ottani, S; Gamberini, M C

    2014-11-01

    In this work polymorphs of α-aminobenzylpenicillin (ampicillin), a β-lactamic antibiotic, were prepared and investigated by several experimental and theoretical methods. Amorphous monohydrate and three crystalline forms, the trihydrate, the crystal form I and the crystal form II, were investigated by FT-IR and micro-Raman. Also data obtained by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD) and hot-stage Raman spectroscopy are reported. Finally, quantum mechanical calculations were performed by density functional theory (DFT) to assist the assignment of spectroscopic experimental bands. For the first time, the ampicillin molecule in its zwitterionic form was studied at the B3LYP/aug-cc-pVDZ level and the corresponding theoretical vibrational spectra were computed. In fact, ampicillin in the crystal is in zwitterionic form and concentrations of this same form are quite relevant in solutions at physiological pH. Experimental and theoretical results allowed identification of specific features for polymorph characterization. Bands typical of the different polymorphs are identified both in IR and Raman spectra: in particular in the NH stretching region (IR), in the amide I+δNH region (both techniques), in the 1520-1490cm(-1) region (IR), in the 1320-1300cm(-1) and 1280-1220cm(-1) (IR), in the 1200-1170cm(-1) (Raman), in the amide V region (IR), and, finally, in the 715-640cm(-1) and 220-200cm(-1) (Raman). Interconversion among different polymorphs was investigated by hot-stage Raman spectroscopy and thermal analysis, clarifying the complex pattern of transformations undergone as a function of temperature and heating rate. In particular, DSC scans show how the trihydrate crystals transform into anhydrous forms on heating. Finally, stability tests demonstrated, after a two years period, that no transformation or degradation of the polymorphs occurred. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. Superhard monoclinic polymorph of carbon.

    PubMed

    Li, Quan; Ma, Yanming; Oganov, Artem R; Wang, Hongbo; Wang, Hui; Xu, Ying; Cui, Tian; Mao, Ho-Kwang; Zou, Guangtian

    2009-05-01

    We report a novel phase of carbon possessing a monoclinic C2/m structure (8 atoms/cell) identified using an ab initio evolutionary structural search. This polymorph, which we call M-carbon, is related to the (2x1) reconstruction of the (111) surface of diamond and can also be viewed as a distorted (through sliding and buckling of the sheets) form of graphite. It is stable over cold-compressed graphite above 13.4 GPa. The simulated x-ray diffraction pattern and near K-edge spectroscopy are in satisfactory agreement with the experimental data [W. L. Mao, Science 302, 425 (2003)10.1126/science.1089713] on overcompressed graphite. The hardness and bulk modulus of this new carbon polymorph are calculated to be 83.1 and 431.2 GPa, respectively, which are comparable to those of diamond.

  7. Superhard Monoclinic Polymorph of Carbon

    SciTech Connect

    Li, Quan; Ma, Yanming; Oganov, Artem R.; Wang, Hongbo; Wang, Hui; Xu, Ying; Cui, Tian; Mao, Ho-Kwang; Zou, Guangtian; Jilin; SBU; CIW

    2009-05-08

    We report a novel phase of carbon possessing a monoclinic C2/m structure (8 atoms/cell) identified using an ab initio evolutionary structural search. This polymorph, which we call M-carbon, is related to the (2x1) reconstruction of the (111) surface of diamond and can also be viewed as a distorted (through sliding and buckling of the sheets) form of graphite. It is stable over cold-compressed graphite above 13.4 GPa. The simulated x-ray diffraction pattern and near K-edge spectroscopy are in satisfactory agreement with the experimental data [W.L. Mao et al., Science 302, 425 (2003)] on overcompressed graphite. The hardness and bulk modulus of this new carbon polymorph are calculated to be 83.1 and 431.2 GPa, respectively, which are comparable to those of diamond.

  8. IPD: the Immuno Polymorphism Database.

    PubMed

    Robinson, James; Marsh, Steven G E

    2007-01-01

    The Immuno Polymorphism Database (IPD) (http://www.ebi.ac.uk/ipd/) is a set of specialist databases related to the study of polymorphic genes in the immune system. IPD currently consists of four databases: IPD-KIR, contains the allelic sequences of killer cell immunoglobulin-like receptors (KIRs); IPD-MHC, a database of sequences of the major histocompatibility complex (MHC) of different species; IPD-HPA, alloantigens expressed only on platelets; and IPD-ESTAB, which provides access to the European Searchable Tumour Cell Line Database, a cell bank of immunologically characterized melanoma cell lines. The IPD project works with specialist groups or nomenclature committees who provide and curate individual sections before they are submitted to IPD for online publication. The IPD project stores all the data in a set of related databases. Those sections with similar data, such as IPD-KIR and IPD-MHC, share the same database structure.

  9. Lipid Polymorphisms and Membrane Shape

    PubMed Central

    Frolov, Vadim A.; Shnyrova, Anna V.; Zimmerberg, Joshua

    2011-01-01

    Morphological plasticity of biological membrane is critical for cellular life, as cells need to quickly rearrange their membranes. Yet, these rearrangements are constrained in two ways. First, membrane transformations may not lead to undesirable mixing of, or leakage from, the participating cellular compartments. Second, membrane systems should be metastable at large length scales, ensuring the correct function of the particular organelle and its turnover during cellular division. Lipids, through their ability to exist with many shapes (polymorphism), provide an adequate construction material for cellular membranes. They can self-assemble into shells that are very flexible, albeit hardly stretchable, which allows for their far-reaching morphological and topological behaviors. In this article, we will discuss the importance of lipid polymorphisms in the shaping of membranes and its role in controlling cellular membrane morphology. PMID:21646378

  10. The Single Nucleotide Polymorphism Consortium

    NASA Technical Reports Server (NTRS)

    Morgan, Michael

    2003-01-01

    I want to discuss both the Single Nucleotide Polymorphism (SNP) Consortium and the Human Genome Project. I am afraid most of my presentation will be thin on law and possibly too high on rhetoric. Having been engaged in a personal and direct way with these issues as a trained scientist, I find it quite difficult to be always as objective as I ought to be.

  11. Explicit Polymorphism and CPS Conversion,

    DTIC Science & Technology

    1992-10-01

    programming language design , the concepts of polymorphism [14, 28, 39] and continuation-passing [38, 41, 43] are of particular interest. The use of...Principles of Programming Languages, January 1991. [9] Matthias Felleisen . The Calculi of X.-CS Conversion: A Syntactic Theory of Control and State in...Imperative Higher-Order Programming Languages. PhD thesis, Indiana University, Bloomington, IN, 1987. 18 [10] Matthias Felleisen and Daniel Friedman

  12. Chemical substitution in silica polymorph

    NASA Technical Reports Server (NTRS)

    Smith, J. V.; Steele, I. M.

    1984-01-01

    Ion and electron probe analyses are presented for trace elements (Al, Na, K, Li, Ti) in quartz, tridymite, cristobalite and melanophlogite. Quartz and melanophlogite show low levels of trace elements relative to tridymite and cristobalite. The previously determined alpha-beta inversion temperature decreases as the Al content of quartz increases. For all silica polymorphs, Al is greater than or equal to Na + K + Li on an atom basis, with the excess Al probably balanced by H.

  13. The Single Nucleotide Polymorphism Consortium

    NASA Technical Reports Server (NTRS)

    Morgan, Michael

    2003-01-01

    I want to discuss both the Single Nucleotide Polymorphism (SNP) Consortium and the Human Genome Project. I am afraid most of my presentation will be thin on law and possibly too high on rhetoric. Having been engaged in a personal and direct way with these issues as a trained scientist, I find it quite difficult to be always as objective as I ought to be.

  14. Electrostatic control of phospholipid polymorphism.

    PubMed

    Tarahovsky, Y S; Arsenault, A L; MacDonald, R C; McIntosh, T J; Epand, R M

    2000-12-01

    A regular progression of polymorphic phase behavior was observed for mixtures of the anionic phospholipid, cardiolipin, and the cationic phospholipid derivative, 1, 2-dioleoyl-sn-glycero-3-ethylphosphocholine. As revealed by freeze-fracture electron microscopy and small-angle x-ray diffraction, whereas the two lipids separately assume only lamellar phases, their mixtures exhibit a symmetrical (depending on charge ratio and not polarity) sequence of nonlamellar phases. The inverted hexagonal phase, H(II,) formed from equimolar mixtures of the two lipids, i.e., at net charge neutrality (charge ratio (CR((+/-))) = 1:1). When one type of lipid was in significant excess (CR((+/-)) = 2:1 or CR((+/-)) = 1:2), a bicontinuous cubic structure was observed. These cubic phases were very similar to those sometimes present in cellular organelles that contain cardiolipin. Increasing the excess of cationic or anionic charge to CR((+/-)) = 4:1 or CR((+/-)) = 1:4 led to the appearance of membrane bilayers with numerous interlamellar contacts, i.e., sponge structures. It is evident that interactions between cationic and anionic moieties can influence the packing of polar heads and hence control polymorphic phase transitions. The facile isothermal, polymorphic interconversion of these lipids may have important biological and technical implications.

  15. Ruminal expression of the NQO1, RGS5, and ACAT1 genes may be indicators of feed efficiency in beef steers

    USDA-ARS?s Scientific Manuscript database

    Ruminal genes differentially expressed in crossbred beef steers with variation in gain and feed intake were identified in a previous study. Genes identified with expression patterns differing between animals with high gain-low feed intake and low gain-high feed intake were evaluated in a separate po...

  16. Chromosomal polymorphism in mammals: an evolutionary perspective.

    PubMed

    Dobigny, Gauthier; Britton-Davidian, Janice; Robinson, Terence J

    2017-02-01

    Although chromosome rearrangements (CRs) are central to studies of genome evolution, our understanding of the evolutionary consequences of the early stages of karyotypic differentiation (i.e. polymorphism), especially the non-meiotic impacts, is surprisingly limited. We review the available data on chromosomal polymorphisms in mammals so as to identify taxa that hold promise for developing a more comprehensive understanding of chromosomal change. In doing so, we address several key questions: (i) to what extent are mammalian karyotypes polymorphic, and what types of rearrangements are principally involved? (ii) Are some mammalian lineages more prone to chromosomal polymorphism than others? More specifically, do (karyotypically) polymorphic mammalian species belong to lineages that are also characterized by past, extensive karyotype repatterning? (iii) How long can chromosomal polymorphisms persist in mammals? We discuss the evolutionary implications of these questions and propose several research avenues that may shed light on the role of chromosome change in the diversification of mammalian populations and species.

  17. Polymorphism and tautomeric preference in fenobam and the utility of NLO response to detect polymorphic impurities.

    PubMed

    Thomas, Sajesh P; Nagarajan, K; Row, T N Guru

    2012-11-04

    Crystal structures of polymorphs and solvatomorphs of the potential anxiolytic drug fenobam exhibit an exclusive preference for one of the two possible tautomeric structures. A novel methodology based on nonlinear optical response has been successfully employed to detect the presence of a polymorphic impurity in a mixture of polymorphs.

  18. Parasitic polymorphism of Coccidioides spp

    PubMed Central

    2014-01-01

    Background Coccidioides spp. is the ethiological agent of coccidioidomycosis, an infection that can be fatal. Its diagnosis is complicated, due to that it shares clinical and histopathological characteristics with other pulmonary mycoses. Coccidioides spp. is a dimorphic fungus and, in its saprobic phase, grows as a mycelium, forming a large amount of arthroconidia. In susceptible persons, arthroconidia induce dimorphic changes into spherules/endospores, a typical parasitic form of Coccidioides spp. In addition, the diversity of mycelial parasitic forms has been observed in clinical specimens; they are scarcely known and produce errors in diagnosis. Methods We presented a retrospective study of images from specimens of smears with 15% potassium hydroxide, cytology, and tissue biopsies of a histopathologic collection from patients with coccidioidomycosis seen at a tertiary-care hospital in Mexico City. Results The parasitic polymorphism of Coccidioides spp. observed in the clinical specimens was as follows: i) spherules/endospores in different maturation stages; ii) pleomorphic cells (septate hyphae, hyphae composed of ovoid and spherical cells, and arthroconidia), and iii) fungal ball formation (mycelia with septate hyphae and arthroconidia). Conclusions The parasitic polymorphism of Coccidioides spp. includes the following: spherules/endospores, arthroconidia, and different forms of mycelia. This knowledge is important for the accurate diagnosis of coccidioidomycosis. In earlier studies, we proposed the integration of this diversity of forms in the Coccidioides spp. parasitic cycle. The microhabitat surrounding the fungus into the host would favor the parasitic polymorphism of this fungus, and this environment may assist in the evolution toward parasitism of Coccidioides spp. PMID:24750998

  19. Calcium acamprosate: a triclinic polymorph.

    PubMed

    Maccaroni, Elisabetta; Panzeri, Walter; Malpezzi, Luciana

    2011-12-01

    The title compound, poly[bis-(μ(3)-4-acetamido-propane-sulfon-ato)-calcium], [Ca(C(5)H(10)NO(4)S)(2)](n), is a triclinic polymorph of the previously reported monoclinic structure [Toffoli et al. (1988 ▶). Acta Cryst. C44, 1493-1494]. The triclinic modification was found to have an all-trans configuration of the acetamido-propane chain, in contrast with the monoclinic polymorph which shows an angle of 74.66 (8)° between the S-C-C-C chain plane and that of the amide group. The Ca(2+) cation is situated on an inversion centre and is hexa-coordinated by six O atoms belonging to different anions in a distorted octa-hedral geometry. This arrangement leads to a layered structure parallel to (011). The layers are held together by N-H⋯O hydrogen bonds and by short C-H⋯O inter-actions, both involving the sulfonate O atoms not coordinated to the Ca(2+) cations. The structure was determined from a crystal twinned by non-merohedry [twin law ([Formula: see text]00, 0[Formula: see text]0, -0.335 -0.85 1), with a fractional contribution of the minor twin domain of 46.7 (1)%].

  20. Spinning up the polymorphs of calcium carbonate

    PubMed Central

    Boulos, Ramiz A.; Zhang, Fei; Tjandra, Edwin S.; Martin, Adam D.; Spagnoli, Dino; Raston, Colin L.

    2014-01-01

    Controlling the growth of the polymorphs of calcium carbonate is important in understanding the changing environmental conditions in the oceans. Aragonite is the main polymorph in the inner shells of marine organisms, and can be readily converted to calcite, which is the most stable polymorph of calcium carbonate. Both of these polymorphs are significantly more stable than vaterite, which is the other naturally occurring polymorph of calcium carbonate, and this is reflected in its limited distribution in nature. We have investigated the effect of high shear forces on the phase behaviour of calcium carbonate using a vortex fluidic device (VFD), with experimental parameters varied to explore calcium carbonate mineralisation. Variation of tilt angle, rotation speed and temperature allow for control over the size, shape and phase of the resulting calcium carbonate. PMID:24448077

  1. Investigation of the riddle of sulfathiazole polymorphism.

    PubMed

    Abu Bakar, Mohd R; Nagy, Zoltan K; Rielly, Chris D; Dann, Sandy E

    2011-07-29

    Since the discovery of sulfathiazole as an antimicrobial agent in 1939, numerous works in the screening for its different polymorphic forms, which is an essential part of drug development, have been conducted and published. These works consequently result in the availability of various methods for generating a particular polymorph. By following these methods, however, one cannot be guaranteed to obtain the intended pure polymorph because most of the methods do not clearly and adequately describe the crystallisation conditions, such as cooling rates and initial solute concentrations. In this paper, the available methods for generating all the known polymorphs of sulfathiazole are reviewed and selected methods for generating certain polymorphs, performed with their processes monitored using process analytical technology tools, i.e. focussed beam reflectance measurement and attenuated total reflectance ultraviolet spectroscopy, are presented. The properties of the obtained crystals, examined using various characterisation methods, are also presented and whenever possible, are compared with those of other workers.

  2. Lactose: a definitive guide to polymorph determination.

    PubMed

    Kirk, J H; Dann, S E; Blatchford, C G

    2007-04-04

    Lactose is a well-known molecule capable of forming a number of different polymorphs with varied chemical and physical properties. To date, no definitive guide for distinguishing between polymorphs using simple analytical techniques has been available. The information presented in this article aims to provide a conclusive guide for identifying the polymorphs of lactose and to successfully unravel years of contradictory research. Data have been collected on single phase polymorphs, prepared from an identical source, adopting the use of in situ and ex situ powder X-ray diffraction, CCD-Raman, FT-IR and (13)C-(1)H cross-polarisation magic angle spinning NMR (CP-MASNMR) spectroscopy, in order to provide simple methods to discriminate between the polymorphs.

  3. The "polymorphous" history of a polymorphous skull bone: the sphenoid.

    PubMed

    Costea, Claudia; Turliuc, Serban; Cucu, Andrei; Dumitrescu, Gabriela; Carauleanu, Alexandru; Buzduga, Catalin; Sava, Anca; Costache, Irina; Turliuc, Dana

    2017-03-27

    For a long time, because of its location at the skull base level, the sphenoid bone was rather mysterious as it was too difficult for anatomists to reach and to elucidate its true configuration. The configuration of the sphenoid bone led to confusion regarding its sutures with the other skull bones, its shape, its detailed anatomy, and the vascular and nervous structures that cross it. This article takes the reader on a journey through time and space, charting the evolution of anatomists' comprehension of sphenoid bone morphology from antiquity to its conception as a bone structure in the eighteenth century, and ranging from ancient Greece to modern Italy and France. The journey illustrates that many anatomists have attempted to name and to best describe the structural elements of this polymorphous bone.

  4. Genetic Polymorphisms and Peritoneal Membrane Function

    PubMed Central

    Siddique, Imad; Brimble, K. Scott; Walkin, Louise; Summers, Angela; Brenchley, Paul; Herrick, Sarah; Margetts, Peter J.

    2015-01-01

    ♦ Background: Outcomes for peritoneal dialysis (PD) patients are affected by the characteristics of the peritoneal membrane, which may be determined by genetic variants. We carried out a systematic review of the literature to identify studies which assessed the association between genetic polymorphisms, peritoneal membrane solute transport, and clinical outcomes for PD patients. ♦ Methods: The National Library of Medicine was searched using a variety of strategies. Studies which met our inclusion criteria were reviewed and data abstracted. Our outcomes of interest included: high transport status peritoneal membrane, risk for peritonitis, encapsulating peritoneal sclerosis (EPS), patient and technique survival. We combined data from studies which evaluated the same genetic polymorphism and the same outcome. ♦ Results: We evaluated 18 relevant studies. All studies used a candidate gene approach. Gene polymorphisms in the interleukin (IL)-6 gene were associated with peritoneal membrane solute transport in several studies in different ethnic populations. Associations with solute transport and polymorphisms in endothelial nitric oxide synthase and receptor for advanced glycation end product genes were also identified. There was evidence of a genetic predisposition for peritonitis found in 2 studies, and for EPS in 1 study. Survival was found to be associated with a polymorphism in vascular endothelial growth factor and technique failure was associated with a polymorphism in the IL-1 receptor antagonist. ♦ Conclusions: There is evidence that characteristics of the peritoneal membrane and clinical outcomes for PD patients have genetic determinants. The most consistent association was between IL-6 gene polymorphisms and peritoneal membrane solute transport. PMID:25395500

  5. Vibrational study of tamoxifen citrate polymorphism

    NASA Astrophysics Data System (ADS)

    Gamberini, M. C.; Baraldi, C.; Tinti, A.; Palazzoli, F.; Ferioli, V.

    2007-09-01

    The trans isomer of ( Z)-2-[ p-(1,2-diphenyl-butenyl)phenoxy]- N, N-dimethyletylamine (tamoxifen) is well known for its endocrine activity as an antiestrogenic agent. Its citrate salt, a widely used pharmaceutical agent, appears in three main polymorphic forms, two of which are well known (I and II) and another form not yet well evidenced. A vibrational study has been conducted for identifying the two known polymorphic forms of tamoxifen citrate (I and II) and for characterising the other form (form III) examined in this study. Other techniques for the characterization of the different polymorphs, such as XRDP, have been used.

  6. Interactions between Glucocorticoid Treatment and Cis-Regulatory Polymorphisms Contribute to Cellular Response Phenotypes

    PubMed Central

    Richards, Allison L.; Wen, Xiaoquan; Witonsky, David B.; Baxter, Shaneen; Stephens, Matthew; Di Rienzo, Anna

    2011-01-01

    Glucocorticoids (GCs) mediate physiological responses to environmental stress and are commonly used as pharmaceuticals. GCs act primarily through the GC receptor (GR, a transcription factor). Despite their clear biomedical importance, little is known about the genetic architecture of variation in GC response. Here we provide an initial assessment of variability in the cellular response to GC treatment by profiling gene expression and protein secretion in 114 EBV-transformed B lymphocytes of African and European ancestry. We found that genetic variation affects the response of nearby genes and exhibits distinctive patterns of genotype-treatment interactions, with genotypic effects evident in either only GC-treated or only control-treated conditions. Using a novel statistical framework, we identified interactions that influence the expression of 26 genes known to play central roles in GC-related pathways (e.g. NQO1, AIRE, and SGK1) and that influence the secretion of IL6. PMID:21750684

  7. Rivastigmine hydrogen tartrate polymorphs: Solid-state characterisation of transition and polymorphic conversion via milling

    NASA Astrophysics Data System (ADS)

    Amaro, Maria Inês; Simon, Alice; Cabral, Lúcio Mendes; de Sousa, Valéria Pereira; Healy, Anne Marie

    2015-11-01

    Rivastigmine (RHT) is an active pharmaceutical ingredient that is used for the treatment of mild to moderately severe dementia in Alzheimer's disease, and is known to present two polymorphic forms and to amorphise upon granulation. To date there is no information in the scientific or patent literature on polymorphic transition and stability. Hence, the aim of the current study was to gain a fundamental understanding of the polymorphic forms by (1) evaluating RHT thermodynamic stability (monotropy or enantiotropy) and (2) investigating the potential for polymorphic transformation upon milling. The two polymorphic and amorphous forms were characterised using X-ray powder diffractometry, thermal analyses, infra-red spectroscopy and water sorption analysis. The polymorphic transition was found to be spontaneous (ΔG0 < 0) and exothermic (ΔH0 < 0), indicative of a monotropic polymorph pair. The kinetic studies showed a fast initial polymorphic transition characterised by a heterogeneous nucleation, followed by a slow crystal growth. Ball milling can be used to promote the polymorphic transition and for the production of RHT amorphous form.

  8. Purification of polymorphic components of complex genomes

    DOEpatents

    Stodolsky, M.

    1988-01-21

    A method for processing related subject and reference macromolecule composed of complementary strand into their respective subject and reference populations of representative fragments and effectuating purification of unique polymorphic subject fragments. 1 fig.

  9. Purification of polymorphic components of complex genomes

    DOEpatents

    Stodolsky, M.

    1991-07-16

    A method is disclosed for processing related subject and reference macromolecule populations composed of complementary strands into their respective subject and reference populations of representative fragments and effectuating purification of unique polymorphic subject fragments. 1 figure.

  10. Purification of polymorphic components of complex genomes

    DOEpatents

    Stodolsky, Marvin

    1991-01-01

    A method is disclosed for processing related subject and reference macromolecule populations composed of complementary strands into their respective subject and reference populations of representative fragments and effectuating purification of unique polymorphic subject fragments.

  11. Polymorph Discrimination using Low Wavenumber Raman Spectroscopy

    PubMed Central

    Roy, Saikat; Chamberlin, Brianna; Matzger, Adam J.

    2016-01-01

    Characterization of crystalline polymorphs and their quantitation has become an integral part of the pre-clinical drug development process. Raman spectroscopy is a powerful technique for the rapid identification of phases of pharmaceuticals. In the present work we demonstrate the use of low wavenumber Raman vibrational spectroscopy (including phonon measurement) for discrimination among polymorphs. A total of 10 polymorphic pharmaceuticals were employed to conduct a critical assessment. Raman scattering in the low frequency region (10–400 cm−1), which includes crystal lattice vibrations, has been analyzed and the results indicate lattice phonon Raman scattering can be used for rapid discrimination of polymorphic phases with additional discriminating power compared to conventional collection strategies. Moreover structural insight and conformational changes can be detected with this approach. PMID:27642248

  12. Gene polymorphisms and chronic obstructive pulmonary disease.

    PubMed

    Wu, Xiaodan; Yuan, Bowei; López, Elena; Bai, Chunxue; Wang, Xiangdong

    2014-01-01

    The genetic component was suggested to contribute to the development of chronic obstructive pulmonary disease (COPD), a major and growing public health burden. The present review aims to characterize the evidence that gene polymorphisms contribute to the aetiology of COPD and related traits, and explore the potential relationship between certain gene polymorphisms and COPD susceptibility, severity, lung function, phenotypes, or drug effects, even though limited results from related studies lacked consistency. Most of these studies were association studies, rather than confirmatory studies. More large-sized and strictly controlled studies are needed to prove the relationship between gene polymorphisms and the reviewed traits. More importantly, prospective confirmatory studies beyond initial association studies will be necessary to evaluate true relationships between gene polymorphisms and COPD and help individualized treatment for patients with COPD.

  13. Polymorphism Control of Poly(vinylidene fluoride)

    NASA Astrophysics Data System (ADS)

    Zheng, Jianfen; He, Aihua; Li, Junxing; Han, Charles C.

    2008-03-01

    Poly(vinylidene fluoride) (PVDF) is well-known for its polymorphism, and can exhibit five different polymorphs depending on its processing conditions. The α-phase is the most common and stable polymorph and the β-phase is the most important one due to its piezoelectric and pyroelectric properties. Polymorphism control of PVDF has been realized through electrospinning. PVDF fibrous membranes with fiber diameter in the range of 100 nm to several micrometers were produced by electrospinning and the crystal phase of electrospun PVDF fibers can be adjusted at the same time. Through the control of electrospinning parameters such as the solvent and electrospinning temperature, PVDF fibrous membranes containing mainly α- or β- or γ-phase could be fabricated successfully.

  14. Tetrazolium Oxidase Polymorphism in Rainbow Trout

    PubMed Central

    Cederbaum, Stephen D.; Yoshida, Akira

    1972-01-01

    Tetrazolium oxidase from the blood and liver of rainbow trout was found to be genetically polymorphic. The inheritance pattern of the liver enzyme was compatible only with a one locus-two allele hypothesis. The enzymes in the blood while having an electrophoretically identical polymorphism could differ genotypically from that of the liver in a given fish. The significance of these findings to the understanding of the evolution of the salmonid genome is discussed. PMID:4675090

  15. DNA polymorphism identity determination using flow cytometry

    DOEpatents

    Nolan, John P.; White, P. Scott; Cai, Hong

    2001-01-01

    DNA polymorphism identity determination using flow cytometry. Primers designed to be immobilized on microspheres are allowed to anneal to the DNA strand under investigation, and are extended by either DNA polymerase using fluorescent dideoxynucleotides or ligated by DNA ligase to fluorescent reporter oligonucleotides. The fluorescence of either the dideoxynucleotide or the reporter oligonucleotide attached to the immobilized primer is measured by flow cytometry, thereby identifying the nucleotide polymorphism on the DNA strand.

  16. Impact polymorphs of quartz: experiments and modelling

    NASA Astrophysics Data System (ADS)

    Price, M. C.; Dutta, R.; Burchell, M. J.; Cole, M. J.

    2013-09-01

    We have used the light gas gun at the University of Kent to perform a series of impact experiments firing quartz projectiles onto metal, quartz and sapphire targets. The aim is to quantify the amount of any high pressure quartz polymorphs produced, and use these data to develop our hydrocode modelling to enable the predict ion of the quantity of polymorphs produced during a planetary scale impact.

  17. Polymorphic crystals selected in the nucleation stage

    NASA Astrophysics Data System (ADS)

    Zhang, Hui-Jun; Peng, Shu-Ming; Zhou, Xiao-Song; Ju, Xin

    2014-08-01

    Molecular dynamics simulations are used to explore the atomic mechanism of formation of polymorphic crystals. Cooling the Lennard-Jones systems, we observe that the system almost always evolves into a polymorphic crystal with either fivefold-symmetric stacking faults or single-direction stacking faults. The detailed analysis reveals that such an evolution depends on the configuration of fcc/hcp concomitance in the nucleation stage. A defect-induced model is then introduced to illustrate these two evolution routes. Through calculating the formation energies of the defective critical nuclei, we find that the polymorphic crystals seem to be determined by their critical nuclei, in which the relatively lower formation energy ensures the preponderance of the fivefold-symmetric cluster. Before the nucleation, we observe that thermal fluctuations prefer hcp-like particles over fcc-like ones while in the nucleation and growth stage this preference reverses. Notably, an extended step rule of Ostwald is seemingly suitable to characterise the growth process because of the temporary hcp layers appearing among fcc layers in the growth stage. Although the crystalline cluster with single-direction stacking faults has higher growth rate and structural order than its competitor, the component (fcc and hcp) proportion of the final crystals is almost always constant regardless of the polymorphic type. Our finding renews the understanding of the polymorphism of crystals, and possibly draws more attention of people intending to control the polymorphic structures through nucleation.

  18. Neotame anhydrate polymorphs I: preparation and characterization.

    PubMed

    Doug, Zedong; Padden, Brian E; Salsbury, Jonathon S; Munson, Eric J; Schroeder, Steve A; Prakash, Indra; Grant, David J W

    2002-03-01

    To prepare, characterize, and compare polymorphs of neotame anhydrate. Neotame anhydrate polymorphs were prepared from amorphous or crystalline anhydrate by crystallization or suspension in various organic solvents, or by dehydration of neotame monohydrate. The following techniques were used for characterization: differential scanning calorimetry, thermogravimetry, hot-stage microscopy, powder X-ray diffractometry (PXRD), 13C solid-state nuclear magnetic resonance (SSNMR) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy, dynamic water vapor sorption/desorption, and density measurements. Seven polymorphs (Forms A-G) of neotame anhydrate were prepared and show different thermal properties and PXRD patterns. Two enantiotropically related pairs were identified: B and C; E and A. 13C SSNMR and FTIR spectroscopy clearly distinguish between Forms A, D, F, and G, which show similar needle-shaped morphology but distinct differences in dynamic water vapor sorption/desorption and density. The 13C SSNMR chemical shifts suggest conformational polymorphism. The stability in the presence of water vapor follows the rank order, G > A > D approximately = F, which resembles the rank orders of the molar volume and of the polarity of the solvents from which they crystallized. The neotame anhydrate polymorphs appear to show different molecular conformations. The less dense polymorphic structures crystallize from solvents of greater polarity and sorb water vapor less rapidly and less completely. Two enantiotropic pairs were discerned.

  19. Extended Polymorphism of Two-Dimensional Material.

    PubMed

    Yoshida, Masaro; Ye, Jianting; Zhang, Yijin; Imai, Yasuhiko; Kimura, Shigeru; Fujiwara, Akihiko; Nishizaki, Terukazu; Kobayashi, Norio; Nakano, Masaki; Iwasa, Yoshihiro

    2017-09-13

    When controlling electronic properties of bulk materials, we usually assume that the basic crystal structure is fixed. However, in two-dimensional (2D) materials, atomic structure or polymorph is attracting growing interest as a controlling parameter to functionalize their properties. Various polymorphs can exist in transition metal dichalcogenides (TMDCs) from which 2D materials are generated, and polymorphism has drastic impacts on the electronic states. Here we report the discovery of an unprecedented polymorph of a TMDC 2D material. By mechanical exfoliation, we made thin flakes from a single crystal of 2Ha-type tantalum disulfide (TaS2), a metallic TMDC with a charge-density-wave (CDW) phase. Microbeam X-ray diffraction measurements and electrical transport measurements indicate that thin flakes possess a polymorph different from any one known in TaS2 bulk crystals. Moreover, the flakes with the unique polymorph displayed the dramatically enhanced CDW ordering temperature. The present results suggest the potential existence of diverse structural and electronic phases accessible only in 2D materials.

  20. Polymorphism in Bacterial Flagella Suspensions

    NASA Astrophysics Data System (ADS)

    Schwenger, Walter J.

    Bacterial flagella are a type of biological polymer studied for its role in bacterial motility and the polymorphic transitions undertaken to facilitate the run and tumble behavior. The naturally rigid, helical shape of flagella gives rise to novel colloidal dynamics and material properties. This thesis studies methods in which the shape of bacterial flagella can be controlled using in vitro methods and the changes the shape of the flagella have on both single particle dynamics and bulk material properties. We observe individual flagellum in both the dilute and semidilute regimes to observe the effects of solvent condition on the shape of the filament as well as the effect the filament morphology has on reptation through a network of flagella. In addition, we present rheological measurements showing how the shape of filaments effects the bulk material properties of flagellar suspensions. We find that the individual particle dynamics in suspensions of flagella can vary with geometry from needing to reptate linearly via rotation for helical filaments to the prevention of long range diffusion for block copolymer filaments. Similarly, for bulk material properties of flagella suspensions, helical geometries show a dramatic enhancement in elasticity over straight filaments while block copolymers form an elastic gel without the aid of crosslinking agents.

  1. Stability and metastability of bromine clathrate polymorphs.

    PubMed

    Nguyen, Andrew H; Molinero, Valeria

    2013-05-23

    Clathrate hydrates are crystals in which water forms a network of fully hydrogen-bonded polyhedral cages that contain small guests. Clathrate hydrates occur mostly in two cubic crystal polymorphs, sI and sII. Bromine is one of two guests that yield a hydrate with the tetragonal structure (TS), the topological dual of the Frank-Kasper σ phase. There has been a long-standing disagreement on whether bromine hydrate also forms metastable sI and sII crystals. To date there are no data on the thermodynamic range of stability (e.g., the melting temperatures) of the metastable polymorphs. Here we use molecular dynamics simulations with the coarse-grained model of water mW to (i) investigate the thermodynamic stability of the empty and guest-filled the sI, sII, TS, and HS-I hydrate polymorphs, (ii) develop a coarse-grained model of bromine compatible with mW water, and (iii) evaluate the stability of the bromine hydrate polymorphs. The mW model predicts the same relative energy of the empty clathrate polymorphs and the same phase diagram as a function of water-guest interaction than the fully atomistic TIP4P water model. There is a narrow region in water-guest parameter space for which TS is marginally more stable than sI or sII. We parametrize a coarse-grained model of bromine compatible with mW water and use it to determine the order of stability of the bromine hydrate polymorphs. The melting temperatures of the bromine hydrate polymorphs predicted by the coarse-grained model are 281 ± 1 K for TS, 279 ± 1 K for sII, and 276 ± 1 K for sI. The closeness of the melting temperatures supports the plausibility of formation of metastable sII and sI bromine hydrates.

  2. Cytochrome P450 gene polymorphism and cancer.

    PubMed

    Agundez, Jose A G

    2004-06-01

    Human cytochrome P450 (CYP) enzymes play a key role in the metabolism of drugs and environmental chemicals. Several CYP enzymes metabolically activate procarcinogens to genotoxic intermediates. Phenotyping analyses revealed an association between CYP enzyme activity and the risk to develop several forms of cancer. Research carried out in the last decade demonstrated that several CYP enzymes are polymorphic due to single nucleotide polymorphisms, gene duplications and deletions. As genotyping procedures became available for most human CYP, an impressive number of association studies on CYP polymorphisms and cancer risk were conducted. Here we review the findings obtained in these studies regarding CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP3A7, CYP8A1 and CYP21 gene polymorphisms. Consistent evidences for association between CYP polymorphisms and lung, head and neck, and liver cancer were reported. Controversial findings suggest that colorectal and prostate cancers may be associated to CYP polymorphisms, whereas no evidences for a relevant association with breast or bladder cancers were reported. We summarize the available information related to the association of CYP polymorphisms with leukaemia, lymphomas and diverse types of cancer that were investigated only for some CYP genes, including brain, esophagus, stomach, pancreas, pituitary, cervical epithelium, melanoma, ovarian, kidney, anal and vulvar cancers. This review discusses on causes of heterogeneity in the proposed associations, controversial findings on cancer risk, and identifies topics that require further investigation. In addition, some recommendations on study design, in order to obtain more conclusive findings in further studies, are provided.

  3. MHC polymorphism under host-pathogen coevolution.

    PubMed

    Borghans, José A M; Beltman, Joost B; De Boer, Rob J

    2004-02-01

    The genes encoding major histocompatibility (MHC) molecules are among the most polymorphic genes known for vertebrates. Since MHC molecules play an important role in the induction of immune responses, the evolution of MHC polymorphism is often explained in terms of increased protection of hosts against pathogens. Two selective pressures that are thought to be involved are (1) selection favoring MHC heterozygous hosts, and (2) selection for rare MHC alleles by host-pathogen coevolution. We have developed a computer simulation of coevolving hosts and pathogens to study the relative impact of these two mechanisms on the evolution of MHC polymorphism. We found that heterozygote advantage per se is insufficient to explain the high degree of polymorphism at the MHC, even in very large host populations. Host-pathogen coevolution, on the other hand, can easily account for realistic polymorphisms of more than 50 alleles per MHC locus. Since evolving pathogens mainly evade presentation by the most common MHC alleles in the host population, they provide a selective pressure for a large variety of rare MHC alleles. Provided that the host population is sufficiently large, a large set of MHC alleles can persist over many host generations under host-pathogen coevolution, despite the fact that allele frequencies continuously change.

  4. Fractalkine receptor polymorphism and chronic tonsillitis.

    PubMed

    Babakurban, Seda Turkoglu; Erbek, Selim S; Terzi, Yunus Kasim; Arslan, Fatih; Sahin, Feride I

    2014-07-01

    The objective of this study is to examine whether there is an association of fractalkine gene receptor polymorphisms with chronic tonsillitis. This is a cross-sectional study in the setting of a tertiary referral center. The study group included 79 patients with chronic tonsillitis and 76 controls without history of chronic tonsillitis. Genotypes were identified by restriction fragment length polymorphism analyses after polymerase chain reaction. c.745G>A (V249I) single nucleotide polymorphism and the frequencies of the G and A alleles did not differ in the patient and control groups (p = 0.363; p = 0.743, respectively). c.839C>T (T280M) single nucleotide polymorphism was found to be higher in controls than in the patients with chronic tonsillitis (p < 0.001). Consistent with this result, T allele frequency was higher in controls than in the patients with chronic tonsillitis (p < 0.001). In this study, we suggested that fractalkine gene receptor c.839C>T (T280M) single nucleotide polymorphism could be associated with a reduced risk of chronic tonsillitis.

  5. Prdm9 polymorphism unveils mouse evolutionary tracks.

    PubMed

    Kono, Hiromitsu; Tamura, Masaru; Osada, Naoki; Suzuki, Hitoshi; Abe, Kuniya; Moriwaki, Kazuo; Ohta, Kunihiro; Shiroishi, Toshihiko

    2014-06-01

    PR/SET domain containing 9 (Prdm9) mediates histone modifications such as H3K4me3 and marks hotspots of meiotic recombination. In many mammalian species, the Prdm9 gene is highly polymorphic. Prdm9 polymorphism is assumed to play two critical roles in evolution: to diversify the spectrum of meiotic recombination hotspots and to cause male hybrid sterility, leading to reproductive isolation and speciation. Nevertheless, information about Prdm9 sequences in natural populations is very limited. In this study, we conducted a comprehensive population survey on Prdm9 polymorphism in the house mouse, Mus musculus. Overall M. musculus Prdm9 displays an extraordinarily high level of polymorphism, particularly in regions encoding zinc finger repeats, which recognize recombination hotspots. Prdm9 alleles specific to various M. musculus subspecies dominate in subspecies territories. Moreover, introgression into other subspecies territories was found for highly divergent Prdm9 alleles associated with t-haplotype. The results of our phylogeographical analysis suggest that the requirement for hotspot diversity depends on geographical range and time span in mouse evolution, and that Prdm9 polymorphism has not been maintained by a simple balanced selection in the population of each subspecies.

  6. Crystal structure of neotame anhydrate polymorph G.

    PubMed

    Dong, Zedong; Young, Victor G; Sheth, Agam; Munson, Eric J; Schroeder, Steve A; Prakash, Indra; Grant, David J W

    2002-10-01

    To determine the crystal structure of the neotame anhydrate polymorph G and to evaluate X-ray powder diffractometry (XRPD) with molecular modeling as an alternative method for determining the crystal structure of this conformationally flexible dipeptide. The crystal structure of polymorph G was determined by single crystal X-ray crystallography (SCXRD) and also from the X-ray powder diffraction (XRPD) pattern using molecular modeling (Cerius2, Powder Solve module). From SCXRD, polymorph G crystals are orthorhombic with space group of P2(1)2(1)2(1) with Z = 4, unit cell constants: a = 5.5999(4), b = 11.8921(8), c = 30.917(2) A, and one neotame molecule per asymmetric unit. The XRPD pattern of polymorph G, analyzed by Cerius2 software, led to the same P2(1)2(1)2(1) space group and almost identical unit cell dimensions. However, with 13 rigid bodies defined, Cerius2 gives a conformation of the neotame molecule, which is different from that determined by SCXRD. For neotame anhydrate polymorph G, the unit cell dimensions calculated from XRPD were almost identical to those determined by SCXRD. However, the crystal structure determined by XRPD closely resembled that determined by SCXRD, only when the correct conformation of the neotame molecule had been chosen before detailed analysis of the XRPD pattern.

  7. Solvable model for polymorphic dynamics of biofilaments.

    PubMed

    Mohrbach, Hervé; Kulić, Igor M

    2012-03-01

    We investigate an analytically tractable toy model for thermally induced polymorphic dynamics of cooperatively rearranging biofilaments-like microtubules. The proposed four-block model, which can be seen as a coarse-grained approximation of the full polymorphic tube model, permits a complete analytical treatment of all thermodynamic properties including correlation functions and angular Fourier mode distributions. Due to its mathematical tractability the model straightforwardly leads to some physical insights in recently discussed phenomena like the "length dependent persistence length." We show that a polymorphic filament can disguise itself as a classical worm-like chain on small and on large scales and yet display distinct anomalous tell-tale features indicating an inner switching dynamics on intermediate length scales.

  8. Human FcR Polymorphism and Disease

    PubMed Central

    Li, Xinrui; Gibson, Andrew W.; Kimberly, Robert P.

    2014-01-01

    Fc receptors play a central role in maintaining the homeostatic balance in the immune system. Our knowledge of the structure and function of these receptors and their naturally occurring polymorphisms, including single nucleotide polymorphisms and/or copy number variations, continues to expand. Through studies of their impact on human biology and clinical phenotype, the contributions of these variants to the pathogenesis, progression, and/or treatment outcome of many diseases that involve immunoglobulin have become evident. They affect susceptibility to bacterial and viral pathogens, constitute as risk factors for IgG or IgE mediated inflammatory diseases, and impact the development of many autoimmune conditions. In this chapter, we will provide an overview of these genetic variations in classical FcγRs, FcRLs, and other Fc receptors, as well as challenges in achieving an accurate and comprehensive understanding of the FcR polymorphisms and genomic architecture. PMID:25116105

  9. Human FcR polymorphism and disease.

    PubMed

    Li, Xinrui; Gibson, Andrew W; Kimberly, Robert P

    2014-01-01

    Fc receptors play a central role in maintaining the homeostatic balance in the immune system. Our knowledge of the structure and function of these receptors and their naturally occurring polymorphisms, including single nucleotide polymorphisms and/or copy number variations, continues to expand. Through studies of their impact on human biology and clinical phenotype, the contributions of these variants to the pathogenesis, progression, and/or treatment outcome of many diseases that involve immunoglobulin have become evident. They affect susceptibility to bacterial and viral pathogens, constitute as risk factors for IgG or IgE mediated inflammatory diseases, and impact the development of many autoimmune conditions. In this chapter, we will provide an overview of these genetic variations in classical FcγRs, FcRLs, and other Fc receptors, as well as challenges in achieving an accurate and comprehensive understanding of the FcR polymorphisms and genomic architecture.

  10. Single Nucleotide Polymorphisms and Osteoarthritis

    PubMed Central

    Wang, Ting; Liang, Yuting; Li, Hong; Li, Haibo; He, Quanze; Xue, Ying; Shen, Cong; Zhang, Chunhua; Xiang, Jingjing; Ding, Jie; Qiao, Longwei; Zheng, Qiping

    2016-01-01

    Abstract Osteoarthritis (OA) is a complex disorder characterized by degenerative articular cartilage and is largely attributed to genetic risk factors. Single nucleotide polymorphisms (SNPs) are common DNA variants that have shown promising and efficiency, compared with positional cloning, to map candidate genes of complex diseases, including OA. In this study, we aim to provide an overview of multiple SNPs from a number of genes that have recently been linked to OA susceptibility. We also performed a comprehensive meta-analysis to evaluate the association of SNP rs7639618 of double von Willebrand factor A domains (DVWA) gene with OA susceptibility. A systematic search of studies on the association of SNPs with susceptibility to OA was conducted in PubMed and Google scholar. Studies subjected to meta-analysis include human and case-control studies that met the Hardy–Weinberg equilibrium model and provide sufficient data to calculate an odds ratio (OR). A total of 9500 OA cases and 9365 controls in 7 case-control studies relating to SNP rs7639618 were included in this study and the ORs with 95% confidence intervals (CIs) were calculated. Over 50 SNPs from different genes have been shown to be associated with either hip (23), or knee (20), or both (13) OA. The ORs of these SNPs for OA and the subtypes are not consistent. As to SNP rs7639618 of DVWA, increased knee OA risk was observed in all genetic models analyzed. Specifically, people from Asian with G-allele showed significantly increased risk of knee OA (A versus G: OR = 1.28, 95% CI 1.13–1.46; AA versus GG: OR = 1.60, 95% CI 1.25–2.05; GA versus GG: OR = 1.31, 95% CI 1.18–1.44; AA versus GA+GG: OR = 1.34, 95% CI 1.12–1.61; AA+GA versus GG: OR = 1.40, 95% CI 1.19–1.64), but not in Caucasians or with hip OA. Our results suggest that multiple SNPs play different roles in the pathogenesis of OA and its subtypes; SNP rs7639618 of DVWA gene is associated with a significantly increased

  11. Polymorphic Phase Transition in Superhydrous Phase B

    SciTech Connect

    Koch-Muller,M.; Dera, P.; Fei, Y.; Hellwig, H.; Liu, Z.; Van Orman, J.; Wirth, R.

    2005-01-01

    We synthesized superhydrous phase B (shy-B) at 22 GPa and two different temperatures: 1200 C (LT) and 1400 C (HT) using a multi-anvil apparatus. The samples were investigated by transmission electron microscopy (TEM), single crystal X-ray diffraction, Raman and IR spectroscopy. The IR spectra were collected on polycrystalline thin-films and single crystals using synchrotron radiation, as well as a conventional IR source at ambient conditions and in situ at various pressures (up to 15 GPa) and temperatures (down to -180 C). Our studies show that shy-B exists in two polymorphic forms. As expected from crystal chemistry, the LT polymorph crystallizes in a lower symmetry space group (Pnn2), whereas the HT polymorph assumes a higher symmetry space group (Pnnm). TEM shows that both modifications consist of nearly perfect crystals with almost no lattice defects or inclusions of additional phases. IR spectra taken on polycrystalline thin films exhibit just one symmetric OH band and 29 lattice modes for the HT polymorph in contrast to two intense but asymmetric OH stretching bands and at least 48 lattice modes for the LT sample. The IR spectra differ not only in the number of bands, but also in the response of the bands to changes in pressure. The pressure derivatives for the IR bands are higher for the HT polymorph indicating that the high symmetry form is more compressible than the low symmetry form. Polarized, low-temperature single-crystal IR spectra indicate that in the LT-polymorph extensive ordering occurs not only at the Mg sites but also at the hydrogen sites.

  12. Mitochondrial DNA polymorphism in mitochondrial myopathy.

    PubMed

    Holt, I J; Harding, A E; Morgan-Hughes, J A

    1988-05-01

    In order to test the hypothesis that mitochondrial myopathy may be caused by mutation of the mitochondrial (mt) genome, restriction fragment length polymorphism in leucocyte mt DNA has been studied in 38 patients with mitochondrial myopathy, 44 of their unaffected matrilineal relatives, and 35 normal control subjects. Previously unreported mt DNA polymorphisms were identified in both patients and controls. No differences in restriction fragment patterns were observed between affected and unaffected individuals in the same maternal line, and there was no evidence of major deletion of mt DNA in patients. This study provides no positive evidence of mitochondrial inheritance in mitochondrial myopathy, but this has not been excluded.

  13. Microfluidic screening of potassium nitrate polymorphism

    NASA Astrophysics Data System (ADS)

    Laval, Philippe; Giroux, Céline; Leng, Jacques; Salmon, Jean-Baptiste

    2008-06-01

    We developed a microfluidic device for the investigation of crystallization kinetics from solution. The device allows to store hundreds of ≈100 nL droplets containing a given solute and to control their temperature within 0.1 °C. Upon cooling, we observe independent and mononuclear crystallization events; crystal dissolution occurs as the temperature is raised. For potassium nitrate (KNO 3) in water, these thermal cycles reveal the existence of two concomitant polymorphic forms. We measured, for the first time, the solubility curves of both these polymorphs, defined unambiguously the metastability extent of the solution and described why these results essentially stem from the miniaturized scale of the crystallization reactors.

  14. Clinical applications of Genome Polymorphism Scans

    PubMed Central

    Weber, James L

    2006-01-01

    Applications of Genome Polymorphism Scans range from the relatively simple such as gender determination and confirmation of biological relationships, to the relatively complex such as determination of autozygosity and propagation of genetic information throughout pedigrees. Unlike nearly all other clinical DNA tests, the Scan is a universal test – it covers all people and all genes. In balance, I argue that the Genome Polymorphism Scan is the most powerful, affordable clinical DNA test available today. Reviewers: This article was reviewed by Scott Weiss (nominated by Neil Smalheiser), Roberta Pagon (nominated by Jerzy Jurka) and Val Sheffield (nominated by Neil Smalheiser). PMID:16756678

  15. Polymorphs calcium carbonate on temperature reaction

    SciTech Connect

    Chong, Kai-Yin; Chia, Chin-Hua; Zakaria, Sarani

    2014-09-03

    Calcium carbonate (CaCO{sub 3}) has three different crystal polymorphs, which are calcite, aragonite and vaterite. In this study, effect of reaction temperature on polymorphs and crystallite structure of CaCO{sub 3} was investigated. X-ray powder diffraction (XRD), fourier transform infrared (FTIR), and variable pressure scanning electron microscope (VPSEM) were used to characterize the obtained CaCO{sub 3} particles. The obtained results showed that CaCO{sub 3} with different crystal and particle structures can be formed by controlling the temperature during the synthesis process.

  16. Migraine and genetic polymorphisms: an overview.

    PubMed

    Pizza, Vincenzo; Agresta, Anella; Agresta, Antonio; Lamaida, Eros; Lamaida, Norman; Infante, Francesco; Capasso, Anna

    2012-01-01

    The relationship between genetic polymorphisms and migraine as a cause of an increased risk of thrombotic disorders development is still debated In this respect, factor V Leiden, factor V (H1299R), prothrombin G20210A, factor XIII (V34L), β-fibrinogen, MTHFR (C677T), MTHFR (A1298C), APO E, PAI-1, HPA-1 and ACE I/D seem to play a determinant role in vascular diseases related to migraine. The present review analyzes both the incidence of the above genetic vascular mutations in migraineurs and the most re-cent developments related to genetic polymorphisms and migraine.

  17. Migraine and Genetic Polymorphisms: An Overview

    PubMed Central

    Pizza, Vincenzo; Agresta, Anella; Agresta, Antonio; Lamaida, Eros; Lamaida, Norman; Infante, Francesco; Capasso, Anna

    2012-01-01

    The relationship between genetic polymorphisms and migraine as a cause of an increased risk of thrombotic disorders development is still debated In this respect, factor V Leiden, factor V (H1299R), prothrombin G20210A, factor XIII (V34L), β-fibrinogen, MTHFR (C677T), MTHFR (A1298C), APO E, PAI-1, HPA-1 and ACE I/D seem to play a determinant role in vascular diseases related to migraine. The present review analyzes both the incidence of the above genetic vascular mutations in migraineurs and the most re-cent developments related to genetic polymorphisms and migraine. PMID:22962564

  18. Polymorphic transformation of helical flagella of bacteria

    NASA Astrophysics Data System (ADS)

    Lim, Sookkyung; Howard Berg Collaboration; William Ko Collaboration; Yongsam Kim Collaboration; Wanho Lee Collaboration; Charles Peskin Collaboration

    2016-11-01

    Bacteria such as E. coli swim in an aqueous environment by utilizing the rotation of flagellar motors and alternate two modes of motility, runs and tumbles. Runs are steady forward swimming driven by bundles of flagellar filaments whose motors are turning CCW; tumbles involve a reorientation of the direction of swimming triggered by motor reversals. During tumbling, the helical flagellum undergoes polymorphic transformations, which is a local change in helical pitch, helical radius, and handedness. In this work, we investigate the underlying mechanism of structural conformation and how this polymorphic transition plays a role in bacterial swimming. National Science Foundation.

  19. TNF-alpha polymorphisms and breast cancer.

    PubMed

    Yang, Yu; Feng, Rennan; Bi, Sheng; Xu, Yuqing

    2011-09-01

    Tumor necrosis factor-α (TNF-α) is an important pro-inflammatory cytokine in the development and progress in human cancer. TNF-α polymorphisms have been confirmed to influence the risk for several types of cancer, however, the associations between TNF-α polymorphisms and breast cancer (BC) remain controversial and ambiguous. The aim of this meta-analysis is to explore more precise estimations regarding this point. Electronic searches of several databases were conducted for all online publications on the associations between TNF-α-238, -308, -857, -863, -1031, -1210 polymorphisms and BC through March 2011. Odds ratios (OR) with 95% confidence intervals (95% CI) were calculated to assess the strength of these associations in fixed- and random-effect models with Review manager 5.0. A total of 17 studies with 44,442 BC patients and 49,926 controls involved were identified. This meta-analysis showed no significant association between TNF-α-308 polymorphism and BC (AA + GA vs. GG: OR = 0.95, 95% CI = 0.82-1.09) in overall and (OR = 1.44, 95% CI = 0.61-3.40) Asian populations, however, a negative association was shown in Caucasian subgroup (OR = 0.91, 95% CI = 0.85-0.97). As regards the TNF-α-238 polymorphism, the OR values (95% CI) were 0.99 (0.94-1.05), 0.94 (0.78-1.14), and 1.00 (0.95-1.05) for the overall, Asian, and Caucasian studies, respectively. No significant associations were found for other polymorphisms. Furthermore, there was a coincidence in the sensitivity analysis of these associations. No publication bias was detected in this study. To sum up, no significant associations were found between the TNF-α-308, -238, -857, -863, -1031, -1210 polymorphisms and the risk for BC in overall populations, whereas a negative association was found between TNF-α-308 polymorphism and BC in Caucasian populations.

  20. Speciation as a sieve for ancestral polymorphism.

    PubMed

    Guerrero, Rafael F; Hahn, Matthew W

    2017-08-09

    Because they are considered rare, balanced polymorphisms are often discounted as crucial constituents of genome-wide variation in sequence diversity. Despite its perceived rarity, however, long-term balancing selection can elevate genetic diversity and significantly affect observed divergence between species. Here, we discuss how ancestral balanced polymorphisms can be "sieved" by the speciation process, which sorts them unequally across descendant lineages. After speciation, ancestral balancing selection is revealed by genomic regions of high divergence between species. This signature, which resembles that of other evolutionary processes, can potentially confound genomic studies of population divergence and inferences of "islands of speciation." © 2017 John Wiley & Sons Ltd.

  1. OXIDATIVE DAMAGE-RELATED GENES AKR1C3 AND OGG1 MODULATE RISKS FOR LUNG CANCER DUE TO EXPOSURE TO PAH-RICH COAL COMBUSTION EMISSIONS

    EPA Science Inventory

    We studied polymorphisms in genes that generate, prevent, or repair oxidative damage and lung cancer risk among 118 cases and 113 controls in Xuan Wei China, where extremely high lung cancer rates are caused by indoor exposure to smoky coal. SOD2-Vak16Ala and NQO1-Pro 187Ser were...

  2. OXIDATIVE DAMAGE-RELATED GENES AKR1C3 AND OGG1 MODULATE RISKS FOR LUNG CANCER DUE TO EXPOSURE TO PAH-RICH COAL COMBUSTION EMISSIONS

    EPA Science Inventory

    We studied polymorphisms in genes that generate, prevent, or repair oxidative damage and lung cancer risk among 118 cases and 113 controls in Xuan Wei China, where extremely high lung cancer rates are caused by indoor exposure to smoky coal. SOD2-Vak16Ala and NQO1-Pro 187Ser were...

  3. Estrogen-DNA Adducts as Novel Biomarkers For Ovarian Cancer Risk and for Use in Prevention

    DTIC Science & Technology

    2011-03-31

    amplification and genotyping of the four single nucleotide polymorphisms , CYP1A1 (I462V), CYP1B1 (V432L), COMT (V158M) and NQO1 (P609S). Task 6. Order...genetic polymorphisms in selected enzymes that metabolize estrogens. The first year of the grant has been spent collecting urine and saliva samples...DNA adducts, estrogen metabolism, genetic polymorphisms , cancer etiology, tool for early diagnosis of ovarian cancer 16. SECURITY CLASSIFICATION OF

  4. Simultaneous detection of the exon 10 polymorphism and a novel intronic single base insertion polymorphism in the XPD gene using single strand conformation polymorphism.

    PubMed

    Kumar, Rajiv; Angelini, Sabrina; Hemminki, Kari

    2003-03-01

    We developed a new method based on the single strand conformation polymorphism (SSCP) technique for the detection of a G23591A (Asp312Asn) polymorphism in exon 10 of the XPD gene. In the process we also identified a novel polymorphism 23623C-ins (IVS10+17C-ins) in intron 10 of the same gene. With this newly developed SSCP-based method of genotyping we could detect both polymorphisms in the same assay and thus consequently determine the haplotype. In order to determine the population frequency of the novel polymorphism and the haplotype frequency, 302 healthy individuals were genotyped. The allelic frequency of the 23623C-ins intronic polymorphism was 0.16, whereas the frequency of the variant allele for the G23591A polymorphism was 0.39. Forty-three individuals (14%) were heterozygous for both polymorphisms but none carried polymorphic variants for both G23591A and 23623C-ins on the same allele. The effect of the novel intronic insertion polymorphism, which is located 16 nt downstream of the 3'-end of exon 10 of the XPD gene and involves a mononucleotide C repeat sequence, on expression remains to be determined.

  5. Phase transformation in conformational polymorphs of nimesulide.

    PubMed

    Sanphui, Palash; Sarma, Bipul; Nangia, Ashwini

    2011-06-01

    Nimesulide is a nonsteroidal anti-inflammatory drug (NSAID) and a COX-2 inhibitor. The native crystal structure of nimesulide (or Form I) has been characterized in the literature by X-ray powder diffraction (XRPD) lines, whereas full three-dimensional coordinates are known for a second polymorph (Form II). A detailed structural characterization and phase stability of nimesulide polymorphs were carried out. Rod-like crystals of Form I (space group Pca2(1); number of symmetry-independent molecules, Z' = 2) were crystallized from EtOH concomitantly with Form II (C2/c, Z' = 1). These conformational polymorphs have different torsion angles at the phenoxy and sulfonamide groups. The crystal structures are stabilized by N-H · · · O hydrogen bonds and C-H · · · O, C-H · · · π interactions. Phase transition from the metastable Form (II) to the stable modification (I) was studied using differential scanning calorimetry, hot-stage microscopy, solid-state grinding, solvent-drop grinding, and slurry crystallization. The phase transition was monitored by infrared, Raman, and ss-nuclear magnetic resonance spectroscopy; and XRPD and single-crystal X-ray diffraction. The stable polymorph I was obtained in excess during solution crystallization, grinding, and slurry methods. Intrinsic dissolution and equilibrium solubility experiments showed that the metastable Form II dissolves much faster than the stable Form I. Copyright © 2011 Wiley-Liss, Inc.

  6. Difficulties in Learning Inheritance and Polymorphism

    ERIC Educational Resources Information Center

    Liberman, Neomi; Beeri, Catriel; Kolikant, Yifat Ben-David

    2011-01-01

    This article reports on difficulties related to the concepts of inheritance and polymorphism, expressed by a group of 22 in-service CS teachers with an experience with the procedural paradigm, as they coped with a course on OOP. Our findings are based on the analysis of tests, questionnaires that the teachers completed in the course, as well as on…

  7. Polymorphism in a high-entropy alloy

    DOE PAGES

    Zhang, Fei; Wu, Yuan; Lou, Hongbo; ...

    2017-06-01

    Polymorphism, which describes the occurrence of different lattice structures in a crystalline material, is a critical phenomenon in materials science and condensed matter physics. Recently, configuration disorder was compositionally engineered into single lattices, leading to the discovery of high-entropy alloys and high-entropy oxides. For these novel entropy-stabilized forms of crystalline matter with extremely high structural stability, is polymorphism still possible? Here by employing in situ high-pressure synchrotron radiation X-ray diffraction, we reveal a polymorphic transition from face-centred-cubic (fcc) structure to hexagonal-close-packing (hcp) structure in the prototype CoCrFeMnNi high-entropy alloy. The transition is irreversible, and our in situ high-temperature synchrotron radiationmore » X-ray diffraction experiments at different pressures of the retained hcp high-entropy alloy reveal that the fcc phase is a stable polymorph at high temperatures, while the hcp structure is more thermodynamically favourable at lower temperatures. Lastly, as pressure is increased, the critical temperature for the hcp-to-fcc transformation also rises.« less

  8. Idealized powder diffraction patterns for cellulose polymorphs

    USDA-ARS?s Scientific Manuscript database

    Cellulose samples are routinely analyzed by X-ray diffraction to determine their crystal type (polymorph) and crystallinity. However, the connection is seldom made between those efforts and the crystal structures of cellulose that have been determined with synchrotron X-radiation and neutron diffrac...

  9. Molecular basis for amyloid-[beta] polymorphism

    SciTech Connect

    Colletier, Jacques-Philippe; Laganowsky, Arthur; Landau, Meytal; Zhao, Minglei; Soriaga, Angela B.; Goldschmidt, Lukasz; Flot, David; Cascio, Duilio; Sawaya, Michael R.; Eisenberga, David

    2011-10-19

    Amyloid-beta (A{beta}) aggregates are the main constituent of senile plaques, the histological hallmark of Alzheimer's disease. A{beta} molecules form {beta}-sheet containing structures that assemble into a variety of polymorphic oligomers, protofibers, and fibers that exhibit a range of lifetimes and cellular toxicities. This polymorphic nature of A{beta} has frustrated its biophysical characterization, its structural determination, and our understanding of its pathological mechanism. To elucidate A{beta} polymorphism in atomic detail, we determined eight new microcrystal structures of fiber-forming segments of A{beta}. These structures, all of short, self-complementing pairs of {beta}-sheets termed steric zippers, reveal a variety of modes of self-association of A{beta}. Combining these atomic structures with previous NMR studies allows us to propose several fiber models, offering molecular models for some of the repertoire of polydisperse structures accessible to A{beta}. These structures and molecular models contribute fundamental information for understanding A{beta} polymorphic nature and pathogenesis.

  10. Treatment of asymptomatic catecholaminergic polymorphic ventricular tachycardia.

    PubMed

    Obeyesekere, Manoj N; Sy, Raymond W; Leong-Sit, Peter; Gula, Lorne J; Yee, Raymond; Skanes, Allan C; Klein, George J; Krahn, Andrew D

    2012-05-01

    Catecholaminergic polymorphic ventricular tachycardia is a rare genetic disorder caused by mutations in genes involved in the intracellular calcium homeostasis of cardiac cells. Affected patients typically present with life-threatening ventricular arrhythmias precipitated by emotional/physical stress. The diagnosis is based on the demonstration of polymorphic or bidirectional ventricular tachycardia associated with adrenergic stress. Genetic testing can be confirmatory in some patients. Treatment for catecholaminergic polymorphic ventricular tachycardia includes medical and surgical efforts to suppress the effects of epinephrine at the myocardial level and/or modulation of calcium homeostasis. Mortality is high when untreated and sudden cardiac death may be the first manifestation of the disease. First-degree relatives of a proband should be offered genetic testing if the causal mutation is known. If the family mutation is not known, relatives should be clinically evaluated with provocative testing. In the absence of rigorous trials, prophylactic treatment of the asymptomatic catecholaminergic polymorphic ventricular tachycardia patient appears to reduce morbidity and mortality.

  11. Difficulties in Learning Inheritance and Polymorphism

    ERIC Educational Resources Information Center

    Liberman, Neomi; Beeri, Catriel; Kolikant, Yifat Ben-David

    2011-01-01

    This article reports on difficulties related to the concepts of inheritance and polymorphism, expressed by a group of 22 in-service CS teachers with an experience with the procedural paradigm, as they coped with a course on OOP. Our findings are based on the analysis of tests, questionnaires that the teachers completed in the course, as well as on…

  12. Polymorphism in a high-entropy alloy

    NASA Astrophysics Data System (ADS)

    Zhang, Fei; Wu, Yuan; Lou, Hongbo; Zeng, Zhidan; Prakapenka, Vitali B.; Greenberg, Eran; Ren, Yang; Yan, Jinyuan; Okasinski, John S.; Liu, Xiongjun; Liu, Yong; Zeng, Qiaoshi; Lu, Zhaoping

    2017-06-01

    Polymorphism, which describes the occurrence of different lattice structures in a crystalline material, is a critical phenomenon in materials science and condensed matter physics. Recently, configuration disorder was compositionally engineered into single lattices, leading to the discovery of high-entropy alloys and high-entropy oxides. For these novel entropy-stabilized forms of crystalline matter with extremely high structural stability, is polymorphism still possible? Here by employing in situ high-pressure synchrotron radiation X-ray diffraction, we reveal a polymorphic transition from face-centred-cubic (fcc) structure to hexagonal-close-packing (hcp) structure in the prototype CoCrFeMnNi high-entropy alloy. The transition is irreversible, and our in situ high-temperature synchrotron radiation X-ray diffraction experiments at different pressures of the retained hcp high-entropy alloy reveal that the fcc phase is a stable polymorph at high temperatures, while the hcp structure is more thermodynamically favourable at lower temperatures. As pressure is increased, the critical temperature for the hcp-to-fcc transformation also rises.

  13. [Connective tissue dysplasia, magnesium, and nucleotide polymorphisms].

    PubMed

    Torshin, I Iu; Gromova, O A

    2008-01-01

    Undifferentiated connective tissue dysplasia (UCTD) is one of most common diseases of the connective tissue. High frequency of UCTD in population along with the fact that it can provoke a number of other diseases make UCTD an important object of the modern biomedical research in the areas of cardiology, neurology, rheumatology and pulmonology. Modern diagnostics and determination of the predisposition to UCTD allow elaboration of personalized therapy. In particular, Mg-containing supplements and medications can be effectively used in the therapy of UCTD. In one of our previous works we have analyzed possible molecular mechanisms of UCTD etiology as well as therapeutic action of magnesium. The use of data on nucleotide polymorphisms as complementation of standard medical diagnostics is one of perspective trends of the post-genomic medical research. The present work suggest a number of nucleotide polymorphisms that can be used in genetic association analyses of the UCTD as of well as therapeutic efficiency of magnesium treatment. Selection and analysis of the polymorphisms was done on the base of molecular mechanisms we had proposed earlier, comprehensive analysis of published data and also with the use of an integral approach to analysis of the functional effects of the nucleotide polymorphisms and corresponding amino acid substitutions.

  14. [Cyclooxigenase-1 gene polymorphism and aspirin resistance].

    PubMed

    Bondar', T N; Kravchenko, N A

    2012-01-01

    The literature data concerning structure of cyclo-oxigenase-1--the key enzyme in prostaglandin biosynthesis and the main target of anti-platelet therapy with the use of acetylsalicilic acid are presented in the review. The data on cyclooxigenase-1 gene polymorphism, distribution of the revealed variants in various populations and their possible correlation with biochemical and functional aspirin resistance are presented.

  15. The Effect of Polymorphism on Surface Energetics of D-Mannitol Polymorphs.

    PubMed

    Smith, Robert R; Shah, Umang V; Parambil, Jose V; Burnett, Daniel J; Thielmann, Frank; Heng, Jerry Y Y

    2017-01-01

    The aim of this work was to assess the effect of different crystalline polymorphism on surface energetics of D-mannitol using finite dilution inverse gas chromatography (FD-IGC). Pure α, β and δ polymorphs were prepared via solution crystallisation and characterised by powder X-ray diffraction (P-XRD). The dispersive surface energies were found to range from 43 to 34 mJ/m(2), 50 to 41 mJ/m(2), and 48 to 38 mJ/m(2), for α, β, and δ, respectively, for surface coverage ranging from 0.006 to 0.095. A deconvolution modelling approach was employed to establish their energy sites. The primary sites corresponded to maxima in the dispersive surface energy of 37.1 and 33.5; 43.3 and 39.5; and 38.6, 38.4 and 33.0; for α, β, and δ, respectively. This methodology was also extended to an α-β polymorph mixture to estimate the amount of the constituent α and β components present in the sample. The dispersive surface energies of the α-β mixture were found to be in the range of 48 to 37 mJ/m(2) with 40.0, 42.4, 38.4 and 33.1 mJ/m(2) sites. The deconvolution modelling method extracted the energy contribution of each of the polymorphs from data for the polymorphic mixture. The mixture was found to have a β-polymorph surface content of ∼19%. This work shows the influence of polymorphism on surface energetics and demonstrates that FD-IGC coupled with a simple modelling approach to be a powerful tool for assessing the specific nature of this energetic distribution including the quantification of polymorphic content on the surface.

  16. Vibrational spectroscopic study of polymorphism and polymorphic transformation of the anti-viral drug lamivudine.

    PubMed

    Du, Yong; Zhang, Huili; Xue, Jiadan; Tang, Wenjian; Fang, Hongxia; Zhang, Qi; Li, Yafang; Hong, Zhi

    2015-02-25

    Vibrational spectra of hydrated and anhydrous lamivudines, and also the dynamic process of polymorphic transformation have been characterized by Fourier transform infrared (FT-IR) and Raman spectroscopic techniques. The vibrational modes of both polymorphic lamivudines are assigned. FT-IR and Raman spectral results show that the interaction between crystalline water and lamivudine molecular has an important effect on the molecular vibration motions of polymorphic lamivudines. The two characteristic Raman peaks at 783 and 798 cm(-1) represent hydrated and anhydrous lamivudine respectively. The relationship between changes of two characteristic peak normalized areas and heating time could be fitted with single exponential functions, and the dynamic information of polymorphic transformation of lamivudine drug is obtained. The decay rate of characteristic peak for hydrated lamivudine and the growth rate of that for anhydrous lamivudine are consistent during dehydration transformation process. The reported results provide us important benchmark for qualitatively monitoring different polymorphic drugs and also establishing the corresponding model for the polymorphic transformation of drugs in related pharmaceutical research fields.

  17. Vibrational spectroscopic study of polymorphism and polymorphic transformation of the anti-viral drug lamivudine

    NASA Astrophysics Data System (ADS)

    Du, Yong; Zhang, Huili; Xue, Jiadan; Tang, Wenjian; Fang, Hongxia; Zhang, Qi; Li, Yafang; Hong, Zhi

    2015-02-01

    Vibrational spectra of hydrated and anhydrous lamivudines, and also the dynamic process of polymorphic transformation have been characterized by Fourier transform infrared (FT-IR) and Raman spectroscopic techniques. The vibrational modes of both polymorphic lamivudines are assigned. FT-IR and Raman spectral results show that the interaction between crystalline water and lamivudine molecular has an important effect on the molecular vibration motions of polymorphic lamivudines. The two characteristic Raman peaks at 783 and 798 cm-1 represent hydrated and anhydrous lamivudine respectively. The relationship between changes of two characteristic peak normalized areas and heating time could be fitted with single exponential functions, and the dynamic information of polymorphic transformation of lamivudine drug is obtained. The decay rate of characteristic peak for hydrated lamivudine and the growth rate of that for anhydrous lamivudine are consistent during dehydration transformation process. The reported results provide us important benchmark for qualitatively monitoring different polymorphic drugs and also establishing the corresponding model for the polymorphic transformation of drugs in related pharmaceutical research fields.

  18. Polymorphism Control in Nanostructured Metal Oxides

    NASA Astrophysics Data System (ADS)

    Sood, Shantanu

    Polymorphic phase transformations are common to all nanocrystalline binary metal oxides. The polymorphic nature of such metal oxides makes available a large number of phases with differing crystal structures, each stable under certain conditions of temperature, pressure, and/or particle size. These different crystal structures translate to unique physical and chemical properties for each structural class of polymorphs. Thus predicting when polymorphic phase transitions are likely to occur becomes important to the synthesis of stable functional materials with desired properties. Theoretical calculations using a heuristic approach have resulted in an accurate estimation of the critical particle size predicting metastable to stable phase transitions. This formula is applied to different case studies: for anatase to rutile titania; gamma-Alumina to alpha-Alumina; and tetragonal to monoclinic zirconia. The theoretical values calculated have been seen to be very close to the experimental results from the literature. Manifestation of the effect of phase transitions in nanostructured metal oxides was provided in the study of metastable to stable phase transitions in WO3. Nanowires of tungsten trioxide have been synthesized in-situ inside an electron microscope. Such structure of tungsten trioxide result due to a metastable to stable phase transformation, from the cubic to the monoclinic phase. The transformation is massive and complete. The structures formed are unique one-dimensional nanowires. Such a method can be scaled inside any equipment equipped with an electron gun, for example lithography systems either using STEM or E-beam lithography. Another study on nanowire formation in binary metal oxides involved the synthesis of stable orthorhombic MoO3 by means of blend electrospinning. Both a traditional single jet electrospinning set up and a novel high-throughput process to get high aspect ratio nanowires. The latter is a jet-controlled and flow controlled

  19. Polymorphic hydroxylation of perhexiline maleate in man.

    PubMed Central

    Cooper, R G; Evans, D A; Whibley, E J

    1984-01-01

    Long term perhexiline maleate therapy causes peripheral neuropathy and hepatic damage in certain subjects. An association between these adverse reactions and a genetically determined relative inability to hydroxylate debrisoquine has been described. This association could indicate either that the effects of perhexiline impair debrisoquine oxidation thus producing a phenocopy, or that perhexiline is polymorphically hydroxylated and that the polymorphism is controlled by the same alleles as control the debrisoquine polymorphism. To test the second possibility, a study investigating the hydroxylation status of a population of healthy volunteer subjects has been performed using perhexiline maleate. Hydroxylation phenotyping was performed on 50 normal volunteers. A standard oral dose was given and plasma and urinary perhexiline, 4-monohydroxyperhexiline (MI metabolite), and 4'monohydroxyperhexiline (MIII metabolite) was measured. The 24-hour plasma perhexiline concentration, the 24-hour plasma MI metabolite concentration, and 12 to 24-hour urinary MI metabolite excretion were clearly bimodal, suggesting the existence of a polymorphism for perhexiline hydroxylation. Poor metabolisers represent 6% of the population studied. Known poor metabolisers of debrisoquine are also poor metabolisers of perhexiline, while known extensive metabolisers of debrisoquine are also extensive metabolisers of perhexiline, indicating that in white British subjects the hydroxylation polymorphism is under identical genetic control for both compounds. The poor metaboliser sub-group exhibited the highest plasma perhexiline levels. Perhexiline phenotyping separates the poor and extensive metaboliser phenotypes much more clearly than other tests and defines a sub-group at risk from perhexiline toxicity. Pretreatment phenotyping using this test, followed by exclusion of poor metabolisers from perhexiline therapy, should substantially reduce the incidence of major adverse effects. PMID:6694182

  20. Wnt antagonist gene polymorphisms and renal cancer

    PubMed Central

    Hirata, Hiroshi; Hinoda, Yuji; Nakajima, Koichi; Kikuno, Nobuyuki; Yamamura, Soichiro; Kawakami, Kazumori; Suehiro, Yutaka; Tabatabai, Z. Laura; Ishii, Nobuhisa; Dahiya, Rajvir

    2014-01-01

    Purpose Epigenetic silencing of several Wnt pathway related genes has been reported in renal cancer. Except for the TCF4 gene, there are no reports regarding Wnt pathway gene polymorphisms in renal cancer. Therefore, we hypothesized that the polymorphisms in Wnt signaling genes may be risk factors for renal cancer. Experimental Design A total of 210 patients (145 male and 65 female) with pathologically confirmed renal cell carcinoma (RCC), and 200 age- and sex-matched control individuals were enrolled in this study. We genotyped 14 SNPs in six genes including DKK2 (rs17037102, rs419558, rs447372), DKK3 (rs3206824, rs11022095, rs1472189, rs7396187, rs2291599), DKK4 (rs2073664), sFRP4 (rs1802073, rs1802074), SMAD7 (rs12953717), DAAM2 (rs6937133, rs2504106) using PCR-RFLP and direct sequencing in RCC and age-matched healthy subjects. We also tested the relationship between these polymorphisms and clinicopathologic data including gender, grade, tumor stage, lymph-node involvement, distant metastasis, and overall survival. Results A significant decrease in the frequency of the G/A+A/A genotypes in the DKK3 codon335 rs3206824 was observed in RCC patients compared with controls. The frequency of the rs3206824 (G/A) A- rs7396187 (G/C) C haplotype was significantly lower in RCC compared with other haplotypes. We also found that DKK3 rs1472189 C/T is associated with distant metastasis and furthermore, DKK2 rs17037102 G homozygous patients had a decreased risk for death by multivariate Cox regression analysis. Conclusions This is the first report documenting that DKK3 polymorphisms are associated with RCC and that the DKK2 rs17037102 polymorphism may be a predictor for survival in RCC patients after radical nephrectomy. PMID:19562778

  1. Computerized polymorphic marker identification: Experimental validation and a predicted human polymorphism catalog

    PubMed Central

    Fondon, John W.; Mele, Gina M.; Brezinschek, Ruth I.; Cummings, Donna; Pande, Ashwini; Wren, Jonathan; O’Brien, Kevin M.; Kupfer, Kenneth C.; Wei, Ming-Hui; Lerman, Michael; Minna, John D.; Garner, Harold R.

    1998-01-01

    A computational system for the prediction of polymorphic loci directly and efficiently from human genomic sequence was developed and verified. A suite of programs, collectively called pompous (polymorphic marker prediction of ubiquitous simple sequences) detects tandem repeats ranging from dinucleotides up to 250 mers, scores them according to predicted level of polymorphism, and designs appropriate flanking primers for PCR amplification. This approach was validated on an approximately 750-kilobase region of human chromosome 3p21.3, involved in lung and breast carcinoma homozygous deletions. Target DNA from 36 paired B lymphoblastoid and lung cancer lines was amplified and allelotyped for 33 loci predicted by pompous to be variable in repeat size. We found that among those 36 predominately Caucasian individuals 22 of the 33 (67%) predicted loci were polymorphic with an average heterozygosity of 0.42. Allele loss in this region was found in 27/36 (75%) of the tumor lines using these markers. pompous provides the genetic researcher with an additional tool for the rapid and efficient identification of polymorphic markers, and through a World Wide Web site, investigators can use pompous to identify polymorphic markers for their research. A catalog of 13,261 potential polymorphic markers and associated primer sets has been created from the analysis of 141,779,504 base pairs of human genomic sequence in GenBank. This data is available on our Web site (pompous.swmed.edu) and will be updated periodically as GenBank is expanded and algorithm accuracy is improved. PMID:9636181

  2. Hyphenated spectroscopy as a polymorph screening tool.

    PubMed

    Aaltonen, Jaakko; Strachan, Clare J; Pöllänen, Kati; Yliruusi, Jouko; Rantanen, Jukka

    2007-06-28

    Polymorph screening of a model compound (nitrofurantoin) was performed. Nitrofurantoin was crystallized from acetone-water mixtures with varying process parameters. Two anhydrate forms (alpha and beta) and one monohydrate form (II) were crystallized in the polymorph screen. The solid forms were analyzed with three complementary spectroscopic techniques: near-infrared (NIR) spectroscopy, Raman spectroscopy and terahertz pulsed spectroscopy (TPS), and the results of the solid phase analysis were verified with X-ray powder diffraction (XRPD). NIR and Raman spectroscopy were coupled to achieve a rapid and comprehensive method of solid phase analysis. The hyphenated NIR/Raman spectroscopic data were analyzed with a multivariate method, principal component analysis (PCA). The combination was found effective in screening solid forms due to the complementary characteristics of the methods. NIR spectroscopy is powerful in differentiating between anhydrate and hydrate forms and intermolecular features, whereas Raman spectroscopy is sensitive to intramolecular alterations in the molecular backbone.

  3. Gene polymorphisms, apoptotic capacity and cancer risk.

    PubMed

    Imyanitov, Evgeny N

    2009-04-01

    Programmed cell death has been implicated in various aspects of cancer development. Apoptotic capacity is a subject of significant interindividual variations, which are largely attributed to hereditary traits. Single nucleotide polymorphisms (SNPs) located within cell death genes may influence cancer risk in various ways. Low activity of apoptosis may favor cancer development because of the failure to eliminate cellular clones carrying DNA damage and propensity to inflammation, but may also protect against malignancy due to preservation of antitumor immune cells. Phenotyping studies assessing cell death rate in cancer patients versus healthy controls are limited in number and produced controversial results. TP53 R72P polymorphism is the only SNP whose functional impact on apoptotic response has been replicated in independent investigations. Intriguingly, meta-analysis of TP53 genotyping studies has provided evidence for the association between apoptosis-deficient TP53 genotype and tumor susceptibility. Systematic analysis of cancer-predisposing relevance of other apoptotic gene SNPs remains to be done.

  4. IPD—the Immuno Polymorphism Database

    PubMed Central

    Robinson, James; Mistry, Kavita; McWilliam, Hamish; Lopez, Rodrigo; Marsh, Steven G. E.

    2010-01-01

    The Immuno Polymorphism Database (IPD) (http://www.ebi.ac.uk/ipd/) is a set of specialist databases related to the study of polymorphic genes in the immune system. The IPD project works with specialist groups or nomenclature committees who provide and curate individual sections before they are submitted to IPD for online publication. The IPD project stores all the data in a set of related databases. IPD currently consists of four databases: IPD-KIR, contains the allelic sequences of Killer-cell Immunoglobulin-like Receptors, IPD-MHC, is a database of sequences of the Major Histocompatibility Complex of different species; IPD-human platelet antigens, alloantigens expressed only on platelets and IPD-ESTDAB, which provides access to the European Searchable Tumour cell-line database, a cell bank of immunologically characterised melanoma cell lines. The data is currently available online from the website and ftp directory. PMID:19875415

  5. IPD--the Immuno Polymorphism Database.

    PubMed

    Robinson, James; Mistry, Kavita; McWilliam, Hamish; Lopez, Rodrigo; Marsh, Steven G E

    2010-01-01

    The Immuno Polymorphism Database (IPD) (http://www.ebi.ac.uk/ipd/) is a set of specialist databases related to the study of polymorphic genes in the immune system. The IPD project works with specialist groups or nomenclature committees who provide and curate individual sections before they are submitted to IPD for online publication. The IPD project stores all the data in a set of related databases. IPD currently consists of four databases: IPD-KIR, contains the allelic sequences of Killer-cell Immunoglobulin-like Receptors, IPD-MHC, is a database of sequences of the Major Histocompatibility Complex of different species; IPD-human platelet antigens, alloantigens expressed only on platelets and IPD-ESTDAB, which provides access to the European Searchable Tumour cell-line database, a cell bank of immunologically characterised melanoma cell lines. The data is currently available online from the website and ftp directory.

  6. IPD--the Immuno Polymorphism Database.

    PubMed

    Robinson, James; Halliwell, Jason A; McWilliam, Hamish; Lopez, Rodrigo; Marsh, Steven G E

    2013-01-01

    The Immuno Polymorphism Database (IPD), http://www.ebi.ac.uk/ipd/ is a set of specialist databases related to the study of polymorphic genes in the immune system. The IPD project works with specialist groups or nomenclature committees who provide and curate individual sections before they are submitted to IPD for online publication. The IPD project stores all the data in a set of related databases. IPD currently consists of four databases: IPD-KIR, contains the allelic sequences of killer-cell immunoglobulin-like receptors, IPD-MHC, a database of sequences of the major histocompatibility complex of different species; IPD-HPA, alloantigens expressed only on platelets; and IPD-ESTDAB, which provides access to the European Searchable Tumour Cell-Line Database, a cell bank of immunologically characterized melanoma cell lines. The data is currently available online from the website and FTP directory. This article describes the latest updates and additional tools added to the IPD project.

  7. Kinetics versus Thermodynamics in Virus Capsid Polymorphism.

    PubMed

    Moerman, Pepijn; van der Schoot, Paul; Kegel, Willem

    2016-07-07

    Virus coat proteins spontaneously self-assemble into empty shells in aqueous solution under the appropriate physicochemical conditions, driven by an interaction free energy per bond on the order of 2-5 times the thermal energy kBT. For this seemingly modest interaction strength, each protein building block nonetheless gains a very large binding free energy, between 10 and 20 kBT. Because of this, there is debate about whether the assembly process is reversible or irreversible. Here we discuss capsid polymorphism observed in in vitro experiments from the perspective of nucleation theory and of the thermodynamics of mass action. We specifically consider the potential contribution of a curvature free energy term to the effective interaction potential between the proteins. From these models, we propose experiments that may conclusively reveal whether virus capsid assembly into a mixture of polymorphs is a reversible or an irreversible process.

  8. APOE gene polymorphisms and diabetic peripheral neuropathy.

    PubMed

    Monastiriotis, Christodoulos; Papanas, Nikolaos; Veletza, Stavroula; Maltezos, Efstratios

    2012-09-08

    Genetic factors may influence the natural course of diabetic peripheral neuropathy and explain some of its variability. The aim of this review was to examine the association between apolipoprotein E (apoE) gene polymorphisms and diabetic peripheral neuropathy. Four relevant studies were identified. The two earlier works provided evidence that the ɛ4 allele is a risk factor for this complication, while the two more recent studies were negative. Important differences in the methodology used and in the populations included are obvious, rendering difficult the comparison between studies. In conclusion, the association between APOE gene polymorphisms and diabetic peripheral neuropathy is still unclear. Available evidence is rather limited and results have so far been contradictory. Future studies should employ more robust methodology, adjusting for potential confounders and for the prevalence of neuropathy in the general population with diabetes.

  9. Carbon nitride frameworks and dense crystalline polymorphs

    NASA Astrophysics Data System (ADS)

    Pickard, Chris J.; Salamat, Ashkan; Bojdys, Michael J.; Needs, Richard J.; McMillan, Paul F.

    2016-09-01

    We used ab initio random structure searching (AIRSS) to investigate polymorphism in C3N4 carbon nitride as a function of pressure. Our calculations reveal new framework structures, including a particularly stable chiral polymorph of space group P 43212 containing mixed s p2 and s p3 bonding, that we have produced experimentally and recovered to ambient conditions. As pressure is increased a sequence of structures with fully s p3 -bonded C atoms and three-fold-coordinated N atoms is predicted, culminating in a dense P n m a phase above 250 GPa. Beyond 650 GPa we find that C3N4 becomes unstable to decomposition into diamond and pyrite-structured CN2.

  10. New polymorphic variants of human blood clotting factor IX

    SciTech Connect

    Surin, V.L.; Luk`yanenko, A.V.; Tagiev, A.F.; Smirnova, O.V.; Plutalov, O.V.; Berlin, Yu.A.

    1995-04-01

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

  11. Calorimetric determinations and theoretical calculations of polymorphs of thalidomide

    NASA Astrophysics Data System (ADS)

    Lara-Ochoa, F.; Pérez, G. Espinosa; Mijangos-Santiago, F.

    2007-09-01

    The analysis of the thermograms of thalidomide obtained for the two reported polymorphs α and β by differential scanning calorimetry (DSC) shows some inconsistencies that are discussed in the present work. The conception of a new polymorph form, named β ∗, allowed us to explain the observed thermal behavior more satisfactorily. This new polymorph shows enantiotropy with both α and β polymorphs, reflected in the unique endotherm obtained in the DSC-thermograms, when a heating rate of 10 °C/min is applied. Several additional experiments, such as re-melting of both polymorph forms, showed that there is indeed a new polymorph with an endotherm located between the endotherms of α and β. IR, Raman, and powder X-ray permit us to characterize the isolated compound, resulting from the re-melting of both polymorph forms. Mechanical calculations were performed to elucidate the conformations of each polymorph, and ab initio quantum chemical calculations were performed to determine the energy of the more stable conformers and the spatial cell energy for both polymorphs α and β. These results suggested a possible conformation for the newly discovered polymorph β ∗.

  12. Innate Immune Gene Polymorphisms in Tuberculosis

    PubMed Central

    Sadee, Wolfgang

    2012-01-01

    Tuberculosis (TB) is a leading cause worldwide of human mortality attributable to a single infectious agent. Recent studies targeting candidate genes and “case-control” association have revealed numerous polymorphisms implicated in host susceptibility to TB. Here, we review current progress in the understanding of causative polymorphisms in host innate immune genes associated with TB pathogenesis. We discuss genes encoding several types of proteins: macrophage receptors, such as the mannose receptor (MR, CD206), dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN, CD209), Dectin-1, Toll-like receptors (TLRs), complement receptor 3 (CR3, CD11b/CD18), nucleotide oligomerization domain 1 (NOD1) and NOD2, CD14, P2X7, and the vitamin D nuclear receptor (VDR); soluble C-type lectins, such as surfactant protein-A (SP-A), SP-D, and mannose-binding lectin (MBL); phagocyte cytokines, such as tumor necrosis factor (TNF), interleukin-1β (IL-1β), IL-6, IL-10, IL-12, and IL-18; chemokines, such as IL-8, monocyte chemoattractant protein 1 (MCP-1), RANTES, and CXCL10; and other important innate immune molecules, such as inducible nitric oxide synthase (iNOS) and solute carrier protein 11A1 (SLC11A1). Polymorphisms in these genes have been variably associated with susceptibility to TB among different populations. This apparent variability is probably accounted for by evolutionary selection pressure as a result of long-term host-pathogen interactions in certain regions or populations and, in part, by lack of proper study design and limited knowledge of molecular and functional effects of the implicated genetic variants. Finally, we discuss genomic technologies that hold promise for resolving questions regarding the evolutionary paths of the human genome, functional effects of polymorphisms, and corollary impacts of adaptation on human health, ultimately leading to novel approaches to controlling TB. PMID:22825450

  13. Bimodal expression level polymorphisms in Arabidopsis thaliana

    PubMed Central

    Nagano, Atsushi J.; Tsuchimatsu, Takashi; Okuyama, Yudai; Hara-Nishimura, Ikuko

    2012-01-01

    Differences in gene expression are termed expression level polymorphisms (ELPs). Here, we propose a new ELP class, bimodal ELPs (bELPs), as a criterion to screen for genes that are responsible for natural phenotypic variation and/or that are targeted by balancing selection. bELP genes are characterized by two expression level modes. Genomic scans based on nucleotide sequences are not ideal for identifying genes targeted for selection. A critical concern is that several genes can be present in the selection-targeted regions identified by such scans. This situation indicates the importance of integrating genomic sequence data and other information, such as gene expression data. Comparative transcriptomics is useful for determining evolutionarily and ecologically important polymorphisms. In a genome-wide expression screen of 34 accessions, we identified 344 Arabidopsis thaliana genes exhibiting bELPs. Population genetic analysis revealed that bELP genes had high nucleotide diversities and long linkage disequilibriums. The highest nucleotide diversity (11-fold greater than the genomic mean) was found in the At1g23780 gene, which encodes a putative F-box protein. We observed a clear association between the expression mode and sequence type of the At1g23780 gene. Our results suggest that bELPs will be useful for the screening and functional analysis of genes responsible for phenotypic polymorphisms. Such a “multi-omics” approach has the potential to facilitate the scanning of genes relevant to balanced polymorphisms not only in A. thaliana, but also in other model and non-model organisms. PMID:22751308

  14. An orthorhombic polymorph of mulinic acid.

    PubMed

    Brito, Iván; Bórquez, Jorge; Loyola, Luis Alberto; López-Rodríguez, Matías; Cárdenas, Alejandro

    2010-01-09

    THE TITLE COMPOUND [SYSTEMATIC NAME: (3S,3aS,10bR)-3-isopropyl-5a,8-dimethyl-2,3,4,5,5a,6,7,10,10a,10b-deca-hydro-endo-epidioxy-cyclo-hepta-[e]indene-3a(1H)-carboxylic acid], C(20)H(30)O(4), is a polymorphic form of a previously reported structure [Loyola et al. (1990 ▶). Tetra-hedron, 46, 5413-5420]. The newly found ortho-rhom-bic polymorph crystallizes in P2(1)2(1)2(1) with two mol-ecules in the asymmetric unit. The mol-ecules are linked into discrete D(2) chains by simple O-H⋯O inter-actions. There are only slight variations in the mol-ecular geometry and supra-molecular organization in the crystal structures of the two polymorphs. The densities are 1.145 (monoclinic, P2(1)) and 1.155 Mg m(-3) (ortho-rhom-bic, P2(1)2(1)2(1)).

  15. Polymorphisms within inflammatory genes and colorectal cancer

    PubMed Central

    Landi, Stefano; Gemignani, Federica; Bottari, Fabio; Gioia-Patricola, Lydie; Guino, Elisabet; Cambray, María; Biondo, Sebastiano; Capella, Gabriel; Boldrini, Laura; Canzian, Federico; Moreno, Victor

    2006-01-01

    Background Chronic inflammation is a risk factor for colorectal cancer and polymorphisms in the inflammatory genes could modulate the levels of inflammation. We have investigated ten single nucleotide polymorphisms (SNPs) in the following inflammation-related genes: TLR4 (Asp299Gly), CD14 (-260 T>C), MCP1 (-2518 A>G), IL12A (+7506 A>T, +8707 A>G, +9177 T>A, +9508 G>A), NOS2A (+524T>C), TNF (-857C>T), and PTGS1 (V444I) in 377 colorectal (CRC) cancer cases and 326 controls from Barcelona (Spain). Results There was no statistically significant association between the SNPs investigated and colorectal cancer risk. Conclusion The lack of association may show that the inflammatory genes selected for this study are not involved in the carcinogenic process of colorectum. Alternatively, the negative results may derive from no particular biological effect of the analysed polymorphisms in relation to CRC. Otherwise, the eventual biological effect is so little to go undetected, unless analysing a much larger sample size. PMID:17062130

  16. Introgressive hybridization in a trophically polymorphic cichlid.

    PubMed

    Hulsey, C Darrin; García-de-León, Francisco J

    2013-11-01

    Trophically polymorphic species could represent lineages that are rapidly diverging along an ecological axis or could phenotypically mark the collapse of species through introgressive hybridization. We investigated patterns of introgression between the trophically polymorphic cichlid fish Herichthys minckleyi and its relative H. cyanoguttatus using a combination of population genetics and species tree analyses. We first examined the distribution of mitochondrial haplotypes within the alternative H. minckleyi pharyngeal jaw morphotypes that are endemic to the small desert valley of Cuatro Ciénegas. We recovered two clusters of mitochondrial haplotypes. The first contained a number of slightly differentiated cytochrome b (cytb) haplotypes that showed some phylogeographic signal and were present in both jaw morphotypes. The other haplotype was monomorphic, highly differentiated from the other cluster, present in equal frequencies in the morphotypes, and identical to H. cyanoguttatus haplotypes found outside Cuatro Ciénegas. Then, we investigated whether H. minckleyi individuals with the H. cyanoguttatus cytb were more evolutionarily similar to H. cyanoguttatus or other H. minckleyi using a species tree analysis of 84 nuclear loci. Both H. minckleyi pharyngeal morphotypes, regardless of their cytb haplotype, were quite distinct from H. cyanoguttatus. However, hybridization could be blurring subdivision within H. minckleyi as the alternative jaw morphotypes were not genetically distinct from one another. Accounting for introgression from H. cyanoguttatus will be essential to understand the evolution of the trophically polymorphic cichlid H. minckleyi.

  17. Introgressive hybridization in a trophically polymorphic cichlid

    PubMed Central

    Hulsey, C Darrin; García-de-León, Francisco J

    2013-01-01

    Trophically polymorphic species could represent lineages that are rapidly diverging along an ecological axis or could phenotypically mark the collapse of species through introgressive hybridization. We investigated patterns of introgression between the trophically polymorphic cichlid fish Herichthys minckleyi and its relative H. cyanoguttatus using a combination of population genetics and species tree analyses. We first examined the distribution of mitochondrial haplotypes within the alternative H. minckleyi pharyngeal jaw morphotypes that are endemic to the small desert valley of Cuatro Ciénegas. We recovered two clusters of mitochondrial haplotypes. The first contained a number of slightly differentiated cytochrome b (cytb) haplotypes that showed some phylogeographic signal and were present in both jaw morphotypes. The other haplotype was monomorphic, highly differentiated from the other cluster, present in equal frequencies in the morphotypes, and identical to H. cyanoguttatus haplotypes found outside Cuatro Ciénegas. Then, we investigated whether H. minckleyi individuals with the H. cyanoguttatus cytb were more evolutionarily similar to H. cyanoguttatus or other H. minckleyi using a species tree analysis of 84 nuclear loci. Both H. minckleyi pharyngeal morphotypes, regardless of their cytb haplotype, were quite distinct from H. cyanoguttatus. However, hybridization could be blurring subdivision within H. minckleyi as the alternative jaw morphotypes were not genetically distinct from one another. Accounting for introgression from H. cyanoguttatus will be essential to understand the evolution of the trophically polymorphic cichlid H. minckleyi. PMID:24340193

  18. Single nucleotide polymorphisms and suicidal behaviour.

    PubMed

    Pregelj, Peter

    2012-09-01

    The World Health Organization estimates that almost one million deaths each year are attributable to suicide, and suicide attempt is close to 10 times more common than suicide completion. Suicidal behaviour has multiple causes that are broadly divided into proximal stressors or triggers and predisposition such as genetic. It is also known that single nucleotide polymorphisms (SNPs) occur throughout a human DNA influencing the structure, quantity and the function of proteins and other molecules. Abnormalities of the serotonergic system were observed in suicide victims. Beside 5-HT1A and other serotonin receptors most studied are the serotonin transporter 5' functional promoter variant, and monoamine oxidase A and the tryptophan-hydroxylase 1 and 2 (TPH) polymorphisms. It seems that especially genes regulating serotoninergic system and neuronal systems involved in stress response are associated with suicidal behaviour. Most genetic studies on suicidal behaviour have considered a small set of functional polymorphisms relevant mostly to monoaminergic neurotransmission. However, genes involved in regulation of other factors such as brain-derived neurotropic factor seems to be even more relevant for further research.

  19. Genetic polymorphisms linked to susceptibility to malaria.

    PubMed

    Driss, Adel; Hibbert, Jacqueline M; Wilson, Nana O; Iqbal, Shareen A; Adamkiewicz, Thomas V; Stiles, Jonathan K

    2011-09-19

    The influence of host genetics on susceptibility to Plasmodium falciparum malaria has been extensively studied over the past twenty years. It is now clear that malaria parasites have imposed strong selective forces on the human genome in endemic regions. Different genes have been identified that are associated with different malaria related phenotypes. Factors that promote severity of malaria include parasitaemia, parasite induced inflammation, anaemia and sequestration of parasitized erythrocytes in brain microvasculature.Recent advances in human genome research technologies such as genome-wide association studies (GWAS) and fine genotyping tools have enabled the discovery of several genetic polymorphisms and biomarkers that warrant further study in host-parasite interactions. This review describes and discusses human gene polymorphisms identified thus far that have been shown to be associated with susceptibility or resistance to P. falciparum malaria. Although some polymorphisms play significant roles in susceptibility to malaria, several findings are inconclusive and contradictory and must be considered with caution. The discovery of genetic markers associated with different malaria phenotypes will help elucidate the pathophysiology of malaria and enable development of interventions or cures. Diversity in human populations as well as environmental effects can influence the clinical heterogeneity of malaria, thus warranting further investigations with a goal of developing new interventions, therapies and better management against malaria.

  20. Polymorphic growth rates in myrmecophilous insects.

    PubMed

    Schönrogge, K; Wardlaw, J C; Thomas, J A; Elmes, G W

    2000-04-22

    A polymorphism in growth rates was recently described affecting the larval development of the myrmecophilous butterfly Maculinea rebeli, spanning different years in a single insect population. The close integration of M. rebeli into the host ant colonies, facilitated by adaptations in behaviour and chemical mimicry, make extended larval development a successful strategy. Here we present additional data for M. rebeli and new data for Maculinea alcon (another cuckoo-feeding lycaenid) and the two myrmecophilous predators Maculinea arion and Microdon mutabilis (Diptera: Syrphidae). As predicted, M. alcon shows the same growth pattern as M. rebeli with a proportion of caterpillars developing in one year and the remainder over two years. This pattern holds in both northern and southern European populations, where M. alcon exploits different species of host. Against expectation, the same bimodal distribution of pre-pupation body weights, indicating one and two year developers, was found for the larvae of M. arion and M. mutabilis. As predators, both species are less closely integrated in their host ant colonies, suggesting that the polymorphism in growth rates is a more general adaptation to a myrmecophilous life style, arrived at by convergent evolution between the Maculinea and Microdon species. For predatory species we suggest that biennialism is an adaptation to the migratory behaviour of the host made possible by the predators' ability to fast over extended periods. We also hypothesize that M. arion represents an ancestral strategy in Maculinea butterflies and that the growth polymorphism might have become genetically fixed in the cuckoo-feeding species.

  1. Colour Polymorphism Protects Prey Individuals and Populations Against Predation

    PubMed Central

    Karpestam, Einat; Merilaita, Sami; Forsman, Anders

    2016-01-01

    Colour pattern polymorphism in animals can influence and be influenced by interactions between predators and prey. However, few studies have examined whether polymorphism is adaptive, and there is no evidence that the co-occurrence of two or more natural prey colour variants can increase survival of populations. Here we show that visual predators that exploit polymorphic prey suffer from reduced performance, and further provide rare evidence in support of the hypothesis that prey colour polymorphism may afford protection against predators for both individuals and populations. This protective effect provides a probable explanation for the longstanding, evolutionary puzzle of the existence of colour polymorphisms. We also propose that this protective effect can provide an adaptive explanation for search image formation in predators rather than search image formation explaining polymorphism. PMID:26902799

  2. Colour Polymorphism Protects Prey Individuals and Populations Against Predation.

    PubMed

    Karpestam, Einat; Merilaita, Sami; Forsman, Anders

    2016-02-23

    Colour pattern polymorphism in animals can influence and be influenced by interactions between predators and prey. However, few studies have examined whether polymorphism is adaptive, and there is no evidence that the co-occurrence of two or more natural prey colour variants can increase survival of populations. Here we show that visual predators that exploit polymorphic prey suffer from reduced performance, and further provide rare evidence in support of the hypothesis that prey colour polymorphism may afford protection against predators for both individuals and populations. This protective effect provides a probable explanation for the longstanding, evolutionary puzzle of the existence of colour polymorphisms. We also propose that this protective effect can provide an adaptive explanation for search image formation in predators rather than search image formation explaining polymorphism.

  3. Genetic Polymorphisms, Hormone Levels, and Hot Flashes in Midlife Women

    PubMed Central

    Schilling, Chrissy; Gallicchio, Lisa; Miller, Susan R.; Langenberg, Patricia; Zacur, Howard; Flaws, Jodi A.

    2007-01-01

    Objective Hot flashes disrupt the lives of millions of women each year. Although hot flashes are a public health concern, little is known about risk factors that predispose women to hot flashes. Thus, the objective of this study was to examine whether sex steroid hormone levels and genetic polymorphisms in hormone biosynthesis and degradation enzymes are associated with the risk of hot flashes. Methods In a cross-sectional study design, midlife women aged 45 to 54 years (n=639) were recruited from Baltimore and its surrounding counties. Participants completed a questionnaire and donated a blood sample for steroid hormone analysis and genotyping. The associations between genetic polymorphisms and hormone levels, as well as the associations between genetic polymorphisms, hormone levels, and hot flashes were examined using statistical models. Results A polymorphism in CYP1B1 was associated with lower dehydroepiandrosterone-sulfate (DHEA-S) and progesterone levels, while a polymorphism in CYP19 (aromatase) was associated with higher testosterone and DHEA-S levels. Lower progesterone and sex hormone binding globulin levels, lower free estradiol index, and a higher ratio of total androgens to total estrogens were associated with the experiencing of hot flashes. A polymorphism in CYP1B1 and a polymorphism in 3βHSD were both associated with hot flashes. Conclusion Some genetic polymorphisms may be associated with altered levels of hormones in midlife women. Further, selected genetic polymorphisms and altered hormone levels may be associated with the risk of hot flashes in midlife women. PMID:17187946

  4. 2-Quinolinecarboxaldehyde: Polymorphic behavior of a small rigid molecule

    NASA Astrophysics Data System (ADS)

    Maria, Teresa M. R.; Ermelinda S. Eusébio, M.; Almeida e Silva, J.; Sobral, Abílio J. F. N.; Cardoso, C.; Paixão, J. A.; Ramos Silva, M.

    2012-12-01

    This work reports an investigation on the polymorphism of 2-quinolinecarboxaldehyde, a quinoline derivative, frequently used as a ligand in the synthesis of metal complexes. 2-Quinolinecarboxaldehyde lacks both molecular flexibility and the ability to form strong hydrogen bonds, two characteristics often seen as driving forces for the occurrence of polymorphism. Nevertheless, a rich polymorphic behavior was found for this substance. Polymorphic forms were generated by crystallization from solutions, and by melt cooling. Four polymorphic forms could be clearly identified by thermal analysis investigation and the crystalline structures of forms I and III were solved by single-crystal X-ray diffraction, at room temperature. In polymorph I, molecules are joined by π-π and weak C-H⋯O interactions while in polymorph III helicoidal chiral chains are formed and very weak C-H⋯O intermolecular interactions can be identified. Neither of these intermolecular interactions involves the formyl hydrogen atom. Concomitant polymorph crystallization from the melt was often observed. XRPD diffractograms which showed similarities to that of polymorph I but presented striking differences were obtained in some experiments. In certain cases the discrepancies may be ascribed to effects of preferential orientation. However, the existence of multiple but slightly different structures with small differences seems to be a better explanation for these experimental observations.

  5. Persistence of neutral polymorphisms in Lake Victoria cichlid fish

    PubMed Central

    Nagl, Sandra; Tichy, Herbert; Mayer, Werner E.; Takahata, Naoyuki; Klein, Jan

    1998-01-01

    Phylogenetic trees for groups of closely related species often have different topologies, depending on the genes used. One explanation for the discordant topologies is the persistence of polymorphisms through the speciation phase, followed by differential fixation of alleles in the resulting species. The existence of transspecies polymorphisms has been documented for alleles maintained by balancing selection but not for neutral alleles. In the present study, transspecific persistence of neutral polymorphisms was tested in the endemic haplochromine species flock of Lake Victoria cichlid fish. Putative noncoding region polymorphisms were identified at four randomly selected nuclear loci and tested on a collection of 12 Lake Victoria species and their putative riverine ancestors. At all loci, the same polymorphism was found to be present in nearly all the tested species, both lacustrine and riverine. Different polymorphisms at these loci were found in cichlids of other East African lakes (Malawi and Tanganyika). The Lake Victoria polymorphisms must have therefore arisen after the flocks now inhabiting the three great lakes diverged from one another, but before the riverine ancestors of the Lake Victoria flock colonized the Lake. Calculations based on the mtDNA clock suggest that the polymorphisms have persisted for about 1.4 million years. To maintain neutral polymorphisms for such a long time, the population size must have remained large throughout the entire period. PMID:9826684

  6. Persistence of neutral polymorphisms in Lake Victoria cichlid fish.

    PubMed

    Nagl, S; Tichy, H; Mayer, W E; Takahata, N; Klein, J

    1998-11-24

    Phylogenetic trees for groups of closely related species often have different topologies, depending on the genes used. One explanation for the discordant topologies is the persistence of polymorphisms through the speciation phase, followed by differential fixation of alleles in the resulting species. The existence of transspecies polymorphisms has been documented for alleles maintained by balancing selection but not for neutral alleles. In the present study, transspecific persistence of neutral polymorphisms was tested in the endemic haplochromine species flock of Lake Victoria cichlid fish. Putative noncoding region polymorphisms were identified at four randomly selected nuclear loci and tested on a collection of 12 Lake Victoria species and their putative riverine ancestors. At all loci, the same polymorphism was found to be present in nearly all the tested species, both lacustrine and riverine. Different polymorphisms at these loci were found in cichlids of other East African lakes (Malawi and Tanganyika). The Lake Victoria polymorphisms must have therefore arisen after the flocks now inhabiting the three great lakes diverged from one another, but before the riverine ancestors of the Lake Victoria flock colonized the Lake. Calculations based on the mtDNA clock suggest that the polymorphisms have persisted for about 1.4 million years. To maintain neutral polymorphisms for such a long time, the population size must have remained large throughout the entire period.

  7. Single-nucleotide polymorphism discovery by targeted DNA photocleavage.

    PubMed

    Hart, Jonathan R; Johnson, Martin D; Barton, Jacqueline K

    2004-09-28

    Single-nucleotide polymorphisms are the largest source of genetic variation in humans. We report a method for the discovery of single-nucleotide polymorphisms within genomic DNA. Pooled genomic samples are amplified, denatured, and annealed to generate mismatches at polymorphic DNA sites. Upon photoactivation, these DNA mismatches are then cleaved site-specifically by using a small molecular probe, a bulky metallointercalator, Rhchrysi or Rhphzi. Fluorescent labeling of the cleaved products and separation by capillary electrophoresis permits rapid identification with single-base resolution of the single-nucleotide polymorphism site. This method is remarkably sensitive and minor allele frequencies as low as 5% can be readily detected.

  8. Apparent scarcity of low-density polymorphs of inorganic solids.

    PubMed

    Zwijnenburg, Martijn A; Illas, Francesc; Bromley, Stefan T

    2010-04-30

    For most inorganic solids, very few dense polymorphs and no low-density polymorphs are observed. Taking a wide range of tetrahedrally-coordinated binary solids (e.g., ZnO, GaN) as a prototypical system, we show that the apparent scarcity of low- density polymorphs is not due to significant structural or energetic limitations. Using databases of periodic networks as sources of novel crystal structures, followed by ab initio energy minimization, we predict a dense spectrum of low-density low-energy polymorphs. The diverse range of materials considered indicates that this is likely to be a general phenomenon.

  9. Novel Processing of Ceramics with Polymorphic Control

    NASA Astrophysics Data System (ADS)

    Jodhani, Gagan

    Polymorphism is an important phenomenon exhibited by many materials, including ceramic oxides. The availability of multiple structural configurations for the same chemical composition opens the pathway to a large number of phases with distinct properties. The formation of the crystal structures can be directly correlated to the processing temperature and/or pressure as well as the particle size for nanomaterials. This work focuses on the tailored synthesis of the desired polymorphs of binary and ternary metal oxides through nanoscale processes with emphasis on flame spray pyrolysis. Flame spray pyrolysis (FSP) is a scalable nano-manufacturing process used for the synthesis of oxide based ceramics. The advantage of this process lies in ease of operation and inexpensive processing as well as the uniformity in the particle size distribution of the products. It is a rapid solidification process involving the atomization of precursor using high temperature gradients and low residence times in the flame. Thus, metastable polymorphs have successfully been synthesized by FSP. Although a wide variety of studies have been conducted on the synthesis and applications of ceramics via FSP there has been scarce knowledge on the actual dynamics of crystal structure formation during the process. Various solution parameters were studied to understand the particle and crystal structure formation for the FSP powders. The process parameters were kept the same; 1.5 slm methane and 3.0 slm O2 was used as fuel for the flame, 5slm oxygen was used as dispersion gas and the precursor was fed at 5ml/min. MoO3 was synthesized using different concentrations of precursor and the particle sizes obtained were correlated to the materials parameters such as solution concentration and amount of organic precursor solvent. Another study was conducted on formation of WO3 polymorphs using organic precursor salts dissolved in organic solvent. The solution was prepared to obtain low particle sizes and to

  10. Polymorphism in phenobarbital: discovery of a new polymorph and crystal structure of elusive form V.

    PubMed

    Roy, Saikat; Goud, N Rajesh; Matzger, Adam J

    2016-03-21

    This report highlights the discovery of a new polymorph of the anticonvulsant drug phenobarbital (PB) using polymer-induced heteronucleation (PIHn) and unravelling the crystal structure of the elusive form V. Both forms are characterized by structural, thermal and VT-Raman spectroscopy methods to elucidate phase transformation behavior and shed light on stability relationships.

  11. Polymorphism in silicate-postperovskite reviewed (Invited)

    NASA Astrophysics Data System (ADS)

    Tschauner, O. D.

    2010-12-01

    Early on in the examination of postperovskite(ppv)-type magnesium metasilicate it had been debated if this potential deep mantle mineral can be subject to further structural transformation as function of composition, pressure, and temperature within the range of conditions in the lower mantle. MgSiO3-perovskite accommodates minor elements through local lattice distortions by tilt of the corner-sharing octahedral framework. The CaIrO3-type ppv structure does not seem to possess a similar mechanism of local relaxation of lattice strain. Instead minor elements may rather be accommodated by periodic kinks in this layered structure (1). This kinking-mechanism allows for generating a plethora of polymorphs similar in structure and free energy (1,2). However, the elastic properties of ppv may be strongly affected by this type of structural modification. While structural analogues of silicate-ppv exhibit this type of polymorphism (3,4) previous attempts to examine polymorphism in silicate-ppv remained suggestive (2,5). This is mostly owed to the severe constraints imposed on powder diffraction studies conducted under the extreme conditions of stability of MgSiO3-ppv. Here I present new results on silicate-ppv based on different experimental strategies which shed more light on this complex yet important issue of structural modifications in minor-element bearing silicate-ppv. (1) Oganov et al. Nature 438, 1142 (2005);(2) Tschauner et al. Am. Min. 93, 533 (2008); (3) Shirako et al. Phys. Chem. Min. 36, 455 (2009); Yakovlev et al. J. Sol. Stat. Chem. 182, 1545 (2009) Work supported through NNSA Cooperative Agreement DOE-FC88-01NV14049

  12. MICA polymorphism: biology and importance in cancer.

    PubMed

    Chen, Dan; Gyllensten, Ulf

    2014-12-01

    The major histocompatibility complex class I polypeptide-related sequence A gene (MICA) encodes a membrane-bound protein acting as a ligand to stimulate an activating receptor, NKG2D, expressed on the surface of essentially all human natural killer (NK), γδ T and CD8(+) αβ T cells. MICA protein is absent from most cells but can be induced by infections and oncogenic transformation and is frequently expressed in epithelial tumors. Upon binding to MICA, NKG2D activates cytolytic responses of NK and γδ T cells against infected and tumor cells expressing MICA. Therefore, membrane-bound MICA acts as a signal during the early immune response against infection or spontaneously arising tumors. On the other hand, human tumor cells spontaneously release a soluble form of MICA, causing the downregulation of NKG2D and in turn severe impairment of the antitumor immune response of NK and CD8(+) T cells. This is considered to promote tumor immune evasion and also to compromise host resistance to infections. MICA is the most polymorphic non-classical class I gene. A possible association of MICA polymorphism with genetic predisposition to different cancer types has been investigated in candidate gene-based studies. Two genome-wide association studies have identified loci in MICA that influence susceptibility to cervical neoplasia and hepatitis C virus-induced hepatocellular carcinoma, respectively. Given the current level of interest in the field of MICA gene, we discuss the genetics and biology of the MICA gene and the role of its polymorphism in cancer. Gaps in our understanding and future research needs are also discussed. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  13. Adrenergic Polymorphism and the Human Stress Response

    PubMed Central

    Rao, Fangwen; Zhang, Lian; Wessel, Jennifer; Zhang, Kuixing; Wen, Gen; Kennedy, Brian P.; Rana, Brinda K.; Das, Madhusudan; Rodriguez-Flores, Juan L.; Smith, Douglas W.; Cadman, Peter E.; Salem, Rany M.; Mahata, Sushil K.; Schork, Nicholas J.; Taupenot, Laurent; Ziegler, Michael G.; O’Connor, Daniel T.

    2009-01-01

    Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis. Does common genetic variation at human TH alter autonomic activity and predispose to cardiovascular disease? We undertook systematic polymorphism discovery at the TH locus, and then tested variants for contributions to sympathetic function and blood pressure. We resequenced 80 ethnically diverse individuals across the TH locus. One hundred seventy-two twin pairs were evaluated for sympathetic traits, including catecholamine production and environmental (cold) stress responses. To evaluate hypertension, we genotyped subjects selected from the most extreme diastolic blood pressure percentiles in the population. Human TH promoter haplotype/reporter plasmids were transfected into chromaffin cells. Forty-nine single nucleotide polymorphisms (SNPs) and one tetranucleotide repeat were discovered, but coding region polymorphism did not account for common phenotypic variation. A block of linkage disequilibrium spanned four common variants in the proximal promoter. Catecholamine secretory traits were significantly heritable, as were stress-induced blood pressure changes. In the TH promoter, significant associations were found for urinary catecholamine excretion, as well as blood pressure response to stress. TH promoter haplotype #2 (TGGG) showed pleiotropy, increasing both norepinephrine excretion and blood pressure during stress. In hypertension, a case–control study (1266 subjects, 53% women) established the effect of C-824T in determination of blood pressure. We conclude that human catecholamine secretory traits are heritable, displaying joint genetic determination (pleiotropy) with autonomic activity and finally with blood pressure in the population. Catecholamine secretion is influenced by genetic variation in the adrenergic pathway encoding catecholamine synthesis, especially at the classically rate-limiting step, TH. The results suggest novel pathophysiological links between a key

  14. Placental glucose dehydrogenase polymorphism in Koreans.

    PubMed

    Kim, Y J; Paik, S G; Park, H Y

    1994-12-01

    The genetic polymorphism of placental glucose dehydrogenase (GDH) was investigated in 300 Korean placentae using horizontal starch gel electrophoresis. The allele frequencies for GDH1, GDH2 and GDH3 were 0.537, 0.440 and 0.005, respectively, which were similar to those in Japanese. We also observed an anodal allele which was similar to the GDH4 originally reported in Chinese populations at a low frequency of 0.015. An additional new cathodal allele (named GDH6) was observed in the present study with a very low frequency of 0.003.

  15. [HLA-B27 polymorphism and spondyloarthropathies].

    PubMed

    Peixoto, M J; Gonzales, T; Spinola, H; Couto, A R; Mora, M Gantes; Brehm, A; Santos, M R; Garrett, F; Armas, J Bruges

    2005-01-01

    The association of HLA-B27 with ankylosing spondylitis (AS), and other spondyloarthropathies (SpA), remains as one of the strongest between HLA molecules and human disease. Since it was reported, in 1973, it has been extensively studied in order to understand the underlying pathogenic mechanism. The objective of this article is to review the current knowledge on the structure and polymorphism of HLA-B27 molecule, as well as describe the main pathogenic hypotheses trying to explain its association with AS.

  16. Cardiac and skeletal muscle myosin polymorphism.

    PubMed

    Lowey, S

    1986-06-01

    Skeletal muscles, unlike cardiac tissue, express several myosin isozymes during development which differ in primary structure from adult myosin. Monoclonal antibodies have shown the presence of at least two embryonic myosins, followed by a post-hatch myosin that persists until the appearance of adult myosin in chicken pectoralis muscle. Although the two major cardiac isozymes differ in enzymatic activity, the avian skeletal myosin isozymes all share the same high level of ATPase activity found for adult pectoralis myosin. The functional basis for the extensive myosin polymorphism in skeletal muscles thus remains to be determined.

  17. [Polymorphous photodermatosis--photobiologic diagnosis and therapy].

    PubMed

    Hönigsmann, H; Ortel, B

    1988-08-15

    Polymorphous light eruption is an acquired photodermatosis, whose causal factors have not yet been identified. The diagnosis is based on the clinical picture and on histology. During the symptomless periods, photo-testing is the most important technique to confirm the diagnosis, since there are no specific laboratory parameters. Regarding our own patients, typical lesions could be provoked by UVA in 50%, by UVB in 20% and by both in 30%. The majority of the patients can be protected during the summer season by intermittent preventive photo(chemo)therapy.

  18. What Determines the Ice Polymorph in Clouds?

    PubMed

    Hudait, Arpa; Molinero, Valeria

    2016-07-20

    Ice crystals in the atmosphere nucleate from supercooled liquid water and grow by vapor uptake. The structure of the ice polymorph grown has strong impact on the morphology and light scattering of the ice crystals, modulates the amount of water vapor in ice clouds, and can impact the molecular uptake and reactivity of atmospheric aerosols. Experiments and molecular simulations indicate that ice nucleated and grown from deeply supercooled liquid water is metastable stacking disordered ice. The ice polymorph grown from vapor has not yet been determined. Here we use large-scale molecular simulations to determine the structure of ice that grows as a result of uptake of water vapor in the temperature range relevant to cirrus and mixed-phase clouds, elucidate the molecular mechanism of the formation of ice at the vapor interface, and compute the free energy difference between cubic and hexagonal ice interfaces with vapor. We find that vapor deposition results in growth of stacking disordered ice only under conditions of extreme supersaturation, for which a nonequilibrium liquid layer completely wets the surface of ice. Such extreme conditions have been used to produce stacking disordered frost ice in experiments and may be plausible in the summer polar mesosphere. Growth of ice from vapor at moderate supersaturations in the temperature range relevant to cirrus and mixed-phase clouds, from 200 to 260 K, produces exclusively the stable hexagonal ice polymorph. Cubic ice is disfavored with respect to hexagonal ice not only by a small penalty in the bulk free energy (3.6 ± 1.5 J mol(-1) at 260 K) but also by a large free energy penalty at the ice-vapor interface (89.7 ± 12.8 J mol(-1) at 260 K). The latter originates in higher vibrational entropy of the hexagonal-terminated ice-vapor interface. We predict that the free energy penalty against the cubic ice interface should decrease strongly with temperature, resulting in some degree of stacking disorder in ice grown from

  19. Genetic salivary protein polymorphism in Mexican population.

    PubMed

    Banderas Tarabay, J A; González Begné, M

    1996-01-01

    Genetic polymorphism is the major contributor that affects human salivary composition. In order to determine the molecular phenotypes in saliva, it is important to know the distribution of proteins with specific functions which allows the clinical diagnosis of specific diseases. Unstimulated human whole saliva samples from 120 subjects were subjected to sodium dodecyl sulfate polyacrylamide slab gel electrophoresis (SDS-PAGE). The phenotype distribution of several molecules including MG1, MG2, alpha-Amylase, PRP-I and cystatins were similar. Qualitative and quantitative characteristics were specific in each subject.

  20. A Simplified Account of Polymorphic References. Revised

    DTIC Science & Technology

    1993-06-01

    CloseA(rl) generalizes t, whereas (’loseA,(r, ) does not. (This observation is due to Foite . who also goes on to provide a counterexample to the theorem [I...thettir ’tomintt’lts and’ Suiggest ions. References [11 Andrew W. Appel attd David B. MacQueen. Standard ML of New Je’rsey. In .1. Malitszvttski antI M...Type inference for polymorphic references. Information and Computation. 89:1--3.1. Noveni- ber 1990. [121 Andrew Wright. Typing references by effect

  1. RADB: a database of rheumatoid arthritis-related polymorphisms

    PubMed Central

    Zhang, Ruijie; Luan, Meiwei; Shang, Zhenwei; Duan, Lian; Tang, Guoping; Shi, Miao; Lv, Wenhua; Zhu, Hongjie; Li, Jin; Lv, Hongchao; Zhang, Mingming; Liu, Guiyou; Chen, He; Jiang, Yongshuai

    2014-01-01

    Rheumatoid arthritis (RA) is an autoimmune disease that has a complex genetic basis. Therefore, it is important to explore the genetic background of RA. The extensive recent application of polymorphic genetic markers, especially single nucleotide polymorphisms, has presented us with a large quantity of genetic data. In this study, we developed the Database of Rheumatoid Arthritis-related Polymorphisms (RADB), to integrate all the RA-related genetic polymorphisms and provide a useful resource for researchers. We manually extracted the RA-related polymorphisms from 686 published reports, including RA susceptibility loci, polymorphisms associated with particular clinical features of RA, polymorphisms associated with drug response in RA and polymorphisms associated with a higher risk of cardiovascular disease in RA. Currently, RADB V1.0 contains 3235 polymorphisms that are associated with 636 genes and refer to 68 countries. The detailed information extracted from the literature includes basic information about the articles (e.g. PubMed ID, title and abstract), population information (e.g. country, geographic area and sample size) and polymorphism information (e.g. polymorphism name, gene, genotype, odds ratio and 95% confidence interval, P-value and risk allele). Meanwhile, useful annotations, such as hyperlinks to dbSNP, GenBank, UCSC, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway, are included. In addition, a tool for meta-analysis was developed to summarize the results of multiple studies. The database is freely available at http://www.bioapp.org/RADB. Database URL: http://www.bioapp.org/RADB. PMID:25228593

  2. Association between Tryptophan Hydroxylase 2 Gene Polymorphism and Completed Suicide

    ERIC Educational Resources Information Center

    Fudalej, Sylwia; Ilgen, Mark; Fudalej, Marcin; Kostrzewa, Grazyna; Barry, Kristen; Wojnar, Marcin; Krajewski, Pawel; Blow, Frederic; Ploski, Rafal

    2010-01-01

    The association between suicide and a single nucleotide polymorphism (rs1386483) was examined in the recently identified tryptophan hydroxylase 2 (TPH2) gene. Blood samples of 143 suicide victims and 162 age- and sex-matched controls were examined. The frequency of the TT genotype in the TPH2 polymorphism was higher in suicide victims than in…

  3. Effects of human SAMHD1 polymorphisms on HIV-1 susceptibility

    SciTech Connect

    White, Tommy E.; Brandariz-Nuñez, Alberto; Valle-Casuso, Jose Carlos; Knowlton, Caitlin; Kim, Baek; Sawyer, Sara L.; Diaz-Griffero, Felipe

    2014-07-15

    SAMHD1 is a human restriction factor that prevents efficient infection of macrophages, dendritic cells and resting CD4+ T cells by HIV-1. Here we explored the antiviral activity and biochemical properties of human SAMHD1 polymorphisms. Our studies focused on human SAMHD1 polymorphisms that were previously identified as evolving under positive selection for rapid amino acid replacement during primate speciation. The different human SAMHD1 polymorphisms were tested for their ability to block HIV-1, HIV-2 and equine infectious anemia virus (EIAV). All studied SAMHD1 variants block HIV-1, HIV-2 and EIAV infection when compared to wild type. We found that these variants did not lose their ability to oligomerize or to bind RNA. Furthermore, all tested variants were susceptible to degradation by Vpx, and localized to the nuclear compartment. We tested the ability of human SAMHD1 polymorphisms to decrease the dNTP cellular levels. In agreement, none of the different SAMHD1 variants lost their ability to reduce cellular levels of dNTPs. Finally, we found that none of the tested human SAMHD1 polymorphisms affected the ability of the protein to block LINE-1 retrotransposition. - Highlights: • Human SAMHD1 single-nucleotide polymorphisms block HIV-1 and HIV-2 infection. • SAMHD1 polymorphisms do not affect its ability to block LINE-1 retrotransposition. • SAMHD1 polymorphisms decrease the cellular levels of dNTPs.

  4. Microhabitat variation and sexual selection can maintain male color polymorphisms.

    PubMed

    Chunco, Amanda J; McKinnon, Jeffrey S; Servedio, Maria R

    2007-11-01

    Male color polymorphism may be an important precursor to sympatric speciation by sexual selection, but the processes maintaining such polymorphisms are not well understood. Here, we develop a formal model of the hypothesis that male color polymorphisms may be maintained by variation in the sensory environment resulting in microhabitat-specific selection pressures. We analyze the evolution of two male color morphs when color perception (by females and predators) is dependent on the microhabitat in which natural and sexual selection occur. We find that an environment of heterogeneous microhabitats can lead to the maintenance of color polymorphism despite asymmetries in the strengths of natural and sexual selection and in microhabitat proportions. We show that sexual selection alone is sufficient for polymorphism maintenance over a wide range of parameter space, even when female preferences are weak. Polymorphisms can also be maintained by natural selection acting alone, but the conditions for polymorphism maintenance by natural selection will usually be unrealistic for the case of microhabitat variation. Microhabitat variation and sexual selection for conspicuous males may thus provide a situation particularly favorable to the maintenance of male color polymorphisms. These results are important both because of the general insight they provide into a little appreciated mechanism for the maintenance of variation in natural populations and because such variation is an important prerequisite for sympatric speciation.

  5. Polymorphisms in Autophagy Genes and Susceptibility to Tuberculosis

    PubMed Central

    Alisjahbana, Bachti; Sahiratmadja, Edhyana; Parwati, Ida; Oosting, Marije; Plantinga, Theo S.; Joosten, Leo A. B.; Netea, Mihai G.; Ottenhoff, Tom H. M.; van de Vosse, Esther; van Crevel, Reinout

    2012-01-01

    Recent data suggest that autophagy is important for intracellular killing of Mycobacterium tuberculosis, and polymorphisms in the autophagy gene IRGM have been linked with susceptibility to tuberculosis (TB) among African-Americans, and with TB caused by particular M. tuberculosis genotypes in Ghana. We compared 22 polymorphisms of 14 autophagy genes between 1022 Indonesian TB patients and 952 matched controls, and between patients infected with different M. tuberculosis genotypes, as determined by spoligotyping. The same autophagy polymorphisms were studied in correlation with ex-vivo production of TNF, IL-1β, IL-6, IL-8, IFN-γ and IL-17 in healthy volunteers. No association was found between TB and polymorphisms in the genes ATG10, ATG16L2, ATG2B, ATG5, ATG9B, IRGM, LAMP1, LAMP3, P2RX7, WIPI1, MTOR and ATG4C. Associations were found between polymorphisms in LAMP1 (p = 0.02) and MTOR (p = 0.02) and infection with the successful M. tuberculosis Beijing genotype. The polymorphisms examined were not associated with M. tuberculosis induced cytokines, except for a polymorphism in ATG10, which was linked with IL-8 production (p = 0.04). All associations found lost statistical significance after correction for multiple testing. This first examination of a broad set of polymorphisms in autophagy genes fails to show a clear association with TB, with M. tuberculosis Beijing genotype infection or with ex-vivo pro-inflammatory cytokine production. PMID:22879892

  6. Association between Tryptophan Hydroxylase 2 Gene Polymorphism and Completed Suicide

    ERIC Educational Resources Information Center

    Fudalej, Sylwia; Ilgen, Mark; Fudalej, Marcin; Kostrzewa, Grazyna; Barry, Kristen; Wojnar, Marcin; Krajewski, Pawel; Blow, Frederic; Ploski, Rafal

    2010-01-01

    The association between suicide and a single nucleotide polymorphism (rs1386483) was examined in the recently identified tryptophan hydroxylase 2 (TPH2) gene. Blood samples of 143 suicide victims and 162 age- and sex-matched controls were examined. The frequency of the TT genotype in the TPH2 polymorphism was higher in suicide victims than in…

  7. Microsatellite markers and polymorphism in cheatgrass (Bromus tectorum L.)

    Treesearch

    Alisa P. Ramakrishnan; Craig E. Coleman; Susan E. Meyer; Daniel J. Fairbanks

    2001-01-01

    Cheatgrass (Bromus tectorum) individuals were genetically characterized using polymorphic microsatellite markers. Through analysis of alleles of five polymorphic loci, genotypes were constructed of individuals from four populations in Utah and Nevada. There were 15 different genotypes: Whiterocks, UT, had nine genotypes, Hobble Creek, UT, had seven genotypes,...

  8. Impact of host genetic polymorphisms on vaccine induced antibody response

    PubMed Central

    Linnik, Janina E.; Egli, Adrian

    2016-01-01

    ABSTRACT Many host- and vaccine-specific factors modulate an antibody response. Host genetic polymorphisms, in particular, modulate the immune response in multiple ways on different scales. This review article describes how information on host genetic polymorphisms and corresponding immune cascades may be used to generate personalized vaccine strategies to optimize the antibody response. PMID:26809773

  9. Human lymphocyte polymorphisms detected by quantitative two-dimensional electrophoresis

    SciTech Connect

    Goldman, D.; Merril, C.R.

    1983-09-01

    A survey of 186 soluble lymphocyte proteins for genetic polymorphism was carried out utilizing two-dimensional electrophoresis of /sup 14/C-labeled phytohemagglutinin (PHA)-stimulated human lymphocyte proteins. Nineteen of these proteins exhibited positional variation consistent with independent genetic polymorphism in a primary sample of 28 individuals. Each of these polymorphisms was characterized by quantitative gene-dosage dependence insofar as the heterozygous phenotype expressed approximately 50% of each allelic gene product as was seen in homozygotes. Patterns observed were also identical in monozygotic twins, replicate samples, and replicate gels. The three expected phenotypes (two homozygotes and a heterozygote) were observed in each of 10 of these polymorphisms while the remaining nine had one of the homozygous classes absent. The presence of the three phenotypes, the demonstration of gene-dosage dependence, and our own and previous pedigree analysis of certain of these polymorphisms supports the genetic basis of these variants. Based on this data, the frequency of polymorphic loci for man is: P . 19/186 . .102, and the average heterozygosity is .024. This estimate is approximately 1/3 to 1/2 the rate of polymorphism previously estimated for man in other studies using one-dimensional electrophoresis of isozyme loci. The newly described polymorphisms and others which should be detectable in larger protein surveys with two-dimensional electrophoresis hold promise as genetic markers of the human genome for use in gene mapping and pedigree analyses.

  10. Effects of functional polymorphisms on beef carcass merit

    USDA-ARS?s Scientific Manuscript database

    To develop a resource to identify polymorphisms present in common beef cattle breeds, and relate those polymorphisms to phenotypic differences, low-coverage genomic sequence was obtained on 186 purebred bulls from 15 predominant breeds in the United States, and 84 crossbred sons of these bulls. The...

  11. Bitter taste receptor polymorphisms and human aging.

    PubMed

    Campa, Daniele; De Rango, Francesco; Carrai, Maura; Crocco, Paolina; Montesanto, Alberto; Canzian, Federico; Rose, Giuseppina; Rizzato, Cosmeri; Passarino, Giuseppe; Barale, Roberto

    2012-01-01

    Several studies have shown that genetic factors account for 25% of the variation in human life span. On the basis of published molecular, genetic and epidemiological data, we hypothesized that genetic polymorphisms of taste receptors, which modulate food preferences but are also expressed in a number of organs and regulate food absorption processing and metabolism, could modulate the aging process. Using a tagging approach, we investigated the possible associations between longevity and the common genetic variation at the three bitter taste receptor gene clusters on chromosomes 5, 7 and 12 in a population of 941 individuals ranging in age from 20 to 106 years from the South of Italy. We found that one polymorphism, rs978739, situated 212 bp upstream of the TAS2R16 gene, shows a statistically significant association (p = 0.001) with longevity. In particular, the frequency of A/A homozygotes increases gradually from 35% in subjects aged 20 to 70 up to 55% in centenarians. These data provide suggestive evidence on the possible correlation between human longevity and taste genetics.

  12. IPD—the Immuno Polymorphism Database

    PubMed Central

    Robinson, James; Halliwell, Jason A.; McWilliam, Hamish; Lopez, Rodrigo; Marsh, Steven G. E.

    2013-01-01

    The Immuno Polymorphism Database (IPD), http://www.ebi.ac.uk/ipd/ is a set of specialist databases related to the study of polymorphic genes in the immune system. The IPD project works with specialist groups or nomenclature committees who provide and curate individual sections before they are submitted to IPD for online publication. The IPD project stores all the data in a set of related databases. IPD currently consists of four databases: IPD-KIR, contains the allelic sequences of killer-cell immunoglobulin-like receptors, IPD-MHC, a database of sequences of the major histocompatibility complex of different species; IPD-HPA, alloantigens expressed only on platelets; and IPD-ESTDAB, which provides access to the European Searchable Tumour Cell-Line Database, a cell bank of immunologically characterized melanoma cell lines. The data is currently available online from the website and FTP directory. This article describes the latest updates and additional tools added to the IPD project. PMID:23180793

  13. Plumage polymorphism and fitness in Swainson's hawks.

    PubMed

    Briggs, C W; Collopy, M W; Woodbridge, B

    2011-10-01

    We examine the maintenance of a plumage polymorphism, variation in plumages among the same age and sex class within a population, in a population of Swainson's Hawks. We take advantage of 32 years of data to examine two prevalent hypotheses used to explain the persistence of morphs: apostatic selection and heterozygous advantage. We investigate differences in fitness among three morph classes of a melanistic trait in Swainson's Hawks: light (7% of the local breeding population), intermediate (57%) and dark (36%). Specifically, we examined morph differences in adult apparent survival, breeding success, annual number of fledglings produced, probability of offspring recruitment into the breeding population and lifetime reproductive success (LRS). If apostatic selection were a factor in maintaining morphs, we would expect that individuals with the least frequent morph would perform best in one or more of these fitness categories. Alternatively, if heterozygous advantage played a role in the maintenance of this polymorphism, we would expect heterozygotes (i.e. intermediate morphs) to have one or more increased rates in these categories. We found no difference in adult apparent survival between morph classes. Similarly, there were no differences in breeding success, nest productivity, LRS or probability of recruitment of offspring between parental morph. We conclude that neither apostatic selection nor heterozygous advantage appear to play a role in maintaining morphs in this population. © 2011 The Authors. Journal of Evolutionary Biology © 2011 European Society For Evolutionary Biology.

  14. Dynamically Alterable Arrays of Polymorphic Data Types

    NASA Technical Reports Server (NTRS)

    James, Mark

    2006-01-01

    An application library package was developed that represents data packets for Deep Space Network (DSN) message packets as dynamically alterable arrays composed of arbitrary polymorphic data types. The software was to address a limitation of the present state of the practice for having an array directly composed of a single monomorphic data type. This is a severe limitation when one is dealing with science data in that the types of objects one is dealing with are typically not known in advance and, therefore, are dynamic in nature. The unique feature of this approach is that it enables one to define at run-time the dynamic shape of the matrix with the ability to store polymorphic data types in each of its indices. Existing languages such as C and C++ have the restriction that the shape of the array must be known in advance and each of its elements be a monomorphic data type that is strictly defined at compile-time. This program can be executed on a variety of platforms. It can be distributed in either source code or binary code form. It must be run in conjunction with any one of a number of Lisp compilers that are available commercially or as shareware.

  15. Polymorphic phase transition mechanism of compressed coesite.

    PubMed

    Hu, Q Y; Shu, J-F; Cadien, A; Meng, Y; Yang, W G; Sheng, H W; Mao, H-K

    2015-03-20

    Silicon dioxide is one of the most abundant natural compounds. Polymorphs of SiO₂ and their phase transitions have long been a focus of great interest and intense theoretical and experimental pursuits. Here, compressing single-crystal coesite SiO₂ under hydrostatic pressures of 26-53 GPa at room temperature, we discover a new polymorphic phase transition mechanism of coesite to post-stishovite, by means of single-crystal synchrotron X-ray diffraction experiment and first-principles computational modelling. The transition features the formation of multiple previously unknown triclinic phases of SiO₂ on the transition pathway as structural intermediates. Coexistence of the low-symmetry phases results in extensive splitting of the original coesite X-ray diffraction peaks that appear as dramatic peak broadening and weakening, resembling an amorphous material. This work sheds light on the long-debated pressure-induced amorphization phenomenon of SiO₂, but also provides new insights into the densification mechanism of tetrahedrally bonded structures common in nature.

  16. Polymorphic phase transition mechanism of compressed coesite

    NASA Astrophysics Data System (ADS)

    Hu, Q. Y.; Shu, J.-F.; Cadien, A.; Meng, Y.; Yang, W. G.; Sheng, H. W.; Mao, H.-K.

    2015-03-01

    Silicon dioxide is one of the most abundant natural compounds. Polymorphs of SiO2 and their phase transitions have long been a focus of great interest and intense theoretical and experimental pursuits. Here, compressing single-crystal coesite SiO2 under hydrostatic pressures of 26-53 GPa at room temperature, we discover a new polymorphic phase transition mechanism of coesite to post-stishovite, by means of single-crystal synchrotron X-ray diffraction experiment and first-principles computational modelling. The transition features the formation of multiple previously unknown triclinic phases of SiO2 on the transition pathway as structural intermediates. Coexistence of the low-symmetry phases results in extensive splitting of the original coesite X-ray diffraction peaks that appear as dramatic peak broadening and weakening, resembling an amorphous material. This work sheds light on the long-debated pressure-induced amorphization phenomenon of SiO2, but also provides new insights into the densification mechanism of tetrahedrally bonded structures common in nature.

  17. TNFA promoter polymorphism and susceptibility to brucellosis.

    PubMed

    Caballero, A; Bravo, M J; Nieto, A; Colmenero, J D; Alonso, A; Martín, J

    2000-09-01

    The aim of this study was to investigate the possible influence of the tumor necrosis factor alpha (TNFA) gene promoter polymorphisms and HLA class II genes on the susceptibility to or development of human brucellosis. TNFA genotypes (at positions -308 and -238) were determined in 59 patients with brucellosis and 160 healthy controls by polymerase chain reaction-restriction fragment length polymorphism. There were no significant differences between the patients and the controls for the TNFA-238 genotypes. However, when the overall TNFA-308 genotype distribution of the brucella patients was compared with that of the control subjects, a significant skewing was observed (P = 0.02). The TNFA-308.1/2 genotype was present at significantly higher frequency in the total patient as a whole compared with control subjects (30% versus 15%; P = 0.01, odds ratio (OR) 2.49, 95% confidence interval (CI) 1.16-5.33). No statistically significant differences in the distribution of HLA-DRB1 or DQB1 alleles were observed between brucella patients and control subjects. Stratification to correct for interdependence of TNFA-308.2 and HLA-DR3 alleles confirmed that, in spite of their strong linkage disequilibrium, the association of TNFA-308.2 with brucellosis was independent of HLA-DR3.

  18. IPD--the Immuno Polymorphism Database.

    PubMed

    Robinson, James; Waller, Matthew J; Stoehr, Peter; Marsh, Steven G E

    2005-01-01

    The Immuno Polymorphism Database (IPD) (http://www.ebi.ac.uk/ipd/) is a set of specialist databases related to the study of polymorphic genes in the immune system. IPD currently consists of four databases: IPD-KIR, contains the allelic sequences of Killer-cell Immunoglobulin-like Receptors; IPD-MHC, a database of sequences of the Major Histocompatibility Complex of different species; IPD-HPA, alloantigens expressed only on platelets; and IPD-ESTAB, which provides access to the European Searchable Tumour Cell-Line Database, a cell bank of immunologically characterized melanoma cell lines. The IPD project works with specialist groups or nomenclature committees who provide and curate individual sections before they are submitted to IPD for online publication. The IPD project stores all the data in a set of related databases. Those sections with similar data, such as IPD-KIR and IPD-MHC share the same database structure. The sharing of a common database structure makes it easier to implement common tools for data submission and retrieval. The data are currently available online from the website and ftp directory; files will also be made available in different formats to download from the website and ftp server. The data will also be included in SRS, BLAST and FASTA search engines at the European Bioinformatics Institute.

  19. Polymorphic collaboration in the global grid

    NASA Astrophysics Data System (ADS)

    McQuay, William K.

    2006-05-01

    Next generation collaborative systems must be able to represent the same information in different forms on a broad spectrum of devices and resources from low end personal digital assistants (PDA) to high performance computers (HPC). Users might be on a desktop then switch to a laptop and then to a PDA while accessing the global grid. The user preference profile for a collaboration session should be capable of moving with them as well as be automatically adjusted for the device type. Collaborative systems must be capable of representing the same information in many forms for different domains and on many devices and thus be polymorphic. Polymorphic collaboration will provide an ability for multiple heterogeneous resources (human to human, human to machine and machine to machine) to share information and activities, as well as the ability to regulate collaborative sessions based on client characteristics and needs; reuse user profiles, tool category choices, and settings in future collaboration session by same or different users; use intelligent agents to assist collaborative systems in learning user/resource preferences and behaviors, and autonomously derive optimal information to provide to users and decision makers. This paper discusses ongoing research in next generation collaborative environments with the goal of making electronic collaboration as easy to use as the telephone - collaboration at the touch of the screen.

  20. Functional relevance of human adh polymorphism.

    PubMed

    Eriksson, C J; Fukunaga, T; Sarkola, T; Chen, W J; Chen, C C; Ju, J M; Cheng, A T; Yamamoto, H; Kohlenberg-Müller, K; Kimura, M; Murayama, M; Matsushita, S; Kashima, H; Higuchi, S; Carr, L; Viljoen, D; Brooke, L; Stewart, T; Foroud, T; Su, J; Li, T K; Whitfield, J B

    2001-05-01

    This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were C. J. Peter Eriksson and Tatsushige Fukunaga. The presentations were (1) 4-Methylpyrazole as a tool in the investigation of the role of ADH in the actions of alcohol in humans, by Taisto Sarkola and C. J. Peter Eriksson; (2) ADH2 polymorphism and flushing in Asian populations, by Wei J. Chen, C. C. Chen, J. M. Ju, and Andrew T. A. Cheng; (3) Role of ADH3 genotypes in the acute effects of alcohol in a Finnish population, by Hidetaka Yamamoto, Kathrin Kohlenberg-Müller, and C. J. Peter Eriksson; (4) Clinical characteristics and disease course of alcoholics with different ADH2 genotypes, by Mitsuru Kimura, Masanobu Murayama, Sachio Matsushita, Haruo Kashima, and Susumu Higuchi; (5) ADH2 polymorphism, alcohol drinking, and birth defects, by Lucinda Carr, D. Viljoen, L. Brooke, T. Stewart, T. Foroud, J. Su, and Ting-Kai Li; and (6) ADH genotypes and alcohol use in Europeans, by John B. Whitfield.

  1. Counterintuitive compaction behavior of clopidogrel bisulfate polymorphs.

    PubMed

    Khomane, Kailas S; More, Parth K; Bansal, Arvind K

    2012-07-01

    Being a density violator, clopidogrel bisulfate (CLP) polymorphic system (forms I and II) allows us to study individually the impact of molecular packing (true density) and thermodynamic properties such as heat of fusion on the compaction behavior. These two polymorphs of CLP were investigated for in-die and out-of-die compaction behavior using CTC profile, Heckel, and Walker equations. Compaction studies were performed on a fully instrumented rotary tabletting machine. Detailed examinations of the molecular packing of each form revealed that arrangement of the sulfate anion differs significantly in both crystal forms, thus conferring different compaction behavior to two forms. Close cluster packing of molecules in form I offers a rigid structure, which has poor compressibility and hence resists deformation under compaction pressure. This results into lower densification, higher yield strength, and mean yield pressure, as compared with form II at a given pressure. However, by virtue of higher bonding strength, form I showed superior tabletability, despite its poor compressibility and deformation behavior. Form I, having higher true density and lower heat of fusion showed higher bonding strength. Hence, true density and not heat of fusion can be considered predictor of bonding strength of the pharmaceutical powders.

  2. Bitter Taste Receptor Polymorphisms and Human Aging

    PubMed Central

    Carrai, Maura; Crocco, Paolina; Montesanto, Alberto; Canzian, Federico; Rose, Giuseppina; Rizzato, Cosmeri

    2012-01-01

    Several studies have shown that genetic factors account for 25% of the variation in human life span. On the basis of published molecular, genetic and epidemiological data, we hypothesized that genetic polymorphisms of taste receptors, which modulate food preferences but are also expressed in a number of organs and regulate food absorption processing and metabolism, could modulate the aging process. Using a tagging approach, we investigated the possible associations between longevity and the common genetic variation at the three bitter taste receptor gene clusters on chromosomes 5, 7 and 12 in a population of 941 individuals ranging in age from 20 to 106 years from the South of Italy. We found that one polymorphism, rs978739, situated 212 bp upstream of the TAS2R16 gene, shows a statistically significant association (p = 0.001) with longevity. In particular, the frequency of A/A homozygotes increases gradually from 35% in subjects aged 20 to 70 up to 55% in centenarians. These data provide suggestive evidence on the possible correlation between human longevity and taste genetics. PMID:23133589

  3. A pilot study on genotype announcement to induce smoking cessation by Japanese smokers.

    PubMed

    Hamajima, Nobuyuki; Atsuta, Yoshiko; Goto, Yasuyuki; Ito, Hidemi

    2004-01-01

    Genotype announcements related to susceptibility to hazardous effects of smoking may be effective to induce smoking cessation. Subjects were municipal government employees, 63 young smokers employed in the previous year and 59 smokers with more than 45 pack-years, who were invited to educational sessions against smoking held in December 2003 and February 2004, respectively. In the session, those who wished genetic susceptibility tests (GSTM1, GSTT1, and NQO1 C609T) were enrolled in the study. The smoking habit was ascertained three times: at the session, one month later, just before the genotype announcement, and at the follow-up three months after the announcement. Fifty eight (92.1%) and 49 (83.1%) smokers participated in the study, respectively. One out of 58 smokers was not a habitual smoker, so was not included in the analysis. The smoking cessation rates were 15.8% (9 participants) and 6.1% (3 participants) just before the genotype announcement, and 7.0% (4 participants) and 10.2% (5 participants) at the follow-up, respectively. All subjects were satisfied with the genotype testing except for two who rather regretted participating, but one of whom actually quit smoking. The present pilot study without controls indicated that the effects of genotype announcements in this framework on smoking cessation were less than might have been expected. The temporary effect of the session on younger smokers may have been due to the participation per se. The potential effects of genotype announcements for heavy smokers should now be examined in studies with adequate controls.

  4. A gene feature enumeration approach for describing HLA allele polymorphism.

    PubMed

    Mack, Steven J

    2015-12-01

    HLA genotyping via next generation sequencing (NGS) poses challenges for the use of HLA allele names to analyze and discuss sequence polymorphism. NGS will identify many new synonymous and non-coding HLA sequence variants. Allele names identify the types of nucleotide polymorphism that define an allele (non-synonymous, synonymous and non-coding changes), but do not describe how polymorphism is distributed among the individual features (the flanking untranslated regions, exons and introns) of a gene. Further, HLA alleles cannot be named in the absence of antigen-recognition domain (ARD) encoding exons. Here, a system for describing HLA polymorphism in terms of HLA gene features (GFs) is proposed. This system enumerates the unique nucleotide sequences for each GF in an HLA gene, and records these in a GF enumeration notation that allows both more granular dissection of allele-level HLA polymorphism and the discussion and analysis of GFs in the absence of ARD-encoding exon sequences.

  5. Special considerations in prognostic research in cancer involving genetic polymorphisms

    PubMed Central

    2013-01-01

    Analysis of genetic polymorphisms may help identify putative prognostic markers and determine the biological basis of variable prognosis in patients. However, in contrast to other variables commonly used in the prognostic studies, there are special considerations when studying genetic polymorphisms. For example, variable inheritance patterns (recessive, dominant, codominant, and additive genetic models) need to be explored to identify the specific genotypes associated with the outcome. In addition, several characteristics of genetic polymorphisms, such as their minor allele frequency and linkage disequilibrium among multiple polymorphisms, and the population substructure of the cohort investigated need to be accounted for in the analyses. In addition, in cancer research due to the genomic differences between the tumor and non-tumor DNA, differences in the genetic information obtained using these tissues need to be carefully assessed in prognostic studies. In this article, we review these and other considerations specific to genetic polymorphism by focusing on genetic prognostic studies in cancer. PMID:23773794

  6. Polymorphism of the IGF-I System and Sports Performance.

    PubMed

    Ben-Zaken, Sigal; Meckel, Yoav; Nemet, Dan; Dror, Nitzan; Eliakim, Alon

    2016-06-01

    The potential use genetic polymorphism, and in particularly polymorphism of hormone genes, as tool to predict athletic performance is currently very challenging. Recent studies suggest that single nucleotide polymorphisms in IGF-I and myostatin may be beneficial for endurance and short distance running, and may even be associated with elite performance. Polymorphism in IGF-I receptor may differentiate between the two edges of the endurance-power athletic performance running spectrum suggesting beneficial effects for endurance and prevent from success in power events. In contrast, and despite similar metabolic demands, the myostatin-IGF-I-IGF-IR system seems not to play an important role in swimming excellence. This suggests that combining different sport disciplines for sports genetic research purposes should be done with extreme caution. Finally, since any phenotype reflects a complex relationship between genes, environment, epigenetic factors, and the interactions between them, consulting the young athlete regarding future success cannot be based solely on genetic polymorphism.

  7. Water ice polymorphs and their significance on planetary surfaces

    NASA Technical Reports Server (NTRS)

    Gaffney, E. S.; Matson, E. L.

    1980-01-01

    Impacts into an icy surface could produce significant amounts of high pressure forms of water ice. Due to the relatively low ambient surface temperatures on satellites in the outer solar system and the modest temperature rises accompanying the impact pressures required for water ice metamorphism, high-pressure polymorphs will be created by and may remain after large cratering events. If so, those high-pressure ices should be ubiquitous. Low-pressure cubic ice may be abundant as well. Impacts into an icy regolith may both produce high-pressure polymorphs from ice I and destroy high-pressure polymorphs already present. The result will be an (unknown) equilibrium concentration of high pressure polymorphs in the regolith. Polymorphs may be detectable and mappable by reflection spectroscopy at vacuum ultraviolet and mid-infrared wavelengths.

  8. Assortative mating counteracts the evolution of dispersal polymorphisms.

    PubMed

    Fronhofer, Emanuel A; Kubisch, Alexander; Hovestadt, Thomas; Poethke, Hans-Joachim

    2011-09-01

    Polymorphic dispersal strategies are found in many plant and animal species. An important question is how the genetic variation underlying such polymorphisms is maintained. Numerous mechanisms have been discussed, including kin competition or frequency-dependent selection. In the context of sympatric speciation events, genetic and phenotypic variation is often assumed to be preserved by assortative mating. Thus, recently, this has been advocated as a possible mechanism leading to the evolution of dispersal polymorphisms. Here, we examine the role of assortative mating for the evolution of trade-off-driven dispersal polymorphisms by modeling univoltine insect species in a metapopulation. We show that assortative mating does not favor the evolution of polymorphisms. On the contrary, assortative mating favors the evolution of an intermediate dispersal type and a uni-modal distribution of traits within populations. As an alternative, mechanism dominance may explain the occurrence of two discrete morphs. © 2011 The Author(s).

  9. Inheritance of restriction fragment length polymorphisms, random amplified polymorphic DNAs and isozymes in coastal Douglas-fir

    Treesearch

    K.D. Jermstad; A.M. Reem; J.R. Henifin; N.C. Wheeler; D.B Neale

    1994-01-01

    A total of 225 new genetic loci [151 restriction fragment length polymorphisms (RFLP) and 74 random amplified polymorphic DNAs (RAPD)] in coastal Douglas- fir [Pseudotsuga menziesii (Mirb.) Franco var. menziesii] have been identified using a three-generation outbred pedigree. The Mendelian inheritance of 16 RFLP loci and 29...

  10. CO2 packing polymorphism under pressure: Mechanism and thermodynamics of the I-III polymorphic transition

    NASA Astrophysics Data System (ADS)

    Gimondi, Ilaria; Salvalaglio, Matteo

    2017-09-01

    In this work, we describe the thermodynamics and mechanism of CO2 polymorphic transitions under pressure from form I to form III combining standard molecular dynamics, well-tempered metadynamics, and committor analysis. We find that the phase transformation takes place through a concerted rearrangement of CO2 molecules, which unfolds via an anisotropic expansion of the CO2 supercell. Furthermore, at high pressures, we find that defected form I configurations are thermodynamically more stable with respect to form I without structural defects. Our computational approach shows the capability of simultaneously providing an extensive sampling of the configurational space, estimates of the thermodynamic stability, and a suitable description of a complex, collective polymorphic transition mechanism.

  11. CO2 packing polymorphism under pressure: Mechanism and thermodynamics of the I-III polymorphic transition.

    PubMed

    Gimondi, Ilaria; Salvalaglio, Matteo

    2017-09-21

    In this work, we describe the thermodynamics and mechanism of CO2 polymorphic transitions under pressure from form I to form III combining standard molecular dynamics, well-tempered metadynamics, and committor analysis. We find that the phase transformation takes place through a concerted rearrangement of CO2 molecules, which unfolds via an anisotropic expansion of the CO2 supercell. Furthermore, at high pressures, we find that defected form I configurations are thermodynamically more stable with respect to form I without structural defects. Our computational approach shows the capability of simultaneously providing an extensive sampling of the configurational space, estimates of the thermodynamic stability, and a suitable description of a complex, collective polymorphic transition mechanism.

  12. An integrated restriction fragment length polymorphism--amplified fragment length polymorphism linkage map for cultivated sunflower.

    PubMed

    Gedil, M A; Wye, C; Berry, S; Segers, B; Peleman, J; Jones, R; Leon, A; Slabaugh, M B; Knapp, S J

    2001-04-01

    Restriction fragment length polymorphism (RFLP) maps have been constructed for cultivated sunflower (Helianthus annuus L.) using three independent sets of RFLP probes. The aim of this research was to integrate RFLP markers from two sets with RFLP markers for resistance gene candidate (RGC) and amplified fragment length polymorphism (AFLP) markers. Genomic DNA samples of HA370 and HA372, the parents of the F2 population used to build the map, were screened for AFLPs using 42 primer combinations and RFLPs using 136 cDNA probes (RFLP analyses were performed on DNA digested with EcoRI, HindIII, EcoRV, or DraI). The AFLP primers produced 446 polymorphic and 1101 monomorphic bands between HA370 and HA372. The integrated map was built by genotyping 296 AFLP and 104 RFLP markers on 180 HA370 x HA372 F2 progeny (the AFLP marker assays were performed using 18 primer combinations). The HA370 x HA372 map comprised 17 linkage groups, presumably corresponding to the 17 haploid chromosomes of sunflower, had a mean density of 3.3 cM, and was 1326 cM long. Six RGC RFLP loci were polymorphic and mapped to three linkage groups (LG8, LG13, and LG15). AFLP markers were densely clustered on several linkage groups, and presumably reside in centromeric regions where recombination is reduced and the ratio of genetic to physical distance is low. Strategies for targeting markers to euchromatic DNA need to be tested in sunflower. The HA370 x HA372 map integrated 14 of 17 linkage groups from two independent RFLP maps. Three linkage groups were devoid of RFLP markers from one of the two maps.

  13. H pylori seropositivity and cytokine gene polymorphisms

    PubMed Central

    Saijo, Yasuaki; Yoshioka, Eiji; Fukui, Tomonori; Kawaharada, Mariko; Sata, Fumihiro; Sato, Hirokazu; Kishi, Reiko

    2007-01-01

    AIM: To investigate whether the pro- and anti-inflammatory cytokine gene polymorphisms, IL1B-511C/T, IL1B-31C/T, IL6-634C/G, TNF-1031T/C, TNF-857C/T, and IL10-1082A/G, interact with smoking and drinking habits to influence infection with H pylori. METHODS: The subjects were 410 Japanese transit company employees. C-reactive protein and conventional cardiovascular risk factors were evaluated. Serum anti-H pylori antibodies were measured. The genotypes of IL1B-511C/T, IL1B-31C/T, IL6-634C/G, TNF-1031T/C, TNF-857C/T, and IL10-1082A/G polymorphisms were determined by allelic discrimination using fluorogenic probes and a 5´nuclease assay. RESULTS: In gender- and age-adjusted logistic analyses, the subjects with TNF-857T/T had a significantly lower odds ratio (OR) for H pylori seropositivity (reference -857C/C; OR = 0.15, 95%CI: 0.03-0.59, P = 0.007). After stratification according to smoking and drinking status, among never-smokers, the subjects with IL1B-511C/T had a significantly lower OR (reference -511C/C; OR = 0.30, 95%CI: 0.10-0.90, P = 0.032). Among drinkers in the 1-5 times/wk category, the subjects with IL1B-511T/T had a significantly lower OR (reference C/C; OR = 0.38, 95%CI: 0.16-0.95, P = 0.039), and the subjects with IL1B-31C/T and T/T had a significantly higher OR (reference C/C; C/T: OR = 2.59, 95%CI, P = 0.042: 1.04-6.47; C/C: OR = 3.17, 95%CI: 1.23-8.14, P = 0.017). Among current smokers, the subjects with IL6-634C/G had a significantly higher OR (reference C/C; OR = 2.28, 95%CI: 1.13-4.58, P = 0.021). However, the interactions terms between the aforementioned genotypes and lifestyles were not statistically significant. CONCLUSION: Contrary to previous findings, the results herein suggest that the TNF-857T/T genotype may be protective against chronic infection with H pylori. Drinking and smoking habits may influence the effect of cytokine gene polymorphisms. Further studies are required to clarify the effects of the pro- and anti-inflammatory cytokine

  14. Association of Reelin gene polymorphisms with autism.

    PubMed

    Serajee, Fatema J; Zhong, Hailang; Mahbubul Huq, A H M

    2006-01-01

    Genome scans indicate a linkage of autism to the chromosome 7q21-q36 region. Recent studies suggest that the Reelin gene may be one of the loci contributing to the positive linkage between chromosome 7q and autism. However, these studies were relatively small scale, using a few markers in the gene. We investigated 34 single nucleotide polymorphisms (SNPs) in the Reelin gene with an average spacing between the SNPs of 15 kb for evidence of association with autism. There were significant differences in the transmission of the alleles of exon 22 and intron 59 SNP to autistic subjects. Our findings support a role for the Reelin gene in the susceptibility to autism.

  15. Polymorphic Alu insertions among Mayan populations.

    PubMed

    Herrera, R J; Rojas, D P; Terreros, M C

    2007-01-01

    The Mayan homeland within Mesoamerica spans five countries: Belize, El Salvador, Guatemala, Honduras and Mexico. There are indications that the people we call the Maya migrated from the north to the highlands of Guatemala as early as 4000 B.C. Their existence was village-based and agricultural. The culture of these Preclassic Mayans owes much to the earlier Olmec civilization, which flourished in the southern portion of North America. In this study, four different Mayan groups were examined to assess their genetic variability. Ten polymorphic Alu insertion (PAI) loci were employed to ascertain the genetic affinities among these Mayan groups. North American, African, European and Asian populations were also examined as reference populations. Our results suggest that the Mayan groups examined in this study are not genetically homogeneous.

  16. Two polymorphs of 1,8-dichloroanthracene.

    PubMed

    Müller, Peter; Fronczek, Frank R; Smith, Stacey J; Mako, Teresa; Levine, Mindy

    2013-02-01

    A second, monoclinic, polymorph of the title compound, C(14)H(8)Cl(2), has been found. In addition to the structure of this monoclinic form, the structure of the previously described orthorhombic form [Desvergne, Chekpo & Bouas-Laurent (1978). J. Chem. Soc. Perkin Trans. 2, pp. 84-87; Benites, Maverick & Fronczek (1996). Acta Cryst. C52, 647-648] has been redetermined at low temperature and using modern methods. The low-temperature structure of the orthorhombic form is of significantly higher quality than the previously published structure and additional details can be derived. A comparison of the crystal packing of the two forms with a focus on weak intermolecular C-H···Cl interactions shows the monoclinic structure to have one such interaction linking the molecules into infinite ribbons, while two crystallographically independent C-H···Cl interactions give rise to an interesting infinite three-dimensional network in the orthorhombic crystal form.

  17. Tubulin bistability and polymorphic dynamics of microtubules.

    PubMed

    Mohrbach, Hervé; Johner, Albert; Kulić, Igor M

    2010-12-31

    Based on the hypothesis that the GDP-tubulin dimer is a conformationally bistable molecule-rapidly fluctuating between a discrete curved and a straight state-we develop a model for polymorphic dynamics of the microtubule lattice. We show that GDP-tubulin bistability consistently explains unusual dynamic fluctuations, the apparent length-stiffness relation of grafted taxol-stabilized microtubules, and the curved-helical appearance of microtubules in general. When clamped by one end the microtubules undergo an unusual zero energy motion-in its effect reminiscent of a limited rotational hinge. We conclude that microtubules exist in highly cooperative energy-degenerate helical states and discuss possible implications in vivo.

  18. Androgen receptor gene mutation, rearrangement, polymorphism

    PubMed Central

    Eisermann, Kurtis; Wang, Dan; Jing, Yifeng; Pascal, Laura E.

    2013-01-01

    Genetic aberrations of the androgen receptor (AR) caused by mutations, rearrangements, and polymorphisms result in a mutant receptor that has varied functions compared to wild type AR. To date, over 1,000 mutations have been reported in the AR with most of these being associated with androgen insensitivity syndrome (AIS). While mutations of AR associated with prostate cancer occur less often in early stage localized disease, mutations in castration-resistant prostate cancer (CRPC) patients treated with anti-androgens occur more frequently with 10-30% of these patients having some form of mutation in the AR. Resistance to anti-androgen therapy usually results from gain-of-function mutations in the LBD such as is seen with bicalutamide and more recently with enzalutamide (MDV3100). Thus, it is crucial to investigate these new AR mutations arising from drug resistance to anti-androgens and other small molecule pharmacological agents. PMID:25045626

  19. Gene Polymorphisms and Pharmacogenetics in Rheumatoid Arthritis

    PubMed Central

    Rego-Pérez, Ignacio; Fernández-Moreno, Mercedes; Blanco, Francisco J

    2008-01-01

    Rheumatoid arthritis (RA) is a systemic, chronic and inflammatory disease of unknown etiology with genetic predisposition. The advent of new biological agents, as well as the more traditional disease-modifying antirheumatic drugs, has resulted in highly efficient therapies for reducing the symptoms and signs of RA; however, not all patients show the same level of response in disease progression to these therapies. These variations suggest that RA patients may have different genetic regulatory mechanisms. The extensive polymorphisms revealed in non-coding gene-regulatory regions in the immune system, as well as genetic variations in drug-metabolizing enzymes, suggest that this type of variation is of functional and evolutionary importance and may provide clues for developing new therapeutic strategies. Pharmacogenetics is a rapidly advancing area of research that holds the promise that therapies will soon be tailored to an individual patient’s genetic profile. PMID:19506728

  20. Tubulin Bistability and Polymorphic Dynamics of Microtubules

    NASA Astrophysics Data System (ADS)

    Mohrbach, Hervé; Johner, Albert; Kulić, Igor M.

    2010-12-01

    Based on the hypothesis that the GDP-tubulin dimer is a conformationally bistable molecule—rapidly fluctuating between a discrete curved and a straight state—we develop a model for polymorphic dynamics of the microtubule lattice. We show that GDP-tubulin bistability consistently explains unusual dynamic fluctuations, the apparent length-stiffness relation of grafted taxol-stabilized microtubules, and the curved-helical appearance of microtubules in general. When clamped by one end the microtubules undergo an unusual zero energy motion—in its effect reminiscent of a limited rotational hinge. We conclude that microtubules exist in highly cooperative energy-degenerate helical states and discuss possible implications in vivo.

  1. Diosgenone: a second P21 polymorph

    PubMed Central

    Hernández Linares, María-Guadalupe; Guerrero-Luna, Gabriel; Bernès, Sylvain; Flores-Alamo, Marcos; Fernández-Herrera, María A.

    2012-01-01

    Diosgenone [(20S,22R,25R)-spirost-4-en-3-one, C27H40O3] has been proposed as a new therapeutic alternative for the treatment of malaria. The first X-ray structure report for diosgenone was by Piro et al. [(2002). Z. Naturforsch. Teil C, 57, 947–950] in the space group P21 (Z′ = 2). We now report a new polymorph in the same space group, with two mol­ecules in the asymmetric unit. Both mol­ecules have similar conformations, characterized by a skewed envelope A ring, which contains the C=C bond conjugated with the ketone functionality at C3. The dimorphism results from a modification of the relative orientation of the mol­ecules in the asymmetric unit: two independent mol­ecules were arranged anti­parallel in the Piro report, while they are parallel in the present determination. PMID:22904824

  2. Single nucleotide polymorphism for animal fibre identification.

    PubMed

    Subramanian, Selvi; Karthik, T; Vijayaraaghavan, N N

    2005-03-16

    Animal fibres are highly valuable industrial products often adulterated during marketing. Currently, there is no precise method available to identify and differentiate the fibres. In this study, a PCR-RFLP technique was exploited to differentiate cashmere and wool fibres derived from goat and sheep, respectively. The presence of DNA in animal hair shafts has enabled the isolation of DNA from scoured cashmere and wool fibres. The mitochondrial cytochrome b sequences of both species were amplified by PCR using primers designed from conserved regions. The polymorphism observed between the two species was detected by restricting the amplified product by endonucleases viz., BamH1 and Ssp1. The RFLP profile clearly distinguishes the cashmere and wool fibres and this technique can also be exploited to test adulteration in animal fibres qualitatively.

  3. Polymorphism of starch pathway genes in cassava.

    PubMed

    Vasconcelos, L M; Brito, A C; Carmo, C D; Oliveira, E J

    2016-12-02

    The distribution and frequency of single nucleotide polymorphisms (SNPs) can help to understand changes associated with characteristics of interest. We aimed to evaluate nucleotide diversity in six genes involved in starch biosynthesis in cassava using a panel of 96 unrelated accessions. The genes were sequenced, aligned, and used to obtain values for nucleotide diversity (π), segregating sites (θ), Tajima's D test, and neighbor-joining (NJ) clustering. On average, one SNP per 147 and 171 bp was identified in exon and intron regions, respectively. Thirteen heterozygous loci were found. Three of seven SNPs in the exon region resulted in non-synonymous replacement or four synonymous substitutions. However, no associations were noted between SNPs and root dry-matter content. The parameter π ranged from 0.0001 (granule bound starch synthase I) to 0.0033 (α-amylase), averaging 0.0011, while θ ranged from 0.00014 (starch branching enzyme) to 0.00584 (starch synthase I), averaging 0.002353. The θ diversity value was typically double that of the π. Results of the D test did not suggest any evidence of deviance of neutrality in these genes. Among the evaluated accession, 82/96 were clustered using the NJ method but without a clear separation of the root dry-matter content, root pulp coloration, and classification of the cyanogenic compound content. High variation in genes of the starch biosynthetic pathway can be used to identify associations with the functional properties of starch for the use of polymorphisms for selection purposes.

  4. Ecological separation in a polymorphic terrestrial salamander.

    PubMed

    Anthony, Carl D; Venesky, Matthew D; Hickerson, Cari-Ann M

    2008-07-01

    1. When studying speciation, researchers commonly examine reproductive isolation in recently diverged populations. Polymorphic species provide an opportunity to examine the role of reproductive isolation in populations that may be in the process of divergence. 2. We examined a polymorphic population of Plethodon cinereus (red-backed salamanders) for evidence of sympatric ecological separation by colour morphology. Recent studies have correlated temperature and climate with colour morphology in this species, but no studies have looked at differences in diet or mate choice between colour morphs. We used artificial cover objects to assess salamander diet, mating preference and surface activity over a 2-year period at a field site in north-eastern Ohio. 3. We detected differences in diet between two colour morphs, striped and unstriped. The diets of striped individuals were significantly more diverse and were made up of more profitable prey than the diets of unstriped salamanders. 4. Opposite sex pairs were made up of individuals of the same colour morph and striped males were found more often with larger females than were unstriped males. 5. We corroborate findings of earlier studies suggesting that the unstriped form is adapted to warmer conditions. Unstriped individuals were the first to withdraw from the forest floor as temperatures fell in the late fall. We found no evidence that the colour morphs responded differently to abiotic factors such as soil moisture and relative humidity, and responses to surface temperatures were also equivocal. 6. We conclude that the two colour morphs exhibit some degree of ecological separation and tend to mate assortatively, but are unlikely to be undergoing divergence given the observed frequency of intermorph pairings.

  5. Consequences of POR mutations and polymorphisms

    PubMed Central

    Miller, Walter L.; Agrawal, Vishal; Sandee, Duanpen; Tee, Meng Kian; Huang, Ningwu; Choi, Ji Ha; Morrissey, Kari; Giacomini, Kathleen M.

    2015-01-01

    P450 oxidoreductase (POR) transports electrons from NADPH to all microsomal cytochrome P450 enzymes, including steroidogenic P450c17, P450c21 and P450aro. Severe POR mutations A287P (in Europeans) and R457H (in Japanese) cause the Antley-Bixler skeletal malformation syndrome (ABS) plus impaired steroidogenesis (causing genital anomalies), but the basis of ABS is unclear. We have characterized the activities of ~40 POR variants, showing that assays based on P450c17 activities, but not cytochrome c assays, correlate with the clinical phenotype. The human POR gene is highly polymorphic: the A503V sequence variant, which decreases P450c17 activities to ~60%, is found on ~28% of human alleles. A promoter polymorphism (~8% of Asians and ~13% of Caucasians) at −152 reduces transcriptional activity by half. Screening of 35 POR variants showed that most mutants lacking activity with P450c17 or cytochrome c also lacked activity to support CYP1A2 and CYP2C19 metabolism of EOMCC (a fluorogenic non-drug substrate), although there were some remarkable differences: Q153R causes ABS and has ~30% of wild-type activity with P450c17 but had 144% of WT activity with CYP1A2 and 284% with CYP2C19. The effects of POR variants on CYP3A4, which metabolizes nearly 50% of clinically used drugs, was examined with multiple, clinically-relevant drug substrates, showing that A287P and R457H dramatically reduce drug metabolism, and that A503V variably impairs drug metabolism. The degree of activity can vary with the drug substrate assayed, as the drugs can influence the conformation of the P450. POR is probably an important contributor to genetic variation in both steroidogenesis and drug metabolism. PMID:21070833

  6. Consequences of POR mutations and polymorphisms.

    PubMed

    Miller, Walter L; Agrawal, Vishal; Sandee, Duanpen; Tee, Meng Kian; Huang, Ningwu; Choi, Ji Ha; Morrissey, Kari; Giacomini, Kathleen M

    2011-04-10

    P450 oxidoreductase (POR) transports electrons from NADPH to all microsomal cytochrome P450 enzymes, including steroidogenic P450c17, P450c21 and P450aro. Severe POR mutations A287P (in Europeans) and R457H (in Japanese) cause the Antley-Bixler skeletal malformation syndrome (ABS) plus impaired steroidogenesis (causing genital anomalies), but the basis of ABS is unclear. We have characterized the activities of ∼40 POR variants, showing that assays based on P450c17 activities, but not cytochrome c assays, correlate with the clinical phenotype. The human POR gene is highly polymorphic: the A503V sequence variant, which decreases P450c17 activities to ∼60%, is found on ∼28% of human alleles. A promoter polymorphism (∼8% of Asians and ∼13% of Caucasians) at -152 reduces transcriptional activity by half. Screening of 35 POR variants showed that most mutants lacking activity with P450c17 or cytochrome c also lacked activity to support CYP1A2 and CYP2C19 metabolism of EOMCC (a fluorogenic non-drug substrate), although there were some remarkable differences: Q153R causes ABS and has ∼30% of wild-type activity with P450c17 but had 144% of WT activity with CYP1A2 and 284% with CYP2C19. The effects of POR variants on CYP3A4, which metabolizes nearly 50% of clinically used drugs, was examined with multiple, clinically relevant drug substrates, showing that A287P and R457H dramatically reduce drug metabolism, and that A503V variably impairs drug metabolism. The degree of activity can vary with the drug substrate assayed, as the drugs can influence the conformation of the P450. POR is probably an important contributor to genetic variation in both steroidogenesis and drug metabolism. Copyright © 2010. Published by Elsevier Ireland Ltd.

  7. KCNN2 polymorphisms and cardiac tachyarrhythmias.

    PubMed

    Yu, Chih-Chieh; Chia-Ti, Tsai; Chen, Pei-Lung; Wu, Cho-Kai; Chiu, Fu-Chun; Chiang, Fu-Tien; Chen, Peng-Sheng; Chen, Chi-Ling; Lin, Lian-Yu; Juang, Jyh-Ming; Ho, Li-Ting; Lai, Ling-Ping; Yang, Wei-Shiung; Lin, Jiunn-Lee

    2016-07-01

    Potassium calcium-activated channel subfamily N member 2 (KCNN2) encodes an integral membrane protein that forms small-conductance calcium-activated potassium (SK) channels. Recent studies in animal models show that SK channels are important in atrial and ventricular repolarization and arrhythmogenesis. However, the importance of SK channels in human arrhythmia remains unclear. The purpose of the present study was to test the association between genetic polymorphism of the SK2 channel and the occurrence of cardiac tachyarrhythmias in humans. We enrolled 327 Han Chinese, including 72 with clinically significant ventricular tachyarrhythmias (VTa) who had a history of aborted sudden cardiac death (SCD) or unexplained syncope, 98 with a history of atrial fibrillation (AF), and 144 normal controls. We genotyped 12 representative tag single nucleotide polymorphisms (SNPs) across a 141-kb genetic region containing the KCNN2 gene; these captured the full haplotype information. The rs13184658 and rs10076582 variants of KCNN2 were associated with VTa in both the additive and dominant models (odds ratio [OR] 2.89, 95% confidence interval [CI] = 1.505-5.545, P = 0.001; and OR 2.55, 95% CI = 1.428-4.566, P = 0.002, respectively). After adjustment for potential risk factors, the association remained significant. The population attributable risks of these 2 variants of VTa were 17.3% and 10.6%, respectively. One variant (rs13184658) showed weak but significant association with AF in a dominant model (OR 1.91, CI = 1.025-3.570], P = 0.042). There was a significant association between the KCNN2 variants and clinically significant VTa. These findings suggest an association between KCNN2 and VTa; it also appears that KCNN2 variants may be adjunctive markers for risk stratification in patients susceptible to SCD.

  8. APOE gene polymorphism analysis in Barranquilla, Colombia.

    PubMed

    Ruiz, Martha; Arias, Isis; Rolón, Gloria; Hernández, Enio; Garavito, Pilar; Silvera-Redondo, Carlos

    2016-03-03

    The genetic variability present in the APOE gene polymorphism is considered an important factor associated with predisposition to diseases affecting lipid metabolism, as well as heart diseases and Alzheimer's disease, among others. Understanding it as a risk factor in different populations and ethnic groups is a useful tool.  To analyze the APOE gene polymorphism and determine allelic and genotypic frequencies of a representative sample of population from Barranquilla, Colombia.  We performed a descriptive and comparative study. The sample size was 227 unrelated individuals from Barranquilla, Colombia.  The most frequent allele was the ε3, with 85%, followed by the ε4 allele (13%) and ε2 (1.8%). The genotypes found were: ε3/ε3: 71.8%, ε3/ε4: 24.2%, ε2/ε3: 2.2%, ε2/ε4: 1.3% and ε4/ε4: 0.4%. The ε2/ε2 genotype was not found in this study. The sample exhibited the Hardy-Weinberg equilibrium.  The frequency of the ε3 allele and the ε3/ε3 genotype was similar to that reported in the literature in countries like Brazil, Mexico, Colombia, and in some Colombian Amerindian ethnic groups. The ε2/ε2 genotype was absent. This result is consistent with those found in other population groups worldwide. The frequency of the ε4 allele and the genotypes associated in this population could be related to the presence of diseases such as hypercholesterolemia, myocardial infarction and Alzheimer.

  9. KCNN2 polymorphisms and cardiac tachyarrhythmias

    PubMed Central

    Yu, Chih-Chieh; Chia-Ti, Tsai; Chen, Pei-Lung; Wu, Cho-Kai; Chiu, Fu-Chun; Chiang, Fu-Tien; Chen, Peng-Sheng; Chen, Chi-Ling; Lin, Lian-Yu; Juang, Jyh-Ming; Ho, Li-Ting; Lai, Ling-Ping; Yang, Wei-Shiung; Lin, Jiunn-Lee

    2016-01-01

    Abstract Potassium calcium-activated channel subfamily N member 2 (KCNN2) encodes an integral membrane protein that forms small-conductance calcium-activated potassium (SK) channels. Recent studies in animal models show that SK channels are important in atrial and ventricular repolarization and arrhythmogenesis. However, the importance of SK channels in human arrhythmia remains unclear. The purpose of the present study was to test the association between genetic polymorphism of the SK2 channel and the occurrence of cardiac tachyarrhythmias in humans. We enrolled 327 Han Chinese, including 72 with clinically significant ventricular tachyarrhythmias (VTa) who had a history of aborted sudden cardiac death (SCD) or unexplained syncope, 98 with a history of atrial fibrillation (AF), and 144 normal controls. We genotyped 12 representative tag single nucleotide polymorphisms (SNPs) across a 141-kb genetic region containing the KCNN2 gene; these captured the full haplotype information. The rs13184658 and rs10076582 variants of KCNN2 were associated with VTa in both the additive and dominant models (odds ratio [OR] 2.89, 95% confidence interval [CI] = 1.505–5.545, P = 0.001; and OR 2.55, 95% CI = 1.428–4.566, P = 0.002, respectively). After adjustment for potential risk factors, the association remained significant. The population attributable risks of these 2 variants of VTa were 17.3% and 10.6%, respectively. One variant (rs13184658) showed weak but significant association with AF in a dominant model (OR 1.91, CI = 1.025–3.570], P = 0.042). There was a significant association between the KCNN2 variants and clinically significant VTa. These findings suggest an association between KCNN2 and VTa; it also appears that KCNN2 variants may be adjunctive markers for risk stratification in patients susceptible to SCD. PMID:27442679

  10. Identification of polymorphism in ethylone hydrochloride: synthesis and characterization.

    PubMed

    Maheux, Chad R; Alarcon, Idralyn Q; Copeland, Catherine R; Cameron, T Stanley; Linden, Anthony; Grossert, J Stuart

    2016-08-01

    Ethylone, a synthetic cathinone with psychoactive properties, is a designer drug which has appeared on the recreational drug market in recent years. Since 2012, illicit shipments of ethylone hydrochloride have been intercepted with increasing frequency at the Canadian border. Analysis has revealed that ethylone hydrochloride exists as two distinct polymorphs. In addition, several minor impurities were detected in some seized exhibits. In this study, the two conformational polymorphs of ethylone hydrochloride have been synthesized and fully characterized by FTIR, FT-Raman, powder XRD, GC-MS, ESI-MS/MS and NMR ((13) C CPMAS, (1) H, (13) C). The two polymorphs can be distinguished by vibrational spectroscopy, solid-state nuclear magnetic resonance spectroscopy and X-ray diffraction. The FTIR data are applied to the identification of both polymorphs of ethylone hydrochloride (mixed with methylone hydrochloride) in a laboratory submission labelled as 'Ocean Snow Ultra'. The data presented in this study will assist forensic scientists in the differentiation of the two ethylone hydrochloride polymorphs. This report, alongside our recent article on the single crystal X-ray structure of a second polymorph of this synthetic cathinone, is the first to confirm polymorphism in ethylone hydrochloride. © 2015 Canada Border Services Agency. Drug Testing and Analysis published by John Wiley & Sons, Ltd. © 2015 Canada Border Services Agency. Drug Testing and Analysis published by John Wiley & Sons, Ltd.

  11. Identification of polymorphism in ethylone hydrochloride: synthesis and characterization

    PubMed Central

    Alarcon, Idralyn Q.; Copeland, Catherine R.; Cameron, T. Stanley; Linden, Anthony; Grossert, J. Stuart

    2015-01-01

    Ethylone, a synthetic cathinone with psychoactive properties, is a designer drug which has appeared on the recreational drug market in recent years. Since 2012, illicit shipments of ethylone hydrochloride have been intercepted with increasing frequency at the Canadian border. Analysis has revealed that ethylone hydrochloride exists as two distinct polymorphs. In addition, several minor impurities were detected in some seized exhibits. In this study, the two conformational polymorphs of ethylone hydrochloride have been synthesized and fully characterized by FTIR, FT‐Raman, powder XRD, GC‐MS, ESI‐MS/MS and NMR (13C CPMAS, 1H, 13C). The two polymorphs can be distinguished by vibrational spectroscopy, solid‐state nuclear magnetic resonance spectroscopy and X‐ray diffraction. The FTIR data are applied to the identification of both polymorphs of ethylone hydrochloride (mixed with methylone hydrochloride) in a laboratory submission labelled as 'Ocean Snow Ultra’. The data presented in this study will assist forensic scientists in the differentiation of the two ethylone hydrochloride polymorphs. This report, alongside our recent article on the single crystal X‐ray structure of a second polymorph of this synthetic cathinone, is the first to confirm polymorphism in ethylone hydrochloride. © 2015 Canada Border Services Agency. Drug Testing and Analysis published by John Wiley & Sons, Ltd. © 2015 Canada Border Services Agency. Drug Testing and Analysis published by John Wiley & Sons, Ltd. PMID:26344849

  12. Sexual selection and genetic colour polymorphisms in animals.

    PubMed

    Wellenreuther, Maren; Svensson, Erik I; Hansson, Bengt

    2014-11-01

    Genetic colour polymorphisms are widespread across animals and often subjected to complex selection regimes. Traditionally, colour morphs were used as simple visual markers to measure allele frequency changes in nature, selection, population divergence and speciation. With advances in sequencing technology and analysis methods, several model systems are emerging where the molecular targets of selection are being described. Here, we discuss recent studies on the genetics of sexually selected colour polymorphisms, aiming at (i) reviewing the evidence of sexual selection on colour polymorphisms, (ii) highlighting the genetic architecture, molecular and developmental basis underlying phenotypic colour diversification and (iii) discuss how the maintenance of such polymorphisms might be facilitated or constrained by these. Studies of the genetic architecture of colour polymorphism point towards the importance of tight clustering of colour loci with other trait loci, such as in the case of inversions and supergene structures. Other interesting findings include linkage between colour loci and mate preferences or sex determination, and the role of introgression and regulatory variation in fuelling polymorphisms. We highlight that more studies are needed that explicitly integrate fitness consequences of sexual selection on colour with the underlying molecular targets of colour to gain insights into the evolutionary consequences of sexual selection on polymorphism maintenance. © 2014 John Wiley & Sons Ltd.

  13. Zoledronic acid: monoclinic and triclinic polymorphs from powder diffraction data.

    PubMed

    Chernyshev, Vladimir V; Shkavrov, Sergey V; Paseshnichenko, Ksenia A; Puryaeva, Tamara P; Velikodny, Yurii A

    2013-03-01

    The crystal structures of the monoclinic and triclinic polymorphs of zoledronic acid, C5H10N2O7P2, have been established from laboratory powder X-ray diffraction data. The molecules in both polymorphs are described as zwitterions, namely 1-(2-hydroxy-2-phosphonato-2-phosphonoethyl)-1H-imidazol-3-ium. Strong intermolecular hydrogen bonds (with donor-acceptor distances of 2.60 Å or less) link the molecules into layers, parallel to the (100) plane in the monoclinic polymorph and to the (1-10) plane in the triclinic polymorph. The phosphonic acid groups form the inner side of each layer, while the imidazolium groups lie to the outside of the layer, protruding in opposite directions. In both polymorphs, layers related by translation along [100] interact through weak hydrogen bonds (with donor-acceptor distances greater than 2.70 Å), forming three-dimensional layered structures. In the monoclinic polymorph, there are hydrogen-bonded centrosymmetric dimers linked by four strong O-H...O hydrogen bonds, which are not present in the triclinic polymorph.

  14. Does colour polymorphism enhance survival of prey populations?

    PubMed Central

    Wennersten, Lena; Forsman, Anders

    2009-01-01

    That colour polymorphism may protect prey populations from predation is an old but rarely tested hypothesis. We examine whether colour polymorphic populations of prey exposed to avian predators in an ecologically valid visual context were exposed to increased extinction risk compared with monomorphic populations. We made 2976 artificial pastry prey, resembling Lepidoptera larvae, in four different colours and presented them in 124 monomorphic and 124 tetramorphic populations on tree trunks and branches such that they would be exposed to predation by free-living birds, and monitored their ‘survival’. Among monomorphic populations, there was a significant effect of prey coloration on survival, confirming that coloration influenced susceptibility to visually oriented predators. Survival of polymorphic populations was inferior to that of monomorphic green populations, but did not differ significantly from monomorphic brown, yellow or red populations. Differences in survival within polymorphic populations paralleled those seen among monomorphic populations; the red morph most frequently went extinct first and the green morph most frequently survived the longest. Our findings do not support the traditional protective polymorphism hypothesis and are in conflict with those of earlier studies. As a possible explanation to our findings, we offer a competing ‘giveaway cue’ hypothesis: that polymorphic populations may include one morph that attracts the attention of predators and that polymorphic populations therefore may suffer increased predation compared with some monomorphic populations. PMID:19324729

  15. Does colour polymorphism enhance survival of prey populations?

    PubMed

    Wennersten, Lena; Forsman, Anders

    2009-06-22

    That colour polymorphism may protect prey populations from predation is an old but rarely tested hypothesis. We examine whether colour polymorphic populations of prey exposed to avian predators in an ecologically valid visual context were exposed to increased extinction risk compared with monomorphic populations. We made 2976 artificial pastry prey, resembling Lepidoptera larvae, in four different colours and presented them in 124 monomorphic and 124 tetramorphic populations on tree trunks and branches such that they would be exposed to predation by free-living birds, and monitored their 'survival'. Among monomorphic populations, there was a significant effect of prey coloration on survival, confirming that coloration influenced susceptibility to visually oriented predators. Survival of polymorphic populations was inferior to that of monomorphic green populations, but did not differ significantly from monomorphic brown, yellow or red populations. Differences in survival within polymorphic populations paralleled those seen among monomorphic populations; the red morph most frequently went extinct first and the green morph most frequently survived the longest. Our findings do not support the traditional protective polymorphism hypothesis and are in conflict with those of earlier studies. As a possible explanation to our findings, we offer a competing 'giveaway cue' hypothesis: that polymorphic populations may include one morph that attracts the attention of predators and that polymorphic populations therefore may suffer increased predation compared with some monomorphic populations.

  16. Alzheimer's Disease and Paraoxonase 1 (PON1) Gene Polymorphisms.

    PubMed

    Saeidi, Mohsen; Shakeri, Raheleh; Marjani, Abdoljalal; Khajeniazi, Safoura

    2017-01-01

    Some studies have indicated that human paraoxonase 1 (PON1) activity shows a polymorphic distribution. The aim of this study was to determine the distribution of PON1 polymorphism in patients with Alzheimer's disease in Gorgan and compare it with a healthy control group. The study included 100 healthy individuals and 50 patients. Enzyme activity and genetic polymorphism of PON1 were determined. There were significant differences in distribution of genotypes and alleles among patients and control group. The most common genotype was CT in patients and control group, while the most frequent alleles were T and C in patients and controls, respectively. There was a statistically significant variation between serum PON1 activity and -108C> T polymorphism. The highest PON1 enzyme activities in the patients and controls were found in CC, while lower enzyme activities were seen in CT and TT genotypes in both genders and age groups. Onset of Alzheimer's disease may depend on different polymorphisms of the PON1 enzyme. Late or early-onset of Alzheimer's disease may also depend on age and gender distribution, especially for arylesterase enzyme. Further studies on polymorphism of the enzyme are necessary for interpretation of possible polymorphic effects of enzyme on PON1 activity in humans.

  17. Neotame anhydrate polymorphs. II: Quantitation and relative physical stability.

    PubMed

    Dong, Zedong; Munson, Eric J; Schroeder, Steve A; Prakash, Indra; Grant, David J W

    2002-09-01

    To study the relative thermodynamic and kinetic stabilities of neotame anhydrate polymorphs A, D, F, and G, and to develop a quantitative method for analyzing polymorphic mixtures of A and G by powder X-ray diffractometry (PXRD). Based on the melting points, heats of fusion, and densities of the four polymorphs, thermodynamic rules were applied to study their thermodynamic relationships. The phase transition temperature of Forms A and G was estimated from their heats of solution and intrinsic dissolution rates (J) in 2-propanol. Using PXRD, a method for the quantitative analysis of polymorphic mixtures of Forms A and G was developed. Binary polymorphic mixtures of Forms A, D, F, or G were stored under zero relative humidity at 23 or 70 degrees C, and their compositions were monitored by PXRD. The endothermic enthalpy of solution of A, D, F, and G follows the rank order: G (29.71 +/- 0.82 kJ/mol, n = 4) > A (28.48 +/- 0.51 kJ/mol, n = 4) > D (20.43 +/- 0.45 kJ/mol, n = 4) > F (18.77 +/- 0.31 kJ/mol, n = 4). The van't Hoff plots of ln(J) against 1/T for A and G show good linearity between 25 degrees C and 32 degrees C. At 23 degrees C polymorphic mixtures remain unchanged for 4 months. However, at 70 degrees C the phase transition is fast and the relative stability of the four polymorphs follows the rank order: G > D > F and G > A. PXRD provides a reliable and accurate technique for the quantitative analysis of polymorphic mixtures of Forms A and G. Among the four polymorphs, A-G and A-D are enantiotropic pairs, whereas D-F, D-G, F-G are monotropic pairs. The phase transition temperature between A and G lies within the range 35-70 degrees C.

  18. Methylenetetrahydrofolate Reductase gene polymorphism in children with allergic rhinitis.

    PubMed

    Dogru, M; Aydin, H; Aktas, A; Cırık, A A

    2015-01-01

    Methylenetetrahydrofolate Reductase (MTHFR) polymorphisms by impairing folate metabolism may influence the development of allergic diseases. The results of studies evaluating the relationship between MTHFR polymorphisms and atopic disease are controversial. The aim of this study was to investigate the association between the polymorphisms of C677T and A1298C for MTHFR gene and allergic rhinitis (AR) in children. Ninety patients followed up with diagnosis of allergic rhinitis in our clinic and 30 children with no allergic diseases were included in the study. All participants were genotyped for the MTHFR (C677T) and (A1298C) polymorphisms. Vitamin b12, folate and homocysteine levels were measured. The mean age of patients was 9.2±2.9 years; 66.7% of the patients were male. There was no significant difference between patient and control groups regarding gender, age and atopy history of the family (p>0.05). The frequency of homozygotes for MTHFR C677T polymorphism in the patient and control groups was 3.3% and 10%, respectively. The frequency of homozygotes for MTHFR A1298C polymorphism among groups was 26.7% and 16.7%, respectively. The association between allergic rhinitis and polymorphisms of C677T and A1298C for MTHFR gene was not statistically significant in patients compared with controls (p>0.05). There were no statistically significant differences between the patients and the control group in terms of serum vitamin b12, folate and homocysteine levels (p>0.05). We found no evidence for an association between allergic rhinitis and polymorphisms of C677T and A1298C for MTHFR gene in children. Further studies investigating the relationship between MTHFR polymorphism and AR are required. Copyright © 2014 SEICAP. Published by Elsevier Espana. All rights reserved.

  19. Fast identification of rubrene polymorphs by lattice phonon Raman microscopy

    NASA Astrophysics Data System (ADS)

    Socci, Joseph; Salzillo, Tommaso; Della Valle, Raffaele Guido; Venuti, Elisabetta; Brillante, Aldo

    2017-09-01

    Confocal Raman microscopy in the lattice phonon region has been used to study the polymorphism of the organic semiconductor 5,6,11,12-tetraphenyl-tetracene (rubrene). Following literature guidelines, crystals of rubrene have been prepared using a number of solution growth and vapour deposition methods, obtaining samples of different morphologies which could be related to the various polymorphs of this compound. The technique has enabled us an easy and non invasive identification of the three known polymorphs and of their phase homogeneity with a lateral spatial resolution below 1 μm.

  20. Prenatal diagnosis of polymorphic ventricular tachycardia using 64-channel magnetocardiography.

    PubMed

    Fukushima, Akimune; Nakai, Kenji; Matsumoto, Atsushi; Strasburger, Janette; Sugiyama, Toru

    2010-05-01

    We describe polymorphic ventricular tachycardia (VT) diagnosed using fetal magnetocardiography (FMCG). The fetus of a 33-year-old Japanese female at 24 weeks of pregnancy was diagnosed as bradycardia (60 beats/min) by fetal cardiotocography (CTG). Ultrasound findings indicated a diagnosis of an atrioventricular (AV) block involving extrasystole, but FMCG revealed a polymorphic VT followed by ventricular asystole. Standard ECG immediately after cesarean section at 37 weeks of pregnancy confirmed long QT syndrome followed by nonsustained polymorphic VT and an advanced AV block with wide QRS. Echocardiography demonstrated moderate left ventricular dysfunction in the neonate requiring implantation with a permanent pacemaker.

  1. CD24 Ala/Val polymorphism and multiple sclerosis.

    PubMed

    Goris, An; Maranian, Melanie; Walton, Amie; Yeo, Tai Wai; Ban, Maria; Gray, Julia; Dubois, Bénédicte; Compston, Alastair; Sawcer, Stephen

    2006-06-01

    CD24 is expressed on a broad range of cells in the immune and central nervous systems and appears to be required for development of experimental autoimmune encephalomyelitis in mice. Association of a CD24 Ala/Val coding polymorphism with susceptibility to and progression of multiple sclerosis was recently reported. We typed this coding polymorphism in a combined cohort of 1,180 cases and 1,168 unrelated and family-based controls from Belgium and the UK, but were unable to confirm either association. Since the CD24 gene is part of a segmental duplication, special care is required for the identification and genotyping of single nucleotide polymorphisms.

  2. Endometriosis and RAS system gene polymorphisms: the association of ACE A2350G polymorphism with endometriosis in Polish individuals.

    PubMed

    Kowalczyńska, Liliana J; Ferenc, Tomasz; Wojciechowski, Michał; Mordalska, Anna; Pogoda, Krzysztof; Malinowski, Andrzej

    2014-05-01

    To analyze the polymorphisms of angiotensin I converting enzyme (ACE) gene (insertion/deletion [I/D], A2350G) and angiotensin II type 1 receptor gene (A1166C) in women with endometriosis and to determine the correlation of the identified genotypes with the severity of the disease. Additionally, to estimate the prognostic value of the polymorphisms in patients with endometriosis treated due to infertility. The study group included 241 women, the control group (without endometriosis)-127. The molecular analysis was performed by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism technique. For I/D ACE and A1166C AT1 polymorphisms no significant differences were observed between the study and control groups and between the severity grades of the disease (p>0.05). For A2350G ACE polymorphism the frequency of genotypes for the study and control groups respectively was the following: AA-31.54%, AG-54.36%, GG-14.11% and AA-55.12%, AG-36.22%, GG-8.66% (x(2)=19.36, p<0.0001). Statistically significant differences were found between the frequency of A and G alleles between both groups (x(2)=15.16, p=0.0001), but not when individual grades of the disease severity were compared. There was no association between the investigated polymorphisms and the effect of infertility treatment. A2350G polymorphism (allele G, AG genotype) of ACE gene seems to be associated with the development of endometriosis.

  3. [Advances in the Association between Apolipoprotein (a) Gene Polymorphisms and Coronary Heart Disease].

    PubMed

    Zhu, Li; L, Zhan; Song, Yong-yan

    2015-08-01

    Human apolipoprotein (a) (LPA) gene is highly polymorphic, and the polymorphic loci on this gene include the Kringle 4 subtype 2(KIV-2) repeat polymorphism, the pentanucleotide repeat (TTTTA)n polymorphism, and a number of single nucleotide polymorphisms. KIV-2 repeat polymorphism was found to be significantly associated with coronary heart disease(CHD), and the reducing number of KIV-2 repeats is a risk factor for CHD. Both the increase and decrease of the pentanucleotide repeat(TTTTA)n polymorphism repeats are possibly associated with CHD risk. In single nucleotide polymorphisms loci, the rs10455872 and rs3798220 loci were widely reported to be associated with CHD, while other loci were less reported. The association between LPA polymorphisms and CHD may be mediated by either the elevation of plasma LPA level or the change of LPA subtypes. This article reviews the association between the LPA polymorphisms and CHD and the underlying mechanisms.

  4. Polymorphic microsatellite loci for the razor clam, Sinonovacula constricta.

    PubMed

    Ma, H-T; Jiang, H-B; Liu, X-Q; Wu, X-P; Wei, X-M

    2015-01-15

    The razor clam, Sinonovacula constricta, is an important commercial bivalve and a popular mollusca food in China. Twelve polymorphic microsatellite markers were isolated from the razor clam using a partial genomic library enriched for tandem repeat sequences of (CA)16, (GA)16. Polymorphisms of these loci were evaluated in a wild population of 30 individuals. The allele number of these polymorphic markers ranged from 5-15 per locus with an average of 9.333. Observed and expected heterozygosity values ranged from 0.192-1.000 and 0.219-0.906. Polymorphism information content ranged from 0.209-0.892 with an average of 0.704. Three loci significantly deviated from Hardy-Weinberg equilibrium after Bonferroni correction. No significant linkage disequilibrium was detected between these loci. This set of microsatellite loci are useful for genetic studies in S. constricta.

  5. Mitochondrial DNA polymorphisms/haplogroups in hereditary spastic paraplegia.

    PubMed

    Sánchez-Ferrero, Elena; Coto, Eliecer; Corao, Ana I; Díaz, Marta; Gámez, Josep; Esteban, Jesús; Gonzalo, Juan F; Pascual-Pascual, Samuel I; López De Munaín, Adolfo; Morís, Germán; Infante, Jon; Del Castillo, Emilia; Márquez, Celedonio; Alvarez, Victoria

    2012-02-01

    Mitochondrial dysfunction could contribute to the development of spastic paraplegia. Among others, two of the genes implicated in hereditary spastic paraplegia encoded mitochondrial proteins and some of the clinical features frequently found in these patients resemble those observed in patients with mitochondrial DNA (mtDNA) mutations. We investigated the association between common mtDNA polymorphisms and spastic paraplegia. The ten mtDNA polymorphisms that defined the common European haplogroups were determined in 424 patients, 19% with a complicated phenotype. A rare haplogroup was associated with the disease in patients without a SPG3A, SPG4, or SPG7 mutation. Allele 10398G was more frequent among patients with a pure versus complicated phenotype. This mtDNA polymorphism was previously associated with the risk of developing other neurodegenerative diseases. In conclusion, some mtDNA polymorphisms could contribute to the development of spastic paraplegia or act as modifiers of the phenotype.

  6. Lowest enthalpy polymorph of cold-compressed graphite phase.

    PubMed

    Li, Da; Bao, Kuo; Tian, Fubo; Zeng, Zhenwu; He, Zhi; Liu, Bingbing; Cui, Tian

    2012-04-07

    Based on an ab initio evolutionary algorithm, a novel carbon polymorph with an orthorhombic Cmcm symmetry is predicted, named as C carbon, which has the lowest enthalpy among the previously proposed cold-compressed graphite phases.

  7. Polymorphs of Serpentine: Identification by Means of Raman Spectroscopy

    NASA Astrophysics Data System (ADS)

    Petriglieri, J. R.; Bersani, D.; Salvioli-Mariani, E.; Mantovani, L.; Tribaudino, M.; Lottici, P. P.; Laporte-Magoni, C.

    2014-06-01

    Raman micro-mapping, based on the OH stretching bands, was successfully employed to identify the four main polymorphs of serpentine directly on cross-sections of rocks coming from the Koniambo massif (New Caledonia).

  8. [Blood polymorphism in the study of isolated communities].

    PubMed

    Fujiki, N; Hirayama, M; Nomura, M; Nakanaga, M; Mano, K

    1988-01-01

    Isolated communities offer a unique opportunity for the study of biological and social consequences of consanguinity and migration. The studies of genetic polymorphisms have contributed greatly, not only to knowledge of the genetic constitution of a given individual and population, but also to clarify either relationship between structure and function of polymorphic traits or the susceptibility to multifactorial diseases, in which interaction between the gene and environment cannot be ignored. For over 25 years, we have investigated the effect of consanguinity and genetic polymorphisms in 9 isolated communities in Western Japan. We reported here different values of gene frequency for each polymorphic trait, compared with the neighboring communities and described how we applied these data to clarification of the genetic constitution of isolated communities as well as of genetic susceptibility to some diseases.

  9. Chromosome Polymorphism in Microtus (Alexandromys) mujanensis (Arvicolinae, Rodentia).

    PubMed

    Lemskaya, Natalya A; Kartavtseva, Irina V; Rubtsova, Nadezhda V; Golenishchev, Fedor N; Sheremetyeva, Irina N; Graphodatsky, Alexander S

    2015-01-01

    The Muya Valley vole (Microtus mujanensis) has a constant diploid chromosome number of 2n = 38, but an unstable karyotype with polymorphic chromosome pairs. Here, we describe 4 karyotypic variants involving 2 polymorphic chromosome pairs, MMUJ8 and MMUJ14, in 6 animals from Buryatia using a combination of GTG-banding and chromosome painting with M. agrestis probes. We suggest that the polymorphic pairs MMUJ8 and MMUJ14 were formed through pericentric inversions that played a major role during karyotype evolution of the species. We also propose that the stable diploid number with some ongoing polymorphism in the number of chromosome arms indicates that this evolutionarily young endemic species of Russian Far East is on the way to karyotype and likely species stabilization.

  10. [Study of Chloroplast DNA Polymorphism in the Sunflower (Helianthus L.)].

    PubMed

    Markina, N V; Usatov, A V; Logacheva, M D; Azarin, K V; Gorbachenko, C F; Kornienko, I V; Gavrilova, V A; Tihobaeva, V E

    2015-08-01

    The polymorphism of microsatellite loci of chloroplast genome in six Helianthus species and 46 lines of cultivated sunflower H. annuus (17 CMS lines and 29 Rf-lines) were studied. The differences between species are confined to four SSR loci. Within cultivated forms of the sunflower H. annuus, the polymorphism is absent. A comparative analysis was performed on sequences of the cpDNA inbred line 3629, line 398941 of the wild sunflower, and the American line HA383 H. annuus. As a result, 52 polymorphic loci represented by 27 SSR and 25 SNP were found; they can be used for genotyping of H. annuus samples, including cultural varieties: twelve polymorphic positions, of which eight are SSR and four are SNP.

  11. Diabat Interpolation for Polymorph Free-Energy Differences.

    PubMed

    Kamat, Kartik; Peters, Baron

    2017-02-02

    Existing methods to compute free-energy differences between polymorphs use harmonic approximations, advanced non-Boltzmann bias sampling techniques, and/or multistage free-energy perturbations. This work demonstrates how Bennett's diabat interpolation method ( J. Comput. Phys. 1976, 22, 245 ) can be combined with energy gaps from lattice-switch Monte Carlo techniques ( Phys. Rev. E 2000, 61, 906 ) to swiftly estimate polymorph free-energy differences. The new method requires only two unbiased molecular dynamics simulations, one for each polymorph. To illustrate the new method, we compute the free-energy difference between face-centered cubic and body-centered cubic polymorphs for a Gaussian core solid. We discuss the justification for parabolic models of the free-energy diabats and similarities to methods that have been used in studies of electron transfer.

  12. No association between apolipoprotein E polymorphisms and recurrent pregnancy loss.

    PubMed

    Bianca, Sebastiano; Barrano, Barbara; Cutuli, Nunzio; Indaco, Lara; Cataliotti, Antonella; Milana, Gabriella; Barone, Chiara; Ettore, Giuseppe

    2010-01-01

    Our study does not support the reported association between APOE and recurrent pregnancy loss (RPL) than the clinical management of these patients should not be influenced by the presence or not of APO E polymorphisms.

  13. Mineralogy of Silica Polymorphs in Basaltic Clasts in Eucrites

    NASA Astrophysics Data System (ADS)

    Ono, H.; Takenouchi, A.; Mikouchi, T.

    2016-08-01

    We analyzed silica polymorphs in basaltic clasts in Y-75011, Pasamonte and Stannern eucrites. Cristobalite and quartz have been found, which suggests wide occurrence of hydrothermal activity throughout the crust of Vesta.

  14. Heme oxygenase-1 promoter polymorphisms and risk of spina bifida.

    PubMed

    Fujioka, Kazumichi; Yang, Wei; Wallenstein, Matthew B; Zhao, Hui; Wong, Ronald J; Stevenson, David K; Shaw, Gary M

    2015-09-01

    Spina bifida is the most common form of neural tube defects (NTDs). Etiologies of NTDs are multifactorial, and oxidative stress is believed to play a key role in NTD development. Heme oxygenase (HO), the rate-limiting enzyme in heme degradation, has multiple protective properties including mediating antioxidant processes, making it an ideal candidate for study. The inducible HO isoform (HO-1) has two functional genetic polymorphisms: (GT)n dinucleotide repeats and A(-413)T SNP (rs2071746), both of which can affect its promoter activity. However, no study has investigated a possible association between HO-1 genetic polymorphisms and risk of NTDs. This case-control study included 152 spina bifida cases (all myelomeningoceles) and 148 non-malformed controls obtained from the California Birth Defects Monitoring Program reflecting births during 1990 to 1999. Genetic polymorphisms were determined by polymerase chain reaction and amplified fragment length polymorphisms/restriction fragment length polymorphisms using genomic DNA extracted from archived newborn blood spots. Genotype and haplotype frequencies of two HO-1 promoter polymorphisms between cases and controls were compared. For (GT)n dinucleotide repeat lengths and the A(-413)T SNP, no significant differences in allele frequencies or genotypes were found. Linkage disequilibrium was observed between the HO-1 polymorphisms (D': 0.833); however, haplotype analyses did not show increased risk of spina bifida overall or by race/ethnicity. Although, an association was not found between HO-1 polymorphisms and risk of spina bifida, we speculate that the combined effect of low HO-1 expression and exposures to known environmental oxidative stressors (low folate status or diabetes), may overwhelm antioxidant defenses and increase risk of NTDs and warrants further study. © 2015 Wiley Periodicals, Inc.

  15. Posterior polymorphous dystrophy and keratoglobus in a child.

    PubMed

    Patel, Sangita P; Sajnani, Manoj M; Pineda, Roberto

    2011-01-01

    A 13-year-old boy presented with gradually progressive deterioration of vision in both eyes, bilateral photophobia, and regular headaches. Clinical examination, anterior segment findings, and specular microscopy findings were consistent with the diagnosis of posterior polymorphous dystrophy and keratoglobus. To the authors' knowledge, this is the first pediatric case and the second case overall of the simultaneous occurrence of posterior polymorphous dystrophy and keratoglobus.

  16. Highly polymorphic microsatellite markers for Radix balthica (Linnaeus 1758).

    PubMed

    Salinger, M; Pfenninger, M

    2009-07-01

    We present data for eight polymorphic microsatellite markers isolated from a microsatellite-enriched DNA library for the freshwater snail Radix balthica. Three of them were specific for R. balthica while five also amplified polymorphic products in two congeneric species. Test application on populations from all over the species range has shown that these loci are highly informative for analysing population structure and estimating migration rates. Observed deviations from Hardy-Weinberg equilibrium are attributed to a mixed mating system.

  17. Isotopically enriched polymorphs of dysprosium single molecule magnets.

    PubMed

    Kishi, Y; Pointillart, F; Lefeuvre, B; Riobé, F; Le Guennic, B; Golhen, S; Cador, O; Maury, O; Fujiwara, H; Ouahab, L

    2017-03-23

    A triclinic polymorph Dy(t) and a monoclinic polymorph Dy(m) of [Dy(tta)3(L)] with L = 4-[6-(1,3-benzothiazol-2-yl)pyridin-3-yl]-4',5'-bis(methylthio)tetrathiafulvene behave as Single-Molecule Magnets with hysteresis loops opened at zero field. Magnetic properties were enhanced through magnetic dilution and (164)Dy isotopic enrichment which definitively support the importance of isotopes for the control of quantum magnets.

  18. Identification of polymorphic inversions from genotypes

    PubMed Central

    2012-01-01

    Background Polymorphic inversions are a source of genetic variability with a direct impact on recombination frequencies. Given the difficulty of their experimental study, computational methods have been developed to infer their existence in a large number of individuals using genome-wide data of nucleotide variation. Methods based on haplotype tagging of known inversions attempt to classify individuals as having a normal or inverted allele. Other methods that measure differences between linkage disequilibrium attempt to identify regions with inversions but unable to classify subjects accurately, an essential requirement for association studies. Results We present a novel method to both identify polymorphic inversions from genome-wide genotype data and classify individuals as containing a normal or inverted allele. Our method, a generalization of a published method for haplotype data [1], utilizes linkage between groups of SNPs to partition a set of individuals into normal and inverted subpopulations. We employ a sliding window scan to identify regions likely to have an inversion, and accumulation of evidence from neighboring SNPs is used to accurately determine the inversion status of each subject. Further, our approach detects inversions directly from genotype data, thus increasing its usability to current genome-wide association studies (GWAS). Conclusions We demonstrate the accuracy of our method to detect inversions and classify individuals on principled-simulated genotypes, produced by the evolution of an inversion event within a coalescent model [2]. We applied our method to real genotype data from HapMap Phase III to characterize the inversion status of two known inversions within the regions 17q21 and 8p23 across 1184 individuals. Finally, we scan the full genomes of the European Origin (CEU) and Yoruba (YRI) HapMap samples. We find population-based evidence for 9 out of 15 well-established autosomic inversions, and for 52 regions previously predicted by

  19. Hydrogen chemisorption on gallium oxide polymorphs.

    PubMed

    Collins, Sebastián E; Baltanás, Miguel A; Bonivardi, Adrian L

    2005-02-01

    The chemisorption of H(2) over a set of gallia polymorphs (alpha-, beta-, and gamma-Ga(2)O(3)) has been studied by temperature-programmed adsorption equilibrium and desorption (TPA and TPD, respectively) experiments, using in situ transmission infrared spectroscopy. Upon heating the gallium oxides above 500 K in 101.3 kPa of H(2), two overlapped infrared signals developed. The 2003- and 1980-cm(-1) bands were assigned to the stretching frequencies of H bonded to coordinatively unsaturated (cus) gallium cations in tetrahedral and octahedral positions [nu(Ga(t)-H) and nu(Ga(o)-H), respectively]. Irrespective to the gallium cation geometrical environment, (i) a linear relationship between the integrated intensity of the whole nu(Ga-H) infrared band versus the Brunauer-Emmett-Teller surface area of the gallia was found and (ii) TPA and TPD results revealed that molecular hydrogen is dissociatively chemisorbed on any bulk gallium oxide polymorph following two reaction pathways. An endothermal, homolytic dissociation occurs over surface cus-gallium sites at T > 450 K, giving rise to Ga-H(I) bonds. The heat and entropy of this type I hydrogen adsorption were determined by the Langmuir's adsorption model as Deltah(I) = 155 +/- 25 kJ mol(-1) and Deltas(I) = 0.27 +/- 0.11 kJ mol(-1) K(-1). In addition, another exothermic, heterolytic adsorption sets in already in the low-temperature region. This type of hydrogen chemisorption involves surface Ga-O-Ga species, originating GaO-H and Ga-H(II) bonds which can only be removed from the gallia surface after heating under evacuation at T > 650 K. The measured desorption energy of this last, second-order process was equal to 77 +/- 10 kJ mol(-1). The potential of the H(2) chemisorption as a tool to measure or estimate the specific surface area of gallia and to discern the nature and proportion of gallium cation coordination sites on the surface of bulk gallium oxides is also analyzed.

  20. Computational Approach for Epitaxial Polymorph Stabilization through Substrate Selection

    SciTech Connect

    Ding, Hong; Dwaraknath, Shyam S.; Garten, Lauren; Ndione, Paul; Ginley, David; Persson, Kristin A.

    2016-05-25

    With the ultimate goal of finding new polymorphs through targeted synthesis conditions and techniques, we outline a computational framework to select optimal substrates for epitaxial growth using first principle calculations of formation energies, elastic strain energy, and topological information. To demonstrate the approach, we study the stabilization of metastable VO2 compounds which provides a rich chemical and structural polymorph space. We find that common polymorph statistics, lattice matching, and energy above hull considerations recommends homostructural growth on TiO2 substrates, where the VO2 brookite phase would be preferentially grown on the a-c TiO2 brookite plane while the columbite and anatase structures favor the a-b plane on the respective TiO2 phases. Overall, we find that a model which incorporates a geometric unit cell area matching between the substrate and the target film as well as the resulting strain energy density of the film provide qualitative agreement with experimental observations for the heterostructural growth of known VO2 polymorphs: rutile, A and B phases. The minimal interfacial geometry matching and estimated strain energy criteria provide several suggestions for substrates and substrate-film orientations for the heterostructural growth of the hitherto hypothetical anatase, brookite, and columbite polymorphs. These criteria serve as a preliminary guidance for the experimental efforts stabilizing new materials and/or polymorphs through epitaxy. The current screening algorithm is being integrated within the Materials Project online framework and data and hence publicly available.

  1. Identification of conserved and polymorphic STRs for personal genomes

    PubMed Central

    2014-01-01

    Background Short tandem repeats (STRs) are abundant in human genomes. Numerous STRs have been shown to be associated with genetic diseases and gene regulatory functions, and have been selected as genetic markers for evolutionary and forensic analyses. High-throughput next generation sequencers have fostered new cutting-edge computing techniques for genome-scale analyses, and cross-genome comparisons have facilitated the efficient identification of polymorphic STR markers for various applications. Results An automated and efficient system for detecting human polymorphic STRs at the genome scale is proposed in this study. Assembled contigs from next generation sequencing data were aligned and calibrated according to selected reference sequences. To verify identified polymorphic STRs, human genomes from the 1000 Genomes Project were employed for comprehensive analyses, and STR markers from the Combined DNA Index System (CODIS) and disease-related STR motifs were also applied as cases for evaluation. In addition, we analyzed STR variations for highly conserved homologous genes and human-unique genes. In total 477 polymorphic STRs were identified from 492 human-unique genes, among which 26 STRs were retrieved and clustered into three different groups for efficient comparison. Conclusions We have developed an online system that efficiently identifies polymorphic STRs and provides novel distinguishable STR biomarkers for different levels of specificity. Candidate polymorphic STRs within a personal genome could be easily retrieved and compared to the constructed STR profile through query keywords, gene names, or assembled contigs. PMID:25560225

  2. Computational Approach for Epitaxial Polymorph Stabilization through Substrate Selection

    DOE PAGES

    Ding, Hong; Dwaraknath, Shyam S.; Garten, Lauren; ...

    2016-05-04

    With the ultimate goal of finding new polymorphs through targeted synthesis conditions and techniques, we outline a computational framework to select optimal substrates for epitaxial growth using first principle calculations of formation energies, elastic strain energy, and topological information. To demonstrate the approach, we study the stabilization of metastable VO 2 compounds which provides a rich chemical and structural polymorph space. Here, we find that common polymorph statistics, lattice matching, and energy above hull considerations recommends homostructural growth on TiO 2 substrates, where the VO 2 brookite phase would be preferentially grown on the a-c TiO 2 brookite plane whilemore » the columbite and anatase structures favor the a-b plane on the respective TiO 2 phases. Overall, we find that a model which incorporates a geometric unit cell area matching between the substrate and the target film as well as the resulting strain energy density of the film provide qualitative agreement with experimental observations for the heterostructural growth of known VO 2 polymorphs: rutile, A and B phases. The minimal interfacial geometry matching and estimated strain energy criteria provide several suggestions for substrates and substrate-film orientations for the heterostructural growth of the hitherto hypothetical anatase, brookite, and columbite polymorphs. Our criteria serve as a preliminary guidance for the experimental efforts stabilizing new materials and/or polymorphs through epitaxy. The current screening algorithm is being integrated within the Materials Project online framework and data and hence publicly available.« less

  3. Major histocompatibility complex class I polymorphism in Asiatic lions.

    PubMed

    Sachdev, M; Sankaranarayanan, R; Reddanna, P; Thangaraj, K; Singh, L

    2005-07-01

    Asiatic lions (Panthera leo persica), whose only natural habitat in the world is the Gir forest sanctuary of Gujarat State in India, are highly endangered and are considered to be highly inbred with narrow genetic diversity. An objective assessment of genetic diversity in their immune loci will help in assessing their survivability and may provide vital clues in designing strategies for their scientific management and conservation. We analyzed the comparative sequence polymorphism at exon 2 and exon 3 of major histocompatibility complex (MHC) class I in three groups of lions, i.e. wild Asiatic (from Gir forest), captive-bred Asiatic (from zoological parks in India), and Afro-Asiatic hybrid groups (from zoological parks in India) through polymorphism chain reaction-assisted sequence-based typing. The two exons were amplified, cloned, sequenced, and analyzed for polymorphism at nucleotide and putative translated product level. The analysis revealed extensive sequence polymorphism not only between clones derived from different lions but also the clones derived from a single lion. Furthermore, the wild Asiatic lions of Gir forest exhibited abundant sequence polymorphism at MHC class I comparable with that of Afro-Asiatic hybrid lions and significantly higher than that of captive-bred Asiatic lions. We hypothesize that Asiatic lions of Gir forest are not highly inbred as thought earlier and they possess abundant sequence polymorphism at MHC class I loci. During this study, 52 new sequences of the multigene MHC class I family were also identified among Asiatic lions.

  4. Polymorphism of CAG repeats in androgen receptor of carnivores.

    PubMed

    Wang, Qin; Zhang, Xiuyue; Wang, Xiaofang; Zeng, Bo; Jia, Xiaodong; Hou, Rong; Yue, Bisong

    2012-03-01

    Androgen effect is mediated by the androgen receptor (AR). The polymorphism of CAG triplet repeat (polyCAG), in the N-terminal transactivation domain of the AR protein, has been involved either in endocrine or neurological disorders in human. We obtained partial sequence of AR exon 1 in 10 carnivore species. In most carnivore species, polyglutamine length polymorphism presented in all three CAG repeat regions of AR, in contrast, only CAG-I site polymorphism presented in primate species, and CAG-I and CAG-III sites polymorphism presented in Canidae. Therefore, studies focusing on disease-associated polymorphism of poly(CAG) in carnivore species AR should investigate all three CAG repeats sites, and should not only consider CAG-I sites as the human disease studies. The trinucleotide repeat length in carnivore AR exon 1 had undergone from expansions to contractions during carnivores evolution, unlike a linear increase in primate species. Furthermore, the polymorphisms of the triplet-repeats in the same tissue (somatic mosaicism) were demonstrated in Moutain weasel, Eurasian lynx, Clouded leopard, Chinese tiger, Black leopard and Leopard AR. And, the abnormal stop codon was found in the exon 1 of three carnivore species AR (Moutain weasel, Eurasian lynx and Black leopard). It seemed to have a high frequency presence of tissue-specific somatic in carnivores AR genes. Thus the in vivo mechanism leading to such highly variable phenotypes of the described mutations, and their impact on these animals, are worthwhile to be further elucidated.

  5. XRCC1 gene polymorphisms and risk of ameloblastoma.

    PubMed

    Yanatatsaneejit, Pattamawadee; Boonsuwan, Titiporn; Mutirangura, Apiwat; Kitkumthorn, Nakarin

    2013-06-01

    Ameloblastoma is a common benign odontogenic tumour with inherently aggressive behaviour. Genetic susceptibility of single nucleotide polymorphism (SNP) can likely predict ameloblastoma at risk patients but this data remains limited. Here, we studied XRCC1 polymorphism as a risk factor for ameloblastoma. Eighty-two ameloblastoma samples and blood from 140 healthy controls were used to perform polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for XRCC1 at codons 194, 280 and 399, and confirmed by sequence analysis. Compare to healthy control, a significant increase was noted in the occurrence of polymorphism at codon 194 and 399 in ameloblastoma patients. At codon 194, tryptophan encoded by T, was the susceptibility allele showed an ODD ratio of (95% CI)=1.62 (1.05-2.48), p=0.027. At codon 399, glycine encoded by A was the susceptibility allele showing ODD ratio of (95% CI)=1.83 (1.19-2.84), p=0.005. Moreover at codon 399, we found AG as the susceptibility genotype (2.06 (1.14-3.72), p=0.015). However, we did not find any significant increase in polymorphic occurrence in ameloblastoma patients at codon 280. For haplotype analysis of 3 codons, we found GGC as protective haplotype, and AGT as the risk haplotype. Our data suggest that polymorphism at codons 194 and 399, likely contributes to the risk of developing ameloblastoma. Copyright © 2012 Elsevier Ltd. All rights reserved.

  6. Effect of Cytokine Signaling 3 Gene Polymorphisms in Childhood Obesity

    PubMed Central

    Boyraz, Mehmet; Yeşilkaya, Ediz; Ezgü, Fatih; Bideci, Aysun; Doğan, Haldun; Ulucan, Korkut; Cinaz, Peyami

    2016-01-01

    Objective: Although polymorphisms in suppressor of cytokine signaling 3 (SOCS3) was reported to be related to obesity, Metabolic syndrome (MS), and type 2 diabetes mellitus in various adult studies, there is a lack of data in children. In this study, we examined eight reported polymorphisms of SOCS3 in obese Turkish children and adolescent with and without MS and compared the results with that of controls. Methods: One hundred and forty eight obese and 63 age- and sex-matched control subjects were enrolled in the study. Obesity classification was carried out according to body mass index. World Health Organization and National Cholesterol Education Program criteria were used for the diagnosis of MS. Genotyping procedure was carried out by polymerase chain reaction and Sanger sequencing protocol. Results: The frequency of rs2280148 polymorphism was significantly higher in obese subjects with MS than in the control group, whereas the frequency of rs8064821 polymorphism was significantly higher in obese subjects with MS than in obese children without MS. Conclusion: The significant associations of certain SOCS3 polymorphisms with obesity parameters in both MS and MS -related insulin resistance, hypertension, and fatty liver suggest that polymorphisms in this gene may play a role in the pathogenesis of MS and also that they can be potentially used as a marker for attenuated or aggressive disease. PMID:27611604

  7. Epitaxial stabilization and phase instability of VO2 polymorphs

    DOE PAGES

    Lee, Shinbuhm; Ivanov, Ilia N.; Keum, Jong K.; ...

    2016-01-20

    The VO2 polymorphs, i.e., VO2(A), VO2(B), VO2(M1) and VO2(R), have a wide spectrum of functionalities useful for many potential applications in information and energy technologies. However, synthesis of phase pure materials, especially in thin film forms, has been a challenging task due to the fact that the VO2 polymorphs are closely related to each other in a thermodynamic framework. Here, we report epitaxial stabilization of the VO2 polymorphs to synthesize high quality single crystalline thin films and study the phase stability of these metastable materials. We selectively deposit all the phases on various perovskite substrates with different crystallographic orientations. Bymore » investigating the phase instability, phonon modes and transport behaviours, not only do we find distinctively contrasting physical properties of the VO2 polymorphs, but that the polymorphs can be on the verge of phase transitions when heated as low as ~400 °C. In conclusion, our successful epitaxy of both VO2(A) and VO2(B) phases, which are rarely studied due to the lack of phase pure materials, will open the door to the fundamental studies of VO2 polymorphs for potential applications in advanced electronic and energy devices.« less

  8. MTHFR Gene C677T Polymorphism in Autism Spectrum Disorders

    PubMed Central

    Oztop, Didem Behice; Ozkul, Yusuf

    2014-01-01

    Aim. Autism is a subgroup of autism spectrum disorders, classified as a heterogeneous neurodevelopmental disorder and symptoms occur in the first three years of life. The etiology of autism is largely unknown, but it has been accepted that genetic and environmental factors may both be responsible for the disease. Recent studies have revealed that the genes involved in the folate/homocysteine pathway may be risk factors for autistic children. In particular, C677T polymorphism in the MTHFR gene as a possible risk factor for autism is still controversial. We aimed to investigate the possible effect of C677T polymorphism in a Turkish cohort. Methods. Autism patients were diagnosed by child psychiatrists according to DSM-IV and DSM-V criteria. A total of 98 children diagnosed as autistic and 70 age and sex-matched children who are nonautistic were tested for C677T polymorphism. This polymorphism was studied by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Results. MTHFR 677T-allele frequency was found to be higher in autistic children compared with nonautistic children (29% versus 24%), but it was not found statistically significant. Conclusions. We conclude that other MTHFR polymorphisms such as A1298C or other folate/homocysteine pathway genes may be studied to show their possible role in autism. PMID:25431675

  9. Epitaxial stabilization and phase instability of VO2 polymorphs

    PubMed Central

    Lee, Shinbuhm; Ivanov, Ilia N.; Keum, Jong K.; Lee, Ho Nyung

    2016-01-01

    The VO2 polymorphs, i.e., VO2(A), VO2(B), VO2(M1) and VO2(R), have a wide spectrum of functionalities useful for many potential applications in information and energy technologies. However, synthesis of phase pure materials, especially in thin film forms, has been a challenging task due to the fact that the VO2 polymorphs are closely related to each other in a thermodynamic framework. Here, we report epitaxial stabilization of the VO2 polymorphs to synthesize high quality single crystalline thin films and study the phase stability of these metastable materials. We selectively deposit all the phases on various perovskite substrates with different crystallographic orientations. By investigating the phase instability, phonon modes and transport behaviours, not only do we find distinctively contrasting physical properties of the VO2 polymorphs, but that the polymorphs can be on the verge of phase transitions when heated as low as ~400 °C. Our successful epitaxy of both VO2(A) and VO2(B) phases, which are rarely studied due to the lack of phase pure materials, will open the door to the fundamental studies of VO2 polymorphs for potential applications in advanced electronic and energy devices. PMID:26787259

  10. Color polymorphism in an aphid is maintained by attending ants

    PubMed Central

    Watanabe, Saori; Murakami, Taiga; Yoshimura, Jin; Hasegawa, Eisuke

    2016-01-01

    The study of polymorphisms is particularly informative for enhancing our understanding of phenotypic and genetic diversity. The persistence of polymorphism in a population is generally explained by balancing selection. Color polymorphisms that are often found in many insects and arthropods are prime examples of the maintenance of polymorphisms via balancing selection. In some aphids, color morphs are maintained through frequency-dependent predation by two predatory insects. However, the presence of color polymorphism in ant-attended aphids cannot be explained by traditional balancing selection because these aphids are free from predation. We examined the selective advantages of the existence of two color (red and green) morphs in the ant-attended aphid, Macrosiphoniella yomogicola, in fields. We measured the degree of ant attendance on aphid colonies with different proportions of color morphs. The results show that the ants strongly favor aphid colonies with intermediate proportions of the two color morphs. The relationship between the degree of ant attendance and the proportion of color morphs in the field is convex when aphid colony size and ant colony size are controlled. This function has a peak of approximately 65% of green morphs in a colony. This system represents the first case of a balancing polymorphism that is not maintained by opposing factors but by a symbiotic relationship. PMID:27617289

  11. Gene Polymorphism Studies in a Teaching Laboratory

    NASA Astrophysics Data System (ADS)

    Shultz, Jeffry

    2009-02-01

    I present a laboratory procedure for illustrating transcription, post-transcriptional modification, gene conservation, and comparative genetics for use in undergraduate biology education. Students are individually assigned genes in a targeted biochemical pathway, for which they design and test polymerase chain reaction (PCR) primers. In this example, students used genes annotated for the steroid biosynthesis pathway in soybean. The authoritative Kyoto encyclopedia of genes and genomes (KEGG) interactive database and other online resources were used to design primers based first on soybean expressed sequence tags (ESTs), then on ESTs from an alternate organism if soybean sequence was unavailable. Students designed a total of 50 gene-based primer pairs (37 soybean, 13 alternative) and tested these for polymorphism state and similarity between two soybean and two pea lines. Student assessment was based on acquisition of laboratory skills and successful project completion. This simple procedure illustrates conservation of genes and is not limited to soybean or pea. Cost per student estimates are included, along with a detailed protocol and flow diagram of the procedure.

  12. Polymorphic Admixture Typing in Human Ethnic Populations

    PubMed Central

    Dean, Michael; Stephens, J. Claiborne; Winkler, Cheryl; Lomb, Deborah A.; Ramsburg, Mark; Boaze, Raleigh; Stewart, Claudia; Charbonneau, Lauren; Goldman, David; Albaugh, Bernard J.; Goedert, James J.; Beasley, R. Palmer; Hwang, Lu-Yu; Buchbinder, Susan; Weedon, Michael; Johnson, Patricia A.; Eichelberger, Mary; O'Brien, Stephen J.

    1994-01-01

    A panel of 257 RFLP loci was selected on the basis of high heterozygosity in Caucasian DNA surveys and equivalent spacing throughout the human genome. Probes from each locus were used in a Southern blot survey of allele frequency distribution for four human ethnic groups: Caucasian, African American, Asian (Chinese), and American Indian (Cheyenne). Nearly all RFLP loci were polymorphic in each group, albeit with a broad range of differing allele frequencies (δ). The distribution of frequency differences (δ values) was used for three purposes: (1) to provide estimates for genetic distance (differentiation) among these ethnic groups, (2) to revisit with a large data set the proportion of human genetic variation attributable to differentiation within ethnic groups, and (3) to identify loci with high δ values between recently admixed populations of use in mapping by admixture linkage disequilibrium (MALD). Although most markers display significant allele frequency differences between ethnic groups, the overall genetic distances between ethnic groups were small (.066–.098), and <10% of the measured overall molecular genetic diversity in these human samples can be attributed to “racial” differentiation. The median δ values for pairwise comparisons between groups fell between .15 and .20, permitting identification of highly informative RFLP loci for MALD disease association studies. PMID:7942857

  13. Dispersal Polymorphisms in Invasive Fire Ants.

    PubMed

    Helms, Jackson A; Godfrey, Aaron

    2016-01-01

    In the Found or Fly (FoF) hypothesis ant queens experience reproduction-dispersal tradeoffs such that queens with heavier abdomens are better at founding colonies but are worse flyers. We tested predictions of FoF in two globally invasive fire ants, Solenopsis geminata (Fabricius, 1804) and S. invicta (Buren, 1972). Colonies of these species may produce two different monogyne queen types-claustral queens with heavy abdomens that found colonies independently, and parasitic queens with small abdomens that enter conspecific nests. Claustral and parasitic queens were similarly sized, but the abdomens of claustral queens weighed twice as much as those of their parasitic counterparts. Their heavier abdomens adversely impacted morphological predictors of flight ability, resulting in 32-38% lower flight muscle ratios, 55-63% higher wing loading, and 32-33% higher abdomen drag. In lab experiments maximum flight durations in claustral S. invicta queens decreased by about 18 minutes for every milligram of abdomen mass. Combining our results into a simple fitness tradeoff model, we calculated that an average parasitic S. invicta queen could produce only 1/3 as many worker offspring as a claustral queen, but could fly 4 times as long and have a 17- to 36-fold larger potential colonization area. Investigations of dispersal polymorphisms and their associated tradeoffs promises to shed light on range expansions in invasive species, the evolution of alternative reproductive strategies, and the selective forces driving the recurrent evolution of parasitism in ants.

  14. Dispersal Polymorphisms in Invasive Fire Ants

    PubMed Central

    Helms, Jackson A.; Godfrey, Aaron

    2016-01-01

    In the Found or Fly (FoF) hypothesis ant queens experience reproduction-dispersal tradeoffs such that queens with heavier abdomens are better at founding colonies but are worse flyers. We tested predictions of FoF in two globally invasive fire ants, Solenopsis geminata (Fabricius, 1804) and S. invicta (Buren, 1972). Colonies of these species may produce two different monogyne queen types—claustral queens with heavy abdomens that found colonies independently, and parasitic queens with small abdomens that enter conspecific nests. Claustral and parasitic queens were similarly sized, but the abdomens of claustral queens weighed twice as much as those of their parasitic counterparts. Their heavier abdomens adversely impacted morphological predictors of flight ability, resulting in 32–38% lower flight muscle ratios, 55–63% higher wing loading, and 32–33% higher abdomen drag. In lab experiments maximum flight durations in claustral S. invicta queens decreased by about 18 minutes for every milligram of abdomen mass. Combining our results into a simple fitness tradeoff model, we calculated that an average parasitic S. invicta queen could produce only 1/3 as many worker offspring as a claustral queen, but could fly 4 times as long and have a 17- to 36-fold larger potential colonization area. Investigations of dispersal polymorphisms and their associated tradeoffs promises to shed light on range expansions in invasive species, the evolution of alternative reproductive strategies, and the selective forces driving the recurrent evolution of parasitism in ants. PMID:27082115

  15. Apolipoprotein E Polymorphism in Tuberculosis Patients

    NASA Astrophysics Data System (ADS)

    Naserpour Farivar, Taghi; Sharifi Moud, Batool; Sargazi, Mansur; Moeenrezakhanlou, Alireza

    In this study, we aimed to determine the significance of association between Tuberculosis and apolipoprotein E polymorphism. The apolipoprotein E genotypes were assayed in 250 tuberculosis patients by polymerase chain reaction followed by enzymatic digestion with Hha I. The results were compared with the results of the same experiments on 250 sex and age matched control peoples. Present results showed that in studied populations, prevalence of E4 genotype was lower in controls than in patients (8 v. 13.2%; OR = 1.75, p<0.05) and prevalence of E3 genotype was high in controls than in patients (86 v.51%; OR = 0.17, p<0.05). Statistically significant difference was found between patients and controls with respect to ɛ2 allele frequencies, while ɛ2 allele frequency was found to be much less prevalent in controls (6%) than in patients (35.8%; OR = 8.72, p<0.05). Also, our study revealed that there is an association between apolipoprotein E genotypes and amplitude to tuberculosis in studied populations. However, large population-based studies are needed to understand the exact role played by the locus in causing the condition.

  16. Insertional Polymorphisms of Endogenous Feline Leukemia Viruses

    PubMed Central

    Roca, Alfred L.; Nash, William G.; Menninger, Joan C.; Murphy, William J.; O'Brien, Stephen J.

    2005-01-01

    The number, chromosomal distribution, and insertional polymorphisms of endogenous feline leukemia viruses (enFeLVs) were determined in four domestic cats (Burmese, Egyptian Mau, Persian, and nonbreed) using fluorescent in situ hybridization and radiation hybrid mapping. Twenty-nine distinct enFeLV loci were detected across 12 of the 18 autosomes. Each cat carried enFeLV at only 9 to 16 of the loci, and many loci were heterozygous for presence of the provirus. Thus, an average of 19 autosomal copies of enFeLV were present per cat diploid genome. Only five of the autosomal enFeLV sites were present in all four cats, and at only one autosomal locus, B4q15, was enFeLV present in both homologues of all four cats. A single enFeLV occurred in the X chromosome of the Burmese cat, while three to five enFeLV proviruses occurred in each Y chromosome. The X chromosome and nine autosomal enFeLV loci were telomeric, suggesting that ectopic recombination between nonhomologous subtelomeres may contribute to enFeLV distribution. Since endogenous FeLVs may affect the infectiousness or pathogenicity of exogenous FeLVs, genomic variation in enFeLVs represents a candidate for genetic influences on FeLV leukemogenesis in cats. PMID:15767400

  17. Intrahaplotype polymorphism at the Brassica S locus.

    PubMed Central

    Miege, C; Ruffio-Châble, V; Schierup, M H; Cabrillac, D; Dumas, C; Gaude, T; Cock, J M

    2001-01-01

    The S locus receptor kinase and the S locus glycoproteins are encoded by genes located at the S locus, which controls the self-incompatibility response in Brassica. In class II self-incompatibility haplotypes, S locus glycoproteins can be encoded by two different genes, SLGA and SLGB. In this study, we analyzed the sequences of these genes in several independently isolated plants, all of which carry the same S haplotype (S(2)). Two groups of S(2) haplotypes could be distinguished depending on whether SRK was associated with SLGA or SLGB. Surprisingly, SRK alleles from the two groups could be distinguished at the sequence level, suggesting that recombination rarely occurs between haplotypes of the two groups. An analysis of the distribution of polymorphisms along the S domain of SRK showed that hypervariable domains I and II tend to be conserved within haplotypes but to be highly variable between haplotypes. This is consistent with these domains playing a role in the determination of haplotype specificity. PMID:11606555

  18. A stable genetic polymorphism underpinning microbial syntrophy

    PubMed Central

    Großkopf, Tobias; Zenobi, Simone; Alston, Mark; Folkes, Leighton; Swarbreck, David; Soyer, Orkun S

    2016-01-01

    Syntrophies are metabolic cooperations, whereby two organisms co-metabolize a substrate in an interdependent manner. Many of the observed natural syntrophic interactions are mandatory in the absence of strong electron acceptors, such that one species in the syntrophy has to assume the role of electron sink for the other. While this presents an ecological setting for syntrophy to be beneficial, the potential genetic drivers of syntrophy remain unknown to date. Here, we show that the syntrophic sulfate-reducing species Desulfovibrio vulgaris displays a stable genetic polymorphism, where only a specific genotype is able to engage in syntrophy with the hydrogenotrophic methanogen Methanococcus maripaludis. This 'syntrophic' genotype is characterized by two genetic alterations, one of which is an in-frame deletion in the gene encoding for the ion-translocating subunit cooK of the membrane-bound COO hydrogenase. We show that this genotype presents a specific physiology, in which reshaping of energy conservation in the lactate oxidation pathway enables it to produce sufficient intermediate hydrogen for sustained M. maripaludis growth and thus, syntrophy. To our knowledge, these findings provide for the first time a genetic basis for syntrophy in nature and bring us closer to the rational engineering of syntrophy in synthetic microbial communities. PMID:27258948

  19. Kinetic Trapping of Metastable Amino Acid Polymorphs

    NASA Astrophysics Data System (ADS)

    Simpson, Garth

    2014-06-01

    Second harmonic generation (SHG) microscopy was integrated with synchrotron X-ray diffraction (XRD) to test the Ostwald Rule of Stages, in which is hypothesized that crystals dynamically transition through metastable polymorphs before settling on the most thermodynamically favored form. The presence or absence of metastable forms has historically been challenging to probe due to the stochastic randomness of crystal nucleation coupled with the relatively short time-frame over which the metastable forms may survive. In this work, inkjet printing of a racemic amino acid solutions results in rapid solvent evaporation, placing crystallization under kinetic rather than thermodynamic control. SHG microscopy is used to rapidly and selectively identify the positions of metastable crystal forms. Coupling this measurement with synchrotron XRD allows diffraction analysis to be performed on individual inkjet printed dots of only a few pg of total material, prepared from single 1 pL droplets. In studies of amino acids, we have shown that the homochiral crystals emerge when printed, while those same solutions exclusively generate the racemic co-crystals upon slow solvent evaporation.

  20. Epitaxial Retrieval of a Disappearing Polymorph

    PubMed Central

    2014-01-01

    Recrystallization of [PdCl2([9]aneS2O)] ([9]aneS2O = 1-oxa-4,7-dithiacyclononane), 1, and [PtCl2([9]aneS2O)], 2, by diffusion of Et2O vapor into solutions of the complexes in MeNO2 yielded three phases of 1 and two phases of 2. The known phase of 1, herein designated α-1, was obtained under ambient conditions. A second phase, designated β-1, was initially also obtained by this method; however, following the advent of a third phase, γ-1, all subsequent efforts over a period of a year to crystallize β-1 yielded either γ-1, obtained by carrying out the recrystallization at elevated temperature, or α-1, commonly found throughout the study. This persistent absence of a phase which could initially be crystallized with ease led us to the conclusion that β-1 was an example of a “disappearing polymorph”. The first phase obtained of 2, designated α-2, was obtained by recrystallization under ambient conditions and is isomorphous and isostructural with α-1. The second phase β-2 was obtained by slight elevation of the recrystallization temperature and was found to be isomorphous and isostructural with β-1. Subsequently, β-2 was used to seed the growth of the disappearing polymorph β-1. No third phase of 2 (γ-2) has been isolated thus far. PMID:25598741

  1. Cell line fingerprinting using retroelement insertion polymorphism.

    PubMed

    Ustyugova, Svetlana V; Amosova, Anna L; Lebedev, Yuri B; Sverdlov, Eugene D

    2005-04-01

    Human cell lines are an indispensable tool for functional studies of living entities in their numerous manifestations starting with integral complex systems such as signal pathways and networks, regulation of gene ensembles, epigenetic factors, and finishing with pathological changes and impact of artificially introduced elements, such as various transgenes, on the behavior of the cell. Therefore, it is highly desirable to have reliable cell line identification techniques to make sure that the cell lines to be used in experiments are exactly what is expected. To this end, we developed a set of informative markers based on insertion polymorphism of human retroelements (REs). The set includes 47 pairs of PCR primers corresponding to introns of the human genes with dimorphic LINE1 (L1) and Alu insertions. Using locus-specific PCR assays, we have genotyped 10 human cell lines of various origins. For each of these cell lines, characteristic fingerprints were obtained. An estimated probability that two different cell lines possess the same marker genotype is about 10-18. Therefore, the proposed set of markers provides a reliable tool for cell line identification.

  2. Polymorphism of the ovine calpastatin gene.

    PubMed

    Zhou, H; Hickford, J G H; Gong, H

    2007-06-01

    Calpastatin is a specific inhibitor of calpains and has been implicated in the regulation of beef tenderization. Variation in the ovine calpastatin gene (CAST) was investigated by amplification of a fragment containing the entire exon 6 using polymerase chain reaction (PCR), followed by single-strand conformational polymorphism (PCR-SSCP) analysis and DNA sequencing. Five novel SSCP patterns, representing five different sequences, were identified. Either one or two different sequences were detected in individual sheep and all the sequences identified shared high homology to the published ovine and bovine CAST sequences, suggesting that these sequences represent allelic variants of the ovine CAST gene. Sequence analysis revealed a non-synonymous amino acid variation in exon 6, which would result in a Gln/Leu substitution in Domain L of the mature protein. Considerable variation was detected in an intron region close to the acceptor splice site, with both sequence variation and length variation being observed in this region. Variation detected here might have an impact on both the function and expression of ovine calpastatin.

  3. [Identification of single nucleotide polymorphisms in centenarians].

    PubMed

    Gambini, Juan; Gimeno-Mallench, Lucía; Inglés, Marta; Olaso, Gloria; Abdelaziz, Kheira Mohamed; Avellana, Juan Antonio; Belenguer, Ángel; Cruz, Raquel; Mas-Bargues, Cristina; Borras, Consuelo; Viña, José

    2016-01-01

    Longevity is determined by genetic and external factors, such as nutritional, environmental, social, etc. Nevertheless, when living conditions are optimal, longevity is determined by genetic variations between individuals. In a same population, with relative genotypic homogeneity, subtle changes in the DNA sequence affecting a single nucleotide can be observed. These changes, called single nucleotide polymorphisms (SNP) are present in 1-5% of the population. A total of 92 subjects were recruited, including 28 centenarians and 64 controls, in order to find SNP that maybe implicated in the extreme longevity, as in the centenarians. Blood samples were collected to isolate and amplify the DNA in order to perform the analysis of SPN by Axiom™ Genotyping of Affymetrix technology. Statistical analyses were performed using the Plink program and libraries SNPassoc and skatMeta. Our results show 12 mutations with a p<.001, where 5 of these (DACH1, LOC91948, BTB16, NFIL3 y HDAC4) have regulatory functions of the expressions of others genes. Therefore, these results suggest that the genetic variation between centenarians and controls occurs in five genes that are involved in the regulation of gene expression to adapt to environmental changes better than controls. Copyright © 2015 SEGG. Published by Elsevier Espana. All rights reserved.

  4. A second triclinic polymorph of azimsulfuron.

    PubMed

    Kwon, Eunjin; Kim, Jineun; Park, Hyunjin; Kim, Tae Ho

    2016-10-01

    The title compound, C13H16N10O5S (systematic name: 1-(4,6-di-meth-oxypyrimidin-2-yl)-3-{[1-methyl-4-(2-methyl-2H-tetra-zol-5-yl)pyrazol-5-yl]sulfonyl}urea), is a second triclinic polymorph of this crystal [for the other, see: Jeon et al., (2015 ▸). Acta Cryst. E71, o470-o471]. There are two mol-ecules, A and B, in the asymmetric unit; the dihedral angles between the pyrazole ring and the tetra-zole and di-meth-oxy-pyrimidine ring planes are 72.84 (10) and 37.24 (14)°, respectively (mol-ecule A) and 84.38 (9) and 26.09 (15)°, respectively (mol-ecule B). Each mol-ecule features an intra-molecular N-H⋯N hydrogen bond. In the crystal, aromatic π-π stacking inter-actions [centroid-centroid separations = 3.9871 (16), 3.4487 (14) and 3.5455 (16) Å] link the mol-ecules into [001] chains. In addition, N-H⋯N, N-H⋯O, C-H⋯O and C-H⋯N hydrogen bonds occur, forming a three-dimensional architecture. We propose that the dimorphism results from differences in conformations and packing owing to different inter-molecular inter-actions, especially aromatic π-π stacking.

  5. Structural study of polymorphism in methylprednisolone aceponate

    NASA Astrophysics Data System (ADS)

    Knyazev, A. V.; Somov, N. V.; Shipilova, A. S.; Gusarova, E. V.; Knyazeva, S. S.; Stepanova, O. V.; Chuprunov, E. V.

    2017-08-01

    The crystal structures of methylprednisolone aceponate were determined by X-ray diffraction analysis at temperatures 90 K and 150 K: space group P212121, a = 14.8592(2), b = 19.6844(5), c = 26.1626(4) Å, Z = 12; R = 0.0598 (T = 90 K); space group P212121, a = 6.57348(14), b = 14.8295(3), c = 26.2214(5) Å, Z = 4; R = 0.0518 (T = 150 K). Features of structural changes in the phase transition were revealed. The abrupt change in the unit cell parameters in the phase transition was shown by low-temperature X-ray powder. The methods of degree of invariance of crystal electron density and molecular Voronoi-Dirichlet polyhedra were used for the analysis of polymorphism in methylprednisolone aceponate. The atomic structure at 90 K have a translational pseudosymmetry of electron density η = 0.329(1). The decrease of number of intermolecular contacts in the high-temperature modification due to rupture of intermolecular non-valence contacts C/O was observed.

  6. Male polymorphism in Limia perugiae (Pisces: Poeciliidae).

    PubMed

    Erbelding-Denk, C; Schröder, J H; Schartl, M; Nanda, I; Schmid, M; Epplen, J T

    1994-01-01

    The male-polymorphic poeciliid fish, Limia perugiae, a small teleostean endemic to the southeast of the Caribbean island Hispañola, consists of three male size morphs with uniform females. Large males differentiate at a size varying between 25 and 38 mm; intermediate males, between 21 and 25 mm. Under competition, large males exhibit an elaborate courtship display, whereas small males show only a sneak-chase behavior. Intermediate males adapt their tactics to the respective competitors. However, all male morphs can switch from courtship display to sneak-chase behavior. In large mating groups with four males of different size and five or six virgin females, large dominant alpha-males as well as small subordinate delta-males did not produce any offspring. Unexpectedly, all progeny were sired exclusively by the intermediate subordinate beta- and gamma-males. Breeding experiments with the three male morphs can best be explained by a model of Y-linked genes for small and large size which are both suspended by the activity of an autosomal recessive repressor responsible for the development of intermediate males. The dominant allele of the recessive repressor, in either its homoorits heterozygous state, activates the Y-chromosomal genes for large or small size, respectively. Accordingly, intermediate males may produce male offspring of all size classes, depending on the presence of either the Y-linked gene or the autosomal repressor.

  7. Surveying expression level polymorphism and single-feature polymorphism in near-isogenic wheat lines differing for the Yr5 stripe rust resistance locus

    USDA-ARS?s Scientific Manuscript database

    DNA polymorphisms are valuable for several applications including genotyping, molecular mapping and marker-assisted selection. The Affymetrix Wheat GeneChip was used to survey expression level polymorphisms (ELPs) and single-feature polymorphisms (SFPs) between two near-isogenic wheat genotypes (BC...

  8. Surveying expression level polymorphism and single-feature polymorphism in near-isogenic wheat lines differing for the Yr5 stripe rust resistance locus

    USDA-ARS?s Scientific Manuscript database

    DNA polymorphisms are valuable for several applications including genotyping, molecular mapping and marker-assisted selection. The Affymetrix Wheat GeneChip was used to survey expression level polymorphisms (ELPs) and single-feature polymorphisms (SFPs) between two near-isogenic wheat genotypes (BC7...

  9. Genetic diversity among elite Sorghum lines revealed by restriction fragment length polymorphisms and random amplified polymorphic DNAs.

    PubMed

    Vierling, R A; Xiang, Z; Joshi, C P; Gilbert, M L; Nguyen, H T

    1994-02-01

    The genetic diversity of sorghum, as compared to corn, is less well characterized at the genetic and molecular levels despite its worldwide economic importance. The objectives of this study were to: (1) investigate genetic diversity for restriction fragment length polymorphism (RFLPs) and random amplified polymorphic DNAs (RAPDs) in elite sorghum lines, (2) compare similarities based on molecular markers with pedigree relationships, and (3) examine the potential of RFLPs and RAPDs for assigning sorghum lines to the A/B (sterile) and R (restorer) groups. Using four restriction enzymes, polymorphism was detected with 61% of the RFLP probes used, compared to 77% of the random primers. One hundred and sixteen (64%) probe-enzyme combinations yielded multiple-band profiles compared to 98% of the random primers. RFLP profiles generated 290 polymorphic bands compared to 177 polymorphic RAPDs. Pair-wise comparisons of polymorphic RFLPs and RAPDs were used to calculate Nei and Jaccard coefficients. These were employed to generate phenograms using UPGMA and neighborjoining clustering methods. Analysis of RFLP data with Jaccard's coefficient and neighbor-joining clustering produced the phenogram with the closest topology to the known pedigree.

  10. Complexity Reduction of Polymorphic Sequences (CRoPS™): A Novel Approach for Large-Scale Polymorphism Discovery in Complex Genomes

    PubMed Central

    van Orsouw, Nathalie J.; Hogers, René C. J.; Janssen, Antoine; Yalcin, Feyruz; Snoeijers, Sandor; Verstege, Esther; Schneiders, Harrie; van der Poel, Hein; van Oeveren, Jan; Verstegen, Harold; van Eijk, Michiel J. T.

    2007-01-01

    Application of single nucleotide polymorphisms (SNPs) is revolutionizing human bio-medical research. However, discovery of polymorphisms in low polymorphic species is still a challenging and costly endeavor, despite widespread availability of Sanger sequencing technology. We present CRoPS™ as a novel approach for polymorphism discovery by combining the power of reproducible genome complexity reduction of AFLP® with Genome Sequencer (GS) 20/GS FLX next-generation sequencing technology. With CRoPS, hundreds-of-thousands of sequence reads derived from complexity-reduced genome sequences of two or more samples are processed and mined for SNPs using a fully-automated bioinformatics pipeline. We show that over 75% of putative maize SNPs discovered using CRoPS are successfully converted to SNPWave® assays, confirming them to be true SNPs derived from unique (single-copy) genome sequences. By using CRoPS, polymorphism discovery will become affordable in organisms with high levels of repetitive DNA in the genome and/or low levels of polymorphism in the (breeding) germplasm without the need for prior sequence information. PMID:18000544

  11. New pressure-induced polymorphic transitions of anhydrous magnesium sulfate.

    PubMed

    Benmakhlouf, A; Errandonea, D; Bouchenafa, M; Maabed, S; Bouhemadou, A; Bentabet, A

    2017-03-31

    The effects of pressure on the crystal structure of the three known polymorphs of magnesium sulfate (α-MgSO4, β-MgSO4, and γ-MgSO4) have been theoretically studied by means of density-functional theory calculations up to 45 GPa. We determined that under ambient conditions γ-MgSO4 is an unstable polymorph, which decomposes into MgO + SO3, and that the response of the other two polymorphs to hydrostatic pressure is non-isotropic. Additionally, we found that at all pressures β-MgSO4 has a larger enthalpy than α-MgSO4. This indicates that β-MgSO4 is thermodynamically unstable versus α-MgSO4 and predicts the occurrence of a β-α phase transition under moderate compression. Our calculations also predict the existence under pressure of additional phase transitions to two new polymorphs of MgSO4, which we named δ-MgSO4 and ε-MgSO4. The α-δ transition is predicted to occur at 17.5 GPa, and the δ-ε transition at 35 GPa, pressures that nowadays can be experimentally easily achieved. All the predicted structural transformations are characterized as first-order transitions. This suggests that they can be non-reversible, and therefore the new polymorphs could be recovered as metastable polymorphs under ambient conditions. The crystal structure of the two new polymorphs is reported. In them, the coordination number of sulfur is four as in the previously known polymorphs, but the coordination number of magnesium is eight instead of six. In this article we will report the axial and bond compressibility for the four polymorphs of MgSO4. The pressure-volume equation of state of each phase is also given, which is described by a third-order Birch-Murnaghan equation. The values obtained for the bulk modulus are 62 GPa, 57 GPa, 102 GPa, and 119 GPa for α-MgSO4, β-MgSO4, δ-MgSO4, and ε-MgSO4, respectively. Finally, the electronic band structure of these four polymorphs of MgSO4 has been calculated for the first time. The obtained results will be presented and discussed.

  12. COMT Val158Met Polymorphism Modulates Huntington's Disease Progression

    PubMed Central

    Rebeix, Isabelle; Dupoux, Emmanuel; Durr, Alexandra; Brice, Alexis; Charles, Perrine; Cleret de Langavant, Laurent; Youssov, Katia; Verny, Christophe; Damotte, Vincent; Azulay, Jean-Philippe; Goizet, Cyril; Simonin, Clémence; Tranchant, Christine; Maison, Patrick; Rialland, Amandine; Schmitz, David; Jacquemot, Charlotte; Fontaine, Bertrand; Bachoud-Lévi, Anne-Catherine

    2016-01-01

    Little is known about the genetic factors modulating the progression of Huntington’s disease (HD). Dopamine levels are affected in HD and modulate executive functions, the main cognitive disorder of HD. We investigated whether the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, which influences dopamine (DA) degradation, affects clinical progression in HD. We carried out a prospective longitudinal multicenter study from 1994 to 2011, on 438 HD gene carriers at different stages of the disease (34 pre-manifest; 172 stage 1; 130 stage 2; 80 stage 3; 17 stage 4; and 5 stage 5), according to Total Functional Capacity (TFC) score. We used the Unified Huntington’s Disease Rating Scale to evaluate motor, cognitive, behavioral and functional decline. We genotyped participants for COMT polymorphism (107 Met-homozygous, 114 Val-homozygous and 217 heterozygous). 367 controls of similar ancestry were also genotyped. We compared clinical progression, on each domain, between groups of COMT polymorphisms, using latent-class mixed models accounting for disease duration and number of CAG (cytosine adenine guanine) repeats. We show that HD gene carriers with fewer CAG repeats and with the Val allele in COMT polymorphism displayed slower cognitive decline. The rate of cognitive decline was greater for Met/Met homozygotes, which displayed a better maintenance of cognitive capacity in earlier stages of the disease, but had a worse performance than Val allele carriers later on. COMT polymorphism did not significantly impact functional and behavioral performance. Since COMT polymorphism influences progression in HD, it could be used for stratification in future clinical trials. Moreover, DA treatments based on the specific COMT polymorphism and adapted according to disease duration could potentially slow HD progression. PMID:27657697

  13. Structural origin of polymorphism of Alzheimer's amyloid β-fibrils.

    PubMed

    Agopian, Audrey; Guo, Zhefeng

    2012-10-01

    Formation of senile plaques containing amyloid fibrils of Aβ (amyloid β-peptide) is a pathological hallmark of Alzheimer's disease. Unlike globular proteins, which fold into unique structures, the fibrils of Aβ and other amyloid proteins often contain multiple polymorphs. Polymorphism of amyloid fibrils leads to different toxicity in amyloid diseases and may be the basis for prion strains, but the structural origin for fibril polymorphism is still elusive. In the present study we investigate the structural origin of two major fibril polymorphs of Aβ40: an untwisted polymorph formed under agitated conditions and a twisted polymorph formed under quiescent conditions. Using electron paramagnetic resonance spectroscopy, we studied the inter-strand side-chain interactions at 14 spin-labelled positions in the Aβ40 sequence. The results of the present study show that the agitated fibrils have stronger inter-strand spin-spin interactions at most of the residue positions investigated. The two hydrophobic regions at residues 17-20 and 31-36 have the strongest interactions in agitated fibrils. Distance estimates on the basis of the spin exchange frequencies suggest that inter-strand distances at residues 17, 20, 32, 34 and 36 in agitated fibrils are approximately 0.2 Å (1 Å=0.1 nm) closer than in quiescent fibrils. We propose that the strength of inter-strand side-chain interactions determines the degree of β-sheet twist, which then leads to the different association patterns between different cross β-units and thus distinct fibril morphologies. Therefore the inter-strand side-chain interaction may be a structural origin for fibril polymorphism in Aβ and other amyloid proteins.

  14. Raman detected differential scanning calorimetry of polymorphic transformations in acetaminophen.

    PubMed

    Kauffman, John F; Batykefer, Linda M; Tuschel, David D

    2008-12-15

    Acetaminophen is known to crystallize in three polymorphic forms. Thermally induced transformations between the crystalline forms and the super-cooled liquid have been observed by differential scanning calorimetry (DSC), but the assignment of calorimetric transitions to specific polymorphic transformations remains challenging, because the transition temperatures for several transformations are close to one another, and the characteristics of the observed transitions depend on experimental variables that are often poorly controlled. This paper demonstrates the simultaneous application of DSC and Raman microscopy for the observation of thermally driven transitions between polymorphs of pharmaceutical materials. Raman detected differential scanning calorimetry (RD-DSC) has been used to monitor the DSC thermograms of super-cooled liquid acetaminophen and confirms the assignment of two exothermic transitions to specific polymorphic transformations. Principal component analysis of the Raman spectra have been used to determine the number of independent components that participate in the phase transformations, and multivariate regression has been used to determine transition temperatures from the spectral data. The influence of the laser excitation source on measured DSC thermograms has also been investigated, and it has been demonstrated that a baseline shift occurs in RD-DSC when a polymorphic transformation occurs between crystalline and amorphous forms. RD-DSC has been used to examine the influence of sample aging and sample pan configuration on the observed polymorphic transformations, and both of these variables were found to influence the thermal behavior of the sample. The results demonstrate the advantage of simultaneous Raman spectroscopy and differential scanning calorimetry for the unambiguous assignment of thermally driven polymorphic transformations.

  15. COMT Val158Met Polymorphism Modulates Huntington's Disease Progression.

    PubMed

    de Diego-Balaguer, Ruth; Schramm, Catherine; Rebeix, Isabelle; Dupoux, Emmanuel; Durr, Alexandra; Brice, Alexis; Charles, Perrine; Cleret de Langavant, Laurent; Youssov, Katia; Verny, Christophe; Damotte, Vincent; Azulay, Jean-Philippe; Goizet, Cyril; Simonin, Clémence; Tranchant, Christine; Maison, Patrick; Rialland, Amandine; Schmitz, David; Jacquemot, Charlotte; Fontaine, Bertrand; Bachoud-Lévi, Anne-Catherine

    Little is known about the genetic factors modulating the progression of Huntington's disease (HD). Dopamine levels are affected in HD and modulate executive functions, the main cognitive disorder of HD. We investigated whether the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, which influences dopamine (DA) degradation, affects clinical progression in HD. We carried out a prospective longitudinal multicenter study from 1994 to 2011, on 438 HD gene carriers at different stages of the disease (34 pre-manifest; 172 stage 1; 130 stage 2; 80 stage 3; 17 stage 4; and 5 stage 5), according to Total Functional Capacity (TFC) score. We used the Unified Huntington's Disease Rating Scale to evaluate motor, cognitive, behavioral and functional decline. We genotyped participants for COMT polymorphism (107 Met-homozygous, 114 Val-homozygous and 217 heterozygous). 367 controls of similar ancestry were also genotyped. We compared clinical progression, on each domain, between groups of COMT polymorphisms, using latent-class mixed models accounting for disease duration and number of CAG (cytosine adenine guanine) repeats. We show that HD gene carriers with fewer CAG repeats and with the Val allele in COMT polymorphism displayed slower cognitive decline. The rate of cognitive decline was greater for Met/Met homozygotes, which displayed a better maintenance of cognitive capacity in earlier stages of the disease, but had a worse performance than Val allele carriers later on. COMT polymorphism did not significantly impact functional and behavioral performance. Since COMT polymorphism influences progression in HD, it could be used for stratification in future clinical trials. Moreover, DA treatments based on the specific COMT polymorphism and adapted according to disease duration could potentially slow HD progression.

  16. Polymorphisms in DNA repair genes and associations with cancer risk.

    PubMed

    Goode, Ellen L; Ulrich, Cornelia M; Potter, John D

    2002-12-01

    Common polymorphisms in DNA repair genes may alter protein function and an individual's capacity to repair damaged DNA; deficits in repair capacity may lead to genetic instability and carcinogenesis. To establish our overall understanding of possible in vivo relationships between DNA repair polymorphisms and the development of cancer, we performed a literature review of epidemiological studies that assessed associations between such polymorphisms and risk of cancer. Thirty studies of polymorphisms in OGG1, XRCC1, ERCC1, XPC, XPD, XPF, BRCA2, and XRCC3 were identified in the April 30, 2002 MEDLINE database (National Center for Biotechnology Information. PubMed Database: http://www.ncbi.nlm.nih.gov/entrez). These studies focused on adult glioma, bladder cancer, breast cancer, esophageal cancer, lung cancer, prostate cancer, skin cancer (melanoma and nonmelanoma), squamous cell carcinoma of the head and neck, and stomach cancer. We found that a small proportion of the published studies were large and population-based. Nonetheless, published data were consistent with associations between: (a) the OGG1 S326C variant and increased risk of various types of cancer; (b) the XRCC1 R194W variant and reduced risk of various types of cancer; and (c) the BRCA2 N372H variant and increased risk of breast cancer. Suggestive results were seen for polymorphisms in other genes; however, small sample sizes may have contributed to false-positive or false-negative findings. We conclude that large, well-designed studies of common polymorphisms in DNA repair genes are needed. Such studies may benefit from analysis of multiple genes or polymorphisms and from the consideration of relevant exposures that may influence the likelihood of cancer in the presence of reduced DNA repair capacity.

  17. CLPTM1L polymorphism and lung cancer risk

    PubMed Central

    Tang, Min; Bian, Xiaonian; Zhao, Qiuliang

    2015-01-01

    The association of Cleft Lip and Palate Transmembrane Protein 1 (CLPTM1L) rs31489 polymorphism with risk of lung cancer has been evaluated in many studies; however, the results from these studies are controversial. Thus, further analysis on association between CLPTM1L rs31489 polymorphism and risk of lung cancer is needed among a larger study population. A literature search in PubMed, Embase, Web of Science, Science Direct, SpringerLink, EBSCO, Wanfang, and Chinese National Knowledge Infrastructure (CNKI) databases was carried out to identify studies investigating the association between lung cancer risk and CLPTM1L rs31489 polymorphism. The strength of the association between CLPTM1L rs31489 polymorphism and lung cancer risk was estimated by calculating odds ratios (ORs) and corresponding 95% confidence intervals (CIs). In the overall analysis, there was significant association between CLPTM1L rs31489 polymorphism and lung cancer risk under an allele model (OR = 1.12; 95% CI, 1.06-1.18; P < 0.00001; I2 = 57%). Subgroup analysis by ethnicity was performed. Stratified analysis by ethnicity showed that a statistically increased cancer risk was found in the Caucasian population (OR = 1.15; 95% CI, 1.10-1.21; P < 0.00001; I2 = 22%), but there was no significant association between lung cancer risk and CLPTM1L rs31489 polymorphism in the Asian population (OR = 1.03; 95% CI, 0.97-1.08; P = 0.37; I2 = 15%). In conclusion, this meta-analysis demonstrates that CLPTM1L rs31489 polymorphism significantly modified the risk of lung cancer. PMID:26064290

  18. CLPTM1L polymorphism and lung cancer risk.

    PubMed

    Tang, Min; Bian, Xiaonian; Zhao, Qiuliang

    2015-01-01

    The association of Cleft Lip and Palate Transmembrane Protein 1 (CLPTM1L) rs31489 polymorphism with risk of lung cancer has been evaluated in many studies; however, the results from these studies are controversial. Thus, further analysis on association between CLPTM1L rs31489 polymorphism and risk of lung cancer is needed among a larger study population. A literature search in PubMed, Embase, Web of Science, Science Direct, SpringerLink, EBSCO, Wanfang, and Chinese National Knowledge Infrastructure (CNKI) databases was carried out to identify studies investigating the association between lung cancer risk and CLPTM1L rs31489 polymorphism. The strength of the association between CLPTM1L rs31489 polymorphism and lung cancer risk was estimated by calculating odds ratios (ORs) and corresponding 95% confidence intervals (CIs). In the overall analysis, there was significant association between CLPTM1L rs31489 polymorphism and lung cancer risk under an allele model (OR = 1.12; 95% CI, 1.06-1.18; P < 0.00001; I(2) = 57%). Subgroup analysis by ethnicity was performed. Stratified analysis by ethnicity showed that a statistically increased cancer risk was found in the Caucasian population (OR = 1.15; 95% CI, 1.10-1.21; P < 0.00001; I(2) = 22%), but there was no significant association between lung cancer risk and CLPTM1L rs31489 polymorphism in the Asian population (OR = 1.03; 95% CI, 0.97-1.08; P = 0.37; I(2) = 15%). In conclusion, this meta-analysis demonstrates that CLPTM1L rs31489 polymorphism significantly modified the risk of lung cancer.

  19. Predicting drug response and toxicity based on gene polymorphisms.

    PubMed

    Robert, Jacques; Morvan, Valérie Le; Smith, Denis; Pourquier, Philippe; Bonnet, Jacques

    2005-06-01

    The sequencing of the human genome has allowed the identification of thousands of gene polymorphisms, most often single nucleotide polymorphims (SNP), which may play an important role in the expression level and activity of the corresponding proteins. When these polymorphisms occur at the level of drug metabolising enzymes or transporters, the disposition of the drug may be altered and, consequently, its efficacy may be compromised or its toxicity enhanced. Polymorphisms can also occur at the level of proteins directly involved in drug action, either when the protein is the target of the drug or when the protein is involved in the repair of drug-induced lesions. There again, these polymorphisms may lead to alterations in drug efficacy and/or toxicity. The identification of functional polymorphisms in patients undergoing chemotherapy may help the clinician prescribe the optimal drug combination or schedule and predict with more accuracy the response to these prescriptions. We have recorded in this review the polymorphisms that have been identified up till now in genes involved in anticancer drug activity. Some of them appear especially important in predicting drug toxicity and should be determined in routine before drug administration; this is the case of the most common variations of thiopurine methyltransferase for 6-mercaptopurine and of dihydropyrimidine dehydrogenase for fluorouracil. Other appear determinant for drug response, such as the common SNPs found in glutathione S-transferase P1 or xereoderma pigmentosum group D enzyme for the activity of oxaliplatin. However, confusion factors may exist between the role of gene polymorphisms in cancer risk or overall prognosis and their role in drug response.

  20. Leptin receptor gene polymorphisms and morbid obesity in Mexican patients.

    PubMed

    Rojano-Rodriguez, Martin Edgardo; Beristain-Hernandez, Jose Luis; Zavaleta-Villa, Beatriz; Maravilla, Pablo; Romero-Valdovinos, Mirza; Olivo-Diaz, Angelica

    2016-01-01

    Human obesity is due to a complex interaction among environmental, behavioral, developmental and genetic factors, including the interaction of leptin (LEP) and leptin receptor (LEPR). Several LEPR mutations and polymorphisms have been described in patients with early onset severe obesity and hyperphagic eating behavior; however, some contradictory findings have also been reported. In the present study we explored the association of six LEPR gene polymorphisms in patients with morbid obesity. Twenty eight patients with morbid obesity and 56 non-obese Mexican Mestizo individuals were included. Typing of rs1137100, rs1137101, rs1805134, Ser492Thr, rs1805094 and rs1805096 LEPR polymorphisms was performed by PCR and allele specific hybridization. The LEPR Ser492Thr polymorphism was monomorphic with the presence of only the Ser492Thr-G allele. Allele C and genotype T/C for rs1805134 polymorphism were associated with susceptibility to morbid obesity (p = 0.02 and p = 0.03, respectively). No association was observed with any haplotype. Linkage disequilibrium (LD) showed that five polymorphisms (rs1137100, rs1137101, rs1805134, rs1805094 and rs1805096) were in absolute (D' = 1) but none in perfect (r(2) = 1) LD. Our results suggest that rs1805134 polymorphism could be involved in the development of morbid obesity, whilst none of the alleles of the LEPR gene, rs1137100, rs1137101, rs1805094 and rs1805096 were associated as risk factors. However, more studies are necessary to confirm or reject this hypothesis.

  1. Human enamel thickness and ENAM polymorphism

    PubMed Central

    Daubert, Diane M; Kelley, Joanna L; Udod, Yuriy G; Habor, Carolina; Kleist, Chris G; Furman, Ilona K; Tikonov, Igor N; Swanson, Willie J; Roberts, Frank A

    2016-01-01

    The tooth enamel development gene, enamelin (ENAM), showed evidence of positive selection during a genome-wide scan of human and primate DNA for signs of adaptive evolution. The current study examined the hypothesis that a single-nucleotide polymorphism (SNP) C14625T (rs7671281) in the ENAM gene identified in the genome-wide scan is associated with a change in enamel phenotype. African Americans were selected as the target population, as they have been reported to have a target SNP frequency of approximately 50%, whereas non-Africans are predicted to have a 96% SNP frequency. Digital radiographs and DNA samples from 244 teeth in 133 subjects were analysed, and enamel thickness was assessed in relation to SNP status, controlling for age, sex, tooth number and crown length. Crown length was found to increase with molar number, and females were found to have thicker enamel. Teeth with larger crowns also had thicker enamel, and older subjects had thinner enamel. Linear regression and generalized estimating equations were used to investigate the relationship between enamel thickness of the mandibular molars and ENAM SNP status; enamel in subjects with the derived allele was significantly thinner (P=0.040) when the results were controlled for sex, age, tooth number and crown length. The derived allele demonstrated a recessive effect on the phenotype. The data indicate that thinner dental enamel is associated with the derived ENAM genotype. This is the first direct evidence of a dental gene implicated in human adaptive evolution as having a phenotypic effect on an oral structure. PMID:27357321

  2. The HLA genes and their diverse polymorphism.

    PubMed

    Mehra, N K

    2000-08-01

    Advanced DNA level studies based on HLA class II sequence analysis have revealed considerable diversity in HLA among Asian Indians. High resolution typing of specific alleles such as DR2 and DR4 in the HLA class II region by PCR-SSP or SSOP hybridization and their associated DR-DQ haplotypes have helped to detect unique haplotypes and novel alleles which have subsequently been confirmed by sequencing. Incidentally, remarkable stability has been maintained in several other DRB1 alleles viz. DR1, DR7, DR9 and DR10. The ARMS-PCR technology has been found to be particularly useful for typing HLA-A, HLA-B and HLA-Cw alleles. These technologies are far superior over serological methods. Our studies have shown remarkable heterogeneity of common HLA-A and B alleles in Asian Indians. Molecular subtyping of HLA-A2 revealed that subtype A(*)0211 is found only in Indian population and may be the result of selection pressure in this population. Investigations into polymorphism in the HLA-B27 gene revealed that subtypes common both to the western caucasians and orientals occur in the Indian population. It is apparent that the population of the Indian subcontinent, placed as it is between the Caucasoids and Negroids on one hand and Australoids and Mongoloids on the other, provides a rich source of many HLA haplotypes. While the most frequent Caucasian haplotypes occur with a reasonable frequency in Asian Indians, those found predominantly in other ethnic groups (e.g., australian Aborigines and populations of Oceania, China and Japan) are also detected. Knowledge on this is most important for donor selection during organ and bone marrow transplantation and for designing MHC targeted vaccines in specific diseases.

  3. A second triclinic polymorph of azimsulfuron

    PubMed Central

    Kwon, Eunjin; Kim, Jineun; Park, Hyunjin; Kim, Tae Ho

    2016-01-01

    The title compound, C13H16N10O5S (systematic name: 1-(4,6-di­meth­oxypyrimidin-2-yl)-3-{[1-methyl-4-(2-methyl-2H-tetra­zol-5-yl)pyrazol-5-yl]sulfonyl}urea), is a second triclinic polymorph of this crystal [for the other, see: Jeon et al., (2015 ▸). Acta Cryst. E71, o470–o471]. There are two mol­ecules, A and B, in the asymmetric unit; the dihedral angles between the pyrazole ring and the tetra­zole and di­meth­oxy­pyrimidine ring planes are 72.84 (10) and 37.24 (14)°, respectively (mol­ecule A) and 84.38 (9) and 26.09 (15)°, respectively (mol­ecule B). Each mol­ecule features an intra­molecular N—H⋯N hydrogen bond. In the crystal, aromatic π–π stacking inter­actions [centroid–centroid separations = 3.9871 (16), 3.4487 (14) and 3.5455 (16) Å] link the mol­ecules into [001] chains. In addition, N—H⋯N, N—H⋯O, C—H⋯O and C—H⋯N hydrogen bonds occur, forming a three-dimensional architecture. We propose that the dimorphism results from differences in conformations and packing owing to different inter­molecular inter­actions, especially aromatic π–π stacking. PMID:27746943

  4. The polymorphisms of the chromatin fiber

    NASA Astrophysics Data System (ADS)

    Boulé, Jean-Baptiste; Mozziconacci, Julien; Lavelle, Christophe

    2015-01-01

    In eukaryotes, the genome is packed into chromosomes, each consisting of large polymeric fibers made of DNA bound with proteins (mainly histones) and RNA molecules. The nature and precise 3D organization of this fiber has been a matter of intense speculations and debates. In the emerging picture, the local chromatin state plays a critical role in all fundamental DNA transactions, such as transcriptional control, DNA replication or repair. However, the molecular and structural mechanisms involved remain elusive. The purpose of this review is to give an overview of the tremendous efforts that have been made for almost 40 years to build physiologically relevant models of chromatin structure. The motivation behind building such models was to shift our representation and understanding of DNA transactions from a too simplistic ‘naked DNA’ view to a more realistic ‘coated DNA’ view, as a step towards a better framework in which to interpret mechanistically the control of genetic expression and other DNA metabolic processes. The field has evolved from a speculative point of view towards in vitro biochemistry and in silico modeling, but is still longing for experimental in vivo validations of the proposed structures or even proof of concept experiments demonstrating a clear role of a given structure in a metabolic transaction. The mere existence of a chromatin fiber as a relevant biological entity in vivo has been put into serious questioning. Current research is suggesting a possible reconciliation between theoretical studies and experiments, pointing towards a view where the polymorphic and dynamic nature of the chromatin fiber is essential to support its function in genome metabolism.

  5. Vitamin D Receptor (VDR) Polymorphisms in Pediatric Patients Presenting With Hodgkin's Lymphoma.

    PubMed

    Tekgündüz, Sibel A; Yeşil, Şule; Ören, Ayşe C; Tanyildiz, Hikmet G; Çandir, Mehmet O; Bozkurt, Ceyhun; Şahin, Gürses

    2017-03-01

    Vitamin D receptor (VDR) polymorphisms are found more commonly in some tumor types than in healthy individuals, suggesting that some polymorphisms (Cdx2, Fok1, Bsm1, Apa1, Taq1) contribute to tumor development. There is no previous report on VDR polymorphism in Hodgkin's lymphoma (HL) patients. VDR polymorphism patterns in 95 pediatric HL cases with 100 healthy controls were compared. No statistically significant difference was found between the patient group and control group in terms of Cdx2, Fok1, Bsm1, Apa1, and Taq1 polymorphisms (P>0.5). Our findings suggest that VDR polymorphisms may not play a role in HL development.

  6. Associations between PPARG polymorphisms and the risk of essential hypertension

    PubMed Central

    Weng, Weijin; Shi, Ganwei; Xue, Sheliang; Zhang, Bifeng

    2017-01-01

    Background Peroxisome proliferator-activated receptor gamma (PPARG) plays an important role in the pathogenesis and maintenance of essential hypertension (EH). It has been suggested that polymorphisms of PPARG are associated with the risk of EH. However, findings to date remain controversial. To elucidate the associations between the PPARG Pro12Ala and C161T polymorphisms and EH risk, a meta-analysis was carried out. Methods A comprehensive literature search of PubMed, Embase, CNKI (Chinese National Knowledge Infrastructure), VIP and Wanfang databases was conducted. The pooled odds ratios (ORs) and 95% confidence interval (CI) were calculated to estimate the size of the effect using the random-effects model. At the same time, the pooled standardized mean difference (SMD) with 95% CI was used for the meta-analysis of the PPARG Pro12Ala polymorphism and blood pressure. Results Finally, Fifteen papers (seventeen studies) including 4,151 cases and 4,997 controls to evaluate the association of the PPARGPro12Ala polymorphism and EH risk, were included in this study. Overall, the results suggested that Ala allele was associated with the decreased EH risk (for allelic model, OR = 0.757, 95%CI: 0.624–0.918, P = 0.005; for dominant model, OR = 0.771, 95%CI: 0.627–0.946, P = 0.013). The subgroup analysis stratified by ethnicity showed that the significant association between the PPARG Pro12Ala polymorphism and EH was only detected in the Asian subgroup. There was no difference in blood pressure values between Ala carriers and non-carriers. For the C161T polymorphism, only 5 studies comprising 1,118 cases and 1,357 controls met the inclusion criteria. The overall results showed that the PPARG C161T polymorphism was not associated with the risk of EH. But in the subgroup analysis, we found that the PPARG C161T polymorphism significantly associated with the risk of EH in the Asian subgroup (for allelic model, OR = 0.719, 95% CI: 0.537–0.963, P = 0.027; for dominant model

  7. Sympatric ecological divergence associated with a color polymorphism.

    PubMed

    Kusche, Henrik; Elmer, Kathryn R; Meyer, Axel

    2015-10-05

    Color polymorphisms are a conspicuous feature of many species and a way to address broad ecological and evolutionary questions. Three potential major evolutionary fates of color polymorphisms are conceivable over time: maintenance, loss, or speciation. However, the understanding of color polymorphisms and their evolutionary implications is frequently impaired by sex-linkage of coloration, unknown inheritance patterns, difficulties in phenotypic characterization, and a lack of evolutionary replicates. Hence, the role of color polymorphisms in promoting ecological and evolutionary diversification remains poorly understood. In this context, we assessed the ecological and evolutionary consequences of a color polymorphic study system that is not hampered by these restrictions: the repeated adaptive radiations of the gold/dark Midas cichlid fishes (the Amphilophus citrinellus species complex) from the great lakes and crater lakes of Nicaragua, Central America. We conducted multi-trait morphological and ecological analyses from ten populations of this young adaptive radiation (<6,000 years old), which revealed sympatric ecological differentiation associated with the conspicuous binary (gold/dark) color polymorphism. Varying degrees of intraspecific ecological divergence were observed across the ten color morph pairs, but most pairs exhibited a consistently parallel ecological and evolutionary trajectory across populations. Specifically, gold Midas cichlids are frequently deeper-bodied, have more robust pharyngeal jaws, and feed at a lower trophic level compared to conspecific, sympatric dark individuals. A common garden experiment suggests there is a genetic correlation of color and eco-morphological traits. We demonstrate unprecedented ecological and evolutionary consequences of color polymorphism in this adaptive radiation. Across the species complex, sympatric conspecific individuals differed in eco-morphology depending on color morph (gold/dark) and the axis of

  8. Efficient development of highly polymorphic microsatellite markers based on polymorphic repeats in transcriptome sequences of multiple individuals.

    PubMed

    Vukosavljev, M; Esselink, G D; van 't Westende, W P C; Cox, P; Visser, R G F; Arens, P; Smulders, M J M

    2015-01-01

    The first hurdle in developing microsatellite markers, cloning, has been overcome by next-generation sequencing. The second hurdle is testing to differentiate polymorphic from nonpolymorphic loci. The third hurdle, somewhat hidden, is that only polymorphic markers with a large effective number of alleles are sufficiently informative to be deployed in multiple studies. Both steps are laborious and still performed manually. We have developed a strategy in which we first screen reads from multiple genotypes for repeats that show the most length variants, and only these are subsequently developed into markers. We validated our strategy in tetraploid garden rose using Illumina paired-end transcriptome sequences of 11 roses. Of 48 tested two markers failed to amplify, but all others were polymorphic. Ten loci amplified more than one locus, indicating duplicated genes or gene families. Completely avoiding duplicated loci will be difficult because the range of numbers of predicted alleles of highly polymorphic single- and multilocus markers largely overlapped. Of the remainder, half were replicate markers (i.e. multiple primer pairs for one locus), indicating the difficulty of correctly filtering short reads containing repeat sequences. We subsequently refined the approach to eliminate multiple primer sets to the same loci. The remaining 18 markers were all highly polymorphic, amplifying on average 11.7 alleles per marker (range = 6-20) in 11 tetraploid roses, exceeding the 8.2 alleles per marker of the 24 most polymorphic markers genotyped previously. This strategy therefore represents a major step forward in the development of highly polymorphic microsatellite markers.

  9. Relationship between TBX20 gene polymorphism and congenital heart disease.

    PubMed

    Yang, X F; Zhang, Y F; Zhao, C F; Liu, M M; Si, J P; Fang, Y F; Xing, W W; Wang, F L

    2016-06-02

    Congenital heart disease in children is a type of birth defect. Previous studies have suggested that the transcription factor, TBX20, is involved in the occurrence and development of congenital heart disease in children; however, the specific regulatory mechanisms are yet to be evaluated. Hence, this study aimed to evaluate the relationship between the TBX20 polymorphism and the occurrence and development of congenital heart disease. The TBX20 gene sequence was obtained from the NCBI database and the polymorphic locus candidate was predicted. Thereafter, the specific gene primers were designed for the restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) of DNA extracted from the blood of 80 patients with congenital heart disease and 80 controls. The results of the PCR were subjected to correlation analysis to identify the differences between the amplicons and to determine the relationship between the TBX20 gene polymorphism and congenital heart disease. One of the single nucleotide polymorphic locus was found to be rs3999950: c.774T>C (Ala265Ala). The TC genotype frequency in the patients was higher than that in the controls, similar to that for the C locus. The odds ratio of the TC genotypes was above 1, indicating that the presence of the TC genotype increases the incidence of congenital heart diseases. Thus, rs3999950 may be associated with congenital heart disease, and TBX20 may predispose children to the defect.

  10. A low-temperature polymorph of m-quinquephenyl.

    PubMed

    Gomes, Ligia R; Howie, R Alan; Low, John Nicolson; Rodrigues, Ana S M C; Santos, Luís M N B F

    2012-12-01

    A low-temperature polymorph of 1,1':3',1'':3'',1''':3''',1''''-quinquephenyl (m-quinquephenyl), C(30)H(22), crystallizes in the space group P2(1)/c with two molecules in the asymmetric unit. The crystal is a three-component nonmerohedral twin. A previously reported room-temperature polymorph [Rabideau, Sygula, Dhar & Fronczek (1993). Chem. Commun. pp. 1795-1797] also crystallizes with two molecules in the asymmetric unit in the space group P-1. The unit-cell volume for the low-temperature polymorph is 4120.5 (4) Å(3), almost twice that of the room-temperature polymorph which is 2102.3 (6) Å(3). The molecules in both structures adopt a U-shaped conformation with similar geometric parameters. The structural packing is similar in both compounds, with the molecules lying in layers which stack perpendicular to the longest unit-cell axis. The molecules pack alternately in the layers and in the stacked columns. In both polymorphs, the only interactions between the molecules which can stabilize the packing are very weak C-H...π interactions.

  11. Identifying potential BO2 oxide polymorphs for epitaxial growth candidates.

    PubMed

    Mehta, Prateek; Salvador, Paul A; Kitchin, John R

    2014-03-12

    Transition metal dioxides (BO2) exhibit a number of polymorphic structures with distinct properties, but the isolation of different polymorphs for a given composition is carried out using trial and error experimentation. We present computational studies of the relative stabilities and equations of state for six polymorphs (anatase, brookite, rutile, columbite, pyrite, and fluorite) of five different BO2 dioxides (B = Ti, V, Ru, Ir, and Sn). These properties were computed in a consistent fashion using several exchange correlation functionals within the density functional theory formalism, and the effects of the different functionals are discussed relative to their impact on predictive synthesis. We compare the computational results to prior observations of high-pressure synthesis and epitaxial film growth and then use this discussion to predict new accessible polymorphs in the context of epitaxial stabilization using isostructural substrates. For example, the relative stabilities of the columbite polymorph for VO2 and RuO2 are similar to those of TiO2 and SnO2, the latter two of which have been previously stabilized as epitaxial films.

  12. CYP2C19 polymorphism influences Helicobacter pylori eradication

    PubMed Central

    Kuo, Chao-Hung; Lu, Chien-Yu; Shih, Hsiang-Yao; Liu, Chung-Jung; Wu, Meng-Chieh; Hu, Huang-Ming; Hsu, Wen-Hung; Yu, Fang-Jung; Wu, Deng-Chyang; Kuo, Fu-Chen

    2014-01-01

    The known factors that have contributed to the decline of Helicobacter pylori (H. pylori) eradication rate include antibiotic resistance, poor compliance, high gastric acidity, high bacterial load, and cytochrome P450 2C19 (CYP2C19) polymorphism. Proton pump inhibitor (PPI) is important in the eradication regimen. The principal enzyme implicated in the metabolism of PPIs is CYP2C19. The effects of PPI depend on metabolic enzyme, cytochrome P450 enzymes, and CYP2C19 with genetic differences in the activity of this enzyme (the homozygous EM, heterozygous EM (HetEM), and poor metabolizer). The frequency of the CYP2C19 polymorphism is highly varied among different ethnic populations. The CYP2C19 genotype is a cardinal factor of H. pylori eradication in patients taking omeprazole- based or lansoprazole-based triple therapies. In contrast, the CYP2C19 polymorphism has no significant effect on the rabeprazole-based or esomeprazole-based triple therapies. The efficacy of levofloxacin-based rescue triple therapy might be also affected by the CYP2C19 polymorphism, but CYP2C19 genotypes did not show obvious impact on other levofloxacin-based rescue therapies. Choice of different PPIs and/or increasing doses of PPIs should be individualized based on the pharmacogenetics background of each patient and pharmacological profile of each drug. Other possible factors influencing gastric acid secretion (e.g., IL-1β- 511 polymorphism) would be also under consideration. PMID:25473155

  13. The associations between MDM4 gene polymorphisms and cancer risk

    PubMed Central

    Xu, Xiao-Liang; Yao, Guo-Liang; Liu, Rui-Ping; Zhao, Hui

    2016-01-01

    Considerable studies have investigated the associations between MDM4 gene polymorphisms and cancer risk recently, but with contradictory results. The aim of this meta-analysis was to evaluate the associations between MDM4 gene polymorphisms and cancer risk. Relevant studies were identified by a systematic search of PubMed, Embase, and CNKI databases. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were used to describe the strength of the associations. Fifty-six studies published in 11 publications involving 18,910 cases and 51,609 controls were included in this meta-analysis. Five MDM4 gene polymorphisms were evaluated: rs4245739, rs1563828, rs11801299, rs10900598, and rs1380576. Our analyses suggested that the rs4245739 polymorphism was significantly associated with overall cancer risk. Furthermore, stratification analyses of ethnicity indicated that rs4245739 decreased the risk of cancer among the Asian population, and stratification analyses of smoking status indicated that rs4245739 decreased the risk of cancer among nonsmokers. However, stratification analyses of cancer type and sex suggested that rs4245739 was not related to cancer risk. There were no associations of rs1563828, rs11801299, rs10900598, or rs1380576 with overall cancer risk. In conclusion, our analyses indicated that rs4245739 polymorphism in the MDM4 gene may play an important role in the etiology of cancer. PMID:27742919

  14. Immune sensitization against epidermal antigens in polymorphous light eruption

    SciTech Connect

    Gonzalez-Amaro, R.; Baranda, L.; Salazar-Gonzalez, J.F.; Abud-Mendoza, C.; Moncada, B. )

    1991-01-01

    To get further insight into the pathogenesis of polymorphous light eruption, we studied nine patients with polymorphous light eruption and six healthy persons. Two skin biopsy specimens were obtained from each person, one from previously ultraviolet light-irradiated skin and another one from unirradiated skin. An epidermal cell suspension, skin homogenate, or both were prepared from each specimen. Autologous cultures were made with peripheral blood mononuclear cells combined with irradiated or unirradiated skin homogenate and peripheral blood mononuclear cells combined with irradiated or unirradiated epidermal cell suspension. Cell proliferation was assessed by 3H-thymidine incorporation assay. The response of peripheral blood mononuclear cells to unirradiated epidermal cells or unirradiated skin homogenate was similar in both patients and controls. However, peripheral blood mononuclear cells from patients with polymorphous light eruption showed a significantly increased proliferative response to both irradiated epidermal cells and irradiated skin homogenate. Our results indicate that ultraviolet light increases the stimulatory capability of polymorphous light eruption epidermal cells in a unidirectional mixed culture with autologous peripheral blood mononuclear cells. This suggests that an immune sensitization against autologous ultraviolet light-modified skin antigens occurs in polymorphous light eruption.

  15. Investigation of polymorphic transitions of piracetam induced during wet granulation.

    PubMed

    Potter, Catherine B; Kollamaram, Gayathri; Zeglinski, Jacek; Whitaker, Darren A; Croker, Denise M; Walker, Gavin M

    2017-10-01

    Piracetam was investigated as a model API which is known to exhibit a number of different polymorphic forms. It is freely soluble in water so the possibility exists for polymorphic transformations to occur during wet granulation. Analysis of the polymorphic form present during lab-scale wet granulation, using water as a granulation liquid, was studied with powder X-ray diffraction and Raman spectroscopy as off-line and inline analysis tools respectively. Different excipients with a range of hydrophilicities, aqueous solubilities and molecular weights were investigated to examine their influence on these solution-mediated polymorphic transitions and experimental results were rationalised using molecular modelling. Our results indicated that as an increasing amount of water was added to the as-received piracetam FIII, a greater amount of the API dissolved which recrystallised upon drying to the metastable FII(6.403) via a monohydrate intermediary. Molecular level analysis revealed that the observed preferential transformation of monohydrate to FII is linked with a greater structural similarity between the monohydrate and FII polymorph in comparison to FIII. The application of Raman spectroscopy as a process analytical technology (PAT) tool to monitor the granulation process for the production of the monohydrate intermediate as a precursor to the undesirable metastable form was demonstrated. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Association between serotonin transporter gene polymorphisms and childhood asthma.

    PubMed

    Farjadian, Shirin; Moghtaderi, Mozhgan; Fakhraei, Bahareh; Nasiri, Mahboubeh; Farjam, Mojtaba

    2013-12-01

    Asthma is a common chronic inflammatory disease of the airways in which genetic factors play a major role in its pathogenesis. High serotonin serum levels in patients with asthma suggest that serotonin is involved in the pathophysiology of the disease. Serotonin clearance is mediated by the serotonin reuptake transporter, and functional polymorphisms in this gene lead to altered serotonin reuptake efficiency. The aim of this study was to investigate the relationship between serotonin transporter gene polymorphisms and asthma. Serotonin transporter gene polymorphisms (5-HTTLPR, rs35521 and STin2.VNTR) were assessed by PCR-based methods in 100 children with mild to moderate persistent asthma and compared with 100 healthy controls. There were no significant differences in allele, genotype or haplotype frequencies between patients and controls. No association was observed between SERT gene polymorphisms after stratification of patients for sex, age, spirometry indices, family history, passive smoking behavior and concomitant allergic rhinitis. Significant differences were observed in the distribution of 5-HTTLPR alleles (p = 0.025) and genotypes (p = 0.021) between patients with and without atopic dermatitis. Despite strong evidence suggesting the role of serotonin in the pathophysiology of asthma, we found no association between serotonin transporter gene polymorphisms and mild to moderate persistent asthma. Further serotonin transporter gene analyses in patients with severe asthma may open up new horizons in the utilization of common serotonin regulators to treat asthma, based on their pharmacogenetic effects. However, serotonin may also be indirectly influenced by emotional stress during asthma attacks.

  17. STAT4 gene polymorphism in patients after renal allograft transplantation

    PubMed Central

    Dąbrowska-Żamojcin, Ewa; Dziedziejko, Violetta; Safranow, Krzysztof; Domański, Leszek; Słuczanowska-Głabowska, Sylwia

    2016-01-01

    Introduction STAT4 (signal transducer and activator of transcription 4) is involved in the regulation of innate and adaptive immune responses. Some studies have suggested that STAT4 may be involved in the immune response after graft transplantation. Several polymorphisms in the STAT4 gene have been identified. The most commonly studied polymorphism in the STAT4 gene is rs7574865. In our study, we examined whether this polymorphism is associated with the early and late functions of renal allografts. Material and methods A total of 270 recipients of first renal transplants were included in the study. Single nucleotide polymorphisms (SNPs) within the STAT4 gene were genotyped using TaqMan genotyping assays. Results There were no statistically significant associations between the STAT4 gene rs7574865 polymorphism and delayed graft function, acute rejection, chronic allograft dysfunction, post-transplant diabetes mellitus, or creatinine serum concentrations after transplantation. Conclusions Our results suggest a lack of association between the STAT4 rs7574865 SNP and kidney allograft function in the Polish population. PMID:27833442

  18. Estrogen Receptor Polymorphisms and the Vascular Effects of Hormone Therapy

    PubMed Central

    Rossouw, Jacques; Bray, Paul; Liu, Jingmin; Kooperberg, Charles; Hsia, Judith; Lewis, Cora; Cushman, Mary; Bonds, Denise; Hendrix, Susan; Papanicolaou, George; Howard, Tim; Herrington, David

    2010-01-01

    Objective To test whether estrogen receptor polymorphisms modify the effects of postmenopausal hormone therapy on biomarkers and on risk of coronary heart disease events, stroke, or venous thrombo-embolism. Methods and Results The design was a nested case-control study in the Women’s Health Initiative trials of postmenopausal hormone therapy. The study included all cases in the first 4 years: coronary heart disease, 359; stroke, 248; venous thrombo-embolism, 217). Six estrogen receptor-αand one estrogen receptor-β polymorphisms were genotyped; 8 biomarkers known to be affected by hormone therapy were measured at baseline and one year after randomization. The polymorphisms were not associated with risk of vascular events, and did not modify the increased risks of coronary heart disease, stroke, or venous thrombo-embolism due to hormone therapy. However, a reduced response of plasmin-antiplasmin (PAP) to hormone therapy was noted for ESR1 IVS1-354 (interaction P<0.0001, corrected for multiple comparisons P=0.014) and ESR1 IVS1-1415 (interaction P<0.0001, corrected P= 0.014). Conclusions Estrogen receptor polymorphisms reduce the effect of postmenopausal hormone therapy on PAP, a marker of coagulation and fibrinolysis. However screening for ER polymorphisms to identify women at less risk of adverse cardiovascular outcomes is not likely to be useful for making HT treatment decisions. PMID:21106950

  19. Association of TNF, MBL, and VDR Polymorphisms with Leprosy Phenotypes

    PubMed Central

    Sapkota, Bishwa R.; Macdonald, Murdo; Berrington, William R.; Misch, E. Ann; Ranjit, Chaman; Siddiqui, M. Ruby; Kaplan, Gilla; Hawn, Thomas R.

    2010-01-01

    Background Although genetic variants in tumor necrosis factor (TNF), mannose binding lectin (MBL), and the vitamin D receptor (VDR) have been associated with leprosy clinical outcomes these findings have not been extensively validated. Methods We used a case-control study design with 933 patients in Nepal, which included 240 patients with type I reversal reaction (RR), and 124 patients with erythema nodosum leprosum (ENL) reactions. We compared genotype frequencies in 933 cases and 101 controls of 7 polymorphisms, including a promoter region variant in TNF (G−308A), three polymorphisms in MBL (C154T, G161A and G170A), and three variants in VDR (FokI, BsmI, and TaqI). Results We observed an association between TNF −308A and protection from leprosy with an odds ratio (OR) of 0.52 (95% confidence interval (CI) of 0.29 to 0.95, P = 0.016). MBL polymorphism G161A was associated with protection from lepromatous leprosy (OR (95% CI) = 0.33 (0.12–0.85), P = 0.010). VDR polymorphisms were not associated with leprosy phenotypes. Conclusion These results confirm previous findings of an association of TNF −308A with protection from leprosy and MBL polymorphisms with protection from lepromatous leprosy. The statistical significance was modest and will require further study for conclusive validation. PMID:20650301

  20. BDNF and TNF-α polymorphisms in memory.

    PubMed

    Yogeetha, B S; Haupt, L M; McKenzie, K; Sutherland, H G; Okolicsyani, R K; Lea, R A; Maher, B H; Chan, R C K; Shum, D H K; Griffiths, L R

    2013-09-01

    Here, we investigate the genetic basis of human memory in healthy individuals and the potential role of two polymorphisms, previously implicated in memory function. We have explored aspects of retrospective and prospective memory including semantic, short term, working and long-term memory in conjunction with brain derived neurotrophic factor (BDNF) and tumor necrosis factor-alpha (TNF-α). The memory scores for healthy individuals in the population were obtained for each memory type and the population was genotyped via restriction fragment length polymorphism for the BDNF rs6265 (Val66Met) SNP and via pyrosequencing for the TNF-α rs113325588 SNP. Using univariate ANOVA, a significant association of the BDNF polymorphism with visual and spatial memory retention and a significant association of the TNF-α polymorphism was observed with spatial memory retention. In addition, a significant interactive effect between BDNF and TNF-α polymorphisms was observed in spatial memory retention. In practice visual memory involves spatial information and the two memory systems work together, however our data demonstrate that individuals with the Val/Val BDNF genotype have poorer visual memory but higher spatial memory retention, indicating a level of interaction between TNF-α and BDNF in spatial memory retention. This is the first study to use genetic analysis to determine the interaction between BDNF and TNF-α in relation to memory in normal adults and provides important information regarding the effect of genetic determinants and gene interactions on human memory.

  1. [Turner syndrome and genetic polymorphism: a systematic review].

    PubMed

    Trovó de Marqui, Alessandra Bernadete

    2015-01-01

    To present the main results of the literature on genetic polymorphisms in Turner Syndrome and their association with the clinical signs and the etiology of this chromosomal disorder. The review was conducted in the PubMed database without any time limit, using the terms Turner syndrome and genetic polymorphism. A total of 116 articles were found, and based on the established inclusion and exclusion criteria 17 were selected for the review. The polymorphisms investigated in patients with Turner Syndrome were associated with growth deficit, causing short stature, low bone mineral density, autoimmunity and cardiac abnormalities, which are frequently found in patients with Turner Syndrome. The role of single nucleotide polymorphisms (SNPs) in the etiology of Turner syndrome, i.e., in chromosomal nondisjunction, was also confirmed. Genetic polymorphisms appear to be associated with Turner Syndrome. However, in view of the small number of published studies and their contradictory findings, further studies in different populations are needed in order to clarify the role of genetic variants in the clinical signs and etiology of the Turner Syndrome. Copyright © 2015 Sociedade de Pediatria de São Paulo. Publicado por Elsevier Editora Ltda. All rights reserved.

  2. PPARγ2Pro12Ala Polymorphism and Human Health

    PubMed Central

    He, Weimin

    2009-01-01

    The nuclear hormone receptor peroxisome proliferator activated receptor gamma (PPARγ) is an important transcription factor regulating adipocyte differentiation, lipid and glucose homeostasis, and insulin sensitivity. Numerous genetic mutations of PPARγ have been identified and these mutations positively or negatively regulate insulin sensitivity. Among these, a relatively common polymorphism of PPARγ, Pro12Ala of PPARγ2, the isoform expressed only in adipose tissue has been shown to be associated with lower body mass index, enhanced insulin sensitivity, and resistance to the risk of type 2 diabetes in human subjects carrying this mutation. Subsequent studies in different ethnic populations, however, have revealed conflicting results, suggesting a complex interaction between the PPARγ2 Pro12Ala polymorphism and environmental factors such as the ratio of dietary unsaturated fatty acids to saturated fatty acids and/or between the PPARγ2 Pro12Ala polymorphism and genetic factors such as polymorphic mutations in other genes. In addition, this polymorphic mutation in PPARγ2 is associated with other aspects of human diseases, including cancers, polycystic ovary syndrome, Alzheimer disease and aging. This review will highlight findings from recent studies. PMID:19390629

  3. Turner syndrome and genetic polymorphism: a systematic review

    PubMed Central

    de Marqui, Alessandra Bernadete Trovó

    2015-01-01

    Objective: To present the main results of the literature on genetic polymorphisms in Turner syndrome and their association with the clinical signs and the etiology of this chromosomal disorder. Data sources: The review was conducted in the PubMed database without any time limit, using the terms Turner syndrome and genetic polymorphism. A total of 116 articles were found, and based on the established inclusion and exclusion criteria 17 were selected for the review. Data synthesis: The polymorphisms investigated in patients with Turner syndrome were associated with growth deficit, causing short stature, low bone mineral density, autoimmunity and cardiac abnormalities, which are frequently found in patients with Turner syndrome. The role of single nucleotide polymorphisms in the etiology of Turner syndrome, i.e., in chromosomal nondisjunction, was also confirmed. Conclusions: Genetic polymorphisms appear to be associated with Turner syndrome. However, in view of the small number of published studies and their contradictory findings, further studies in different populations are needed in order to clarify the role of genetic variants in the clinical signs and etiology of the Turner syndrome. PMID:25765448

  4. The evolution of polymorphic sexual systems in daffodils (Narcissus).

    PubMed

    Barrett, Spencer C H; Harder, Lawrence D

    2005-01-01

    Narcissus, the daffodil genus, exhibits an unusual diversity of sexual systems, with populations that are monomorphic, dimorphic or trimorphic for style length. Associated with this variation are striking differences among species in floral morphology and pollination biology. This diversity provides an opportunity to investigate the evolution of mating polymorphisms, and to determine how floral morphology promotes transitions among sexual systems. Because of the absence of heteromorphic incompatibility in Narcissus, floral morphology plays a key role in governing patterns of outcrossed mating. Phylogenetic evidence indicates that stylar monomorphism is ancestral in the genus, with multiple origins of stylar polymorphism, including independent origins of stigma-height dimorphism, distyly and tristyly. Sexual polymorphisms have evolved only in lineages with narrow floral tubes that are pollinated by Lepidoptera and/or long-tongued bees. Populations of polymorphic Narcissus species are typically dominated by the long-styled morph and display imperfect reciprocity in the positions of sexual organs. These features are consequences of the unusual association between stylar polymorphism and a self-incompatibility system that permits intramorph mating.

  5. Polymorphisms in chronic rhinosinusitis with nasal polyps - a systematic review.

    PubMed

    Dinarte, Vanessa Ramos Pires; Santos, Anemari Ramos Dinarte Dos; Araújo, Luiza Ferreira de; Reis, Mariah Guieiro Alves Dos; Tamashiro, Edwin; Valera, Fabiana Cardoso Pereira; Silva Júnior, Wilson Araújo da; Anselmo-Lima, Wilma Terezinha

    2017-03-23

    Chronic rhinosinusitis with nasal polyps is a multifactorial disease with a complex pathophysiology involving multiple genetic and environmental factors. The purpose of this work review is to focus on the importance of genetic studies in chronic rhinosinusitis with nasal polyps besides the several barriers that exists for its understanding. A systematic review on studies of association between single nucleotide polymorphisms and chronic rhinosinusitis with nasal polyps based on a PubMed/Medline and Periódicos CAPES search of all articles published between January 2005 and January 2015 was made. The search was guided on studies containing the terms polymorphisms, rhinosinusitis, and polyps. Two studies found an association of MMP-9 and MMP-2 polymorphisms and chronic rhinosinusitis with nasal polyps, but not in patients with recurrent nasal polyps. Other studies found an association of nasal polyps with MMP-9 polymorphisms, but not with MMP-2 ones. There is evidence of an association of LTC4S, NOS2A, PTGDR, MET, COX-2, OSF-2, and LF polymorphisms and the risk of developing nasal polyps, especially when combined with chronic allergic rhinitis and asthma. Genetic studies on chronic rhinosinusitis with nasal polyps are promising and may offer insights into its pathophysiology, which is likely affected by multiple genetic factors. Copyright © 2017 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

  6. Effects of human SAMHD1 Polymorphisms on HIV-1 Susceptibility

    PubMed Central

    White, Tommy E.; Brandariz-Nuñez, Alberto; Valle-Casuso, Jose Carlos; Knowlton, Caitlin; Kim, Baek; Sawyer, Sara L.; Diaz-Griffero, Felipe

    2014-01-01

    SAMHD1 is a human restriction factor that prevents efficient infection of macrophages, dendritic cells and resting CD4+ T cells by HIV-1. Here we explored the antiviral activity and biochemical properties of human SAMHD1 polymorphisms. Our studies focused on human SAMHD1 polymorphisms that were previously identified as evolving under positive selection for rapid amino acid replacement during primate speciation. The different human SAMHD1 polymorphisms were tested for their ability to block HIV-1, HIV-2 and equine infectious anemia virus (EIAV). All studied SAMHD1 variants block HIV-1, HIV-2 and EIAV infection when compared to wild type. We found that these variants did not lose their ability to oligomerize or to bind RNA. Furthermore, all tested variants were susceptible to degradation by Vpx, and localized to the nuclear compartment. We tested the ability of human SAMHD1 polymorphisms to decrease the dNTP cellular levels. In agreement, none of the different SAMHD1 variants lost their ability to reduce cellular levels of dNTPs. Finally, we found that none of the tested human SAMHD1 polymorphisms affected the ability of the protein to block LINE-1 retrotransposition. PMID:25010268

  7. Development of novel polymorphic microsatellite markers in Siganus fuscescens.

    PubMed

    Mao, X Q; Li, Z B; Ning, Y F; Shangguan, J B; Yuan, Y; Huang, Y S; Li, B B

    2016-07-29

    Rabbitfish, Siganus fuscescens, is widely distributed in the Indo-Pacific regions and eastern Mediterranean. Its dwelling place includes reef flats, coral reef regions, and seagrass meadows in tropical area and reef areas or shallow waters in locations at high latitudes. In the present study, 10 new polymorphic microsatellite markers were screened from 30 wild S. fuscescens individuals, using a method of fast isolation protocol and amplified fragment length polymorphism of sequences containing repeats. The number of polymorphic alleles per locus was 3 to 5 with a mean of 4.3, while the value of polymorphic information content ranged from 0.283 to 0.680. The values of the observed and expected heterozygosities were in the range 0.3333-0.8462 and 0.3011-0.7424, respectively. Deviation from Hardy-Weinberg equilibrium was not observed in this study. These polymorphic loci are expected to be effective in evaluating the genetic diversity, population structure, and gene flow and in determining the paternity in S. fuscescens, as well as for conservation management.

  8. ID4 gene polymorphism and osteoporosis in Thai menopausal women.

    PubMed

    Chupeerach, Chaowanee; Kulanuwat, Sirikul; Chuenta, Wanida; Wannaiampikul, Sivaporn; Schuh, Vanessa Anne; Preutthipan, Sangchai; Tungtrongchitr, Rungsunn

    2014-10-01

    The inhibitor of DNA binding 4 (ID4) protein regulates osteogenic and adipogenic cell fate and lack of lD4 gene expression decreased osteoblast differentiation. Variant in the ID4 gene polymorphism has not been reported with osteoporosis. To identify whether ID4 can be a marker gene for osteoporosis in Thai menopausal women. The 3 'UTR of lD4 (rs3798339) single nucleotide polymorphism was examined bypolymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP), together with lumbar spine bone mineral density (BAMD) in 160 Thai menopausal women. Lumbar spine 3 (L3) had a significantly lower BMD score in women with the TT genotype, compared with the CT+CC genotypes (p = 0.037). This disappeared after the adjustment of various factors. The polymorphism at 3'UTR of lD4 gene can alter ID4 mRNA stability, and may be linked to the function of proteins. However, this needs confirmation in larger populations. The present study is useful as an initial investigation into ID4 gene polymorphism in osteoporosis.

  9. Germline TP53 mutations and single nucleotide polymorphisms in children.

    PubMed

    Valva, Pamela; Becker, Pablo; Streitemberger, Patricia; Lombardi, García Mercedes; Rey, Guadalupe; Guzman, Carlos A; Preciado, María Victoria

    2009-01-01

    Mutations in the gene TP53, which codifies the tumor suppressor protein p53, are found in about 50% of tumors. These mutations can occur not only at somatic level, but also in germline. Pediatric cancer patients, mostly with additional family history of malignancy, should be considered as potential TP53 germline mutation carriers. Germline TP53 mutations and polymorphisms have been widely studied to determine their relation with different tumors' pathogenesis. Our aim was to analyze the occurrence frequency of germline TP53 mutations and polymorphisms and to relate these to tumor development in a pediatric series. Peripheral blood mononuclear cell samples from 26 children with solid tumors [PST] and 21 pediatric healthy donors [HD] were analyzed for germline mutations and polymorphisms in TP53 gene spanning from exon 5 to 8 including introns 5 and 7. These PCR amplified fragments were sequenced to determine variations. A heterozygous mutation at codon 245 was found in 1/26 PST and 0/21 HD. Comparative polymorphisms distribution, at position 14181 and 14201(intron 7), between HD and PST revealed a trend of association (p= 0.07) with cancer risk. HD group disclosed a similar polymorphism distribution as published data for Caucasian and Central/South American populations. This is the first study about TP53 variant frequency and distribution in healthy individuals and cancer patients in Argentina.

  10. No associations between five polymorphisms in COMT gene and migraine.

    PubMed

    Takigawa, H; Kowa, H; Nakashima, K

    2017-02-01

    The pathophysiology of migraine headaches is not clearly understood yet. The dopaminergic system has been hypothesized to be involved in migraine pathogenesis. The aim of this study was to investigate catechol-O-methyltransferase (COMT) polymorphisms and chronic headaches. We analyzed five single nucleotide polymorphisms (SNPs) in COMT. The study population consisted of 71 patients with migraine with aura, 152 patients with migraine without aura, 86 patients with tension-type headache, and 191 healthy controls. The selected polymorphic markers included one causing His62His (rs4633) and two non-synonymous SNPs, Ala72Ser and Val158Met (rs6267, rs4680 respectively). Two other non-polymorphic SNPs (rs6270, rs740602) were examined. We found no significant differences in any genotypes, allele frequencies, or haplotypes among the patient groups and controls. Our results indicate that the five polymorphisms in COMT have no association with migraineurs in Western Japan. The possibility that segments elsewhere in the gene may contain a mutation responsible for modifying the expression of COMT or the activity of the enzyme is important. We cannot conclusively exclude the entire COMT gene from being involved in migraine pathogenesis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Micro-Evolution in Grasshoppers Mediated by Polymorphic Robertsonian Translocations

    PubMed Central

    Colombo, Pablo C.

    2013-01-01

    This review focuses on grasshoppers that are polymorphic for Robertsonian translocations because in these organisms the clarity of meiotic figures allows the study of both chiasma distribution and the orientation of trivalents and multivalents in metaphase I. Only five species of such grasshoppers were found in the literature, and all of them were from the New World: Oedaleonotus enigma (Scudder) (Orthoptera: Acrididae), Leptysma argentina Bruner, Dichroplus pratensis Bruner, Sinipta dalmani Stål, and Cornops aquaticum Bruner. A general feature of these species (except O. enigma) is that fusion carriers suffer a marked reduction of proximal and interstitial (with respect to the centromere) chiasma frequency; this fact, along with the reduction in the number of linkage groups with the consequent loss of independent segregation, produces a marked decrease of recombination in fusion carriers. This reduction in recombination has led to the conclusion that Robertsonian polymorphic grasshopper species share some properties with inversion polymorphic species of Drosophila, such as the central-marginal pattern (marginal populations are monomorphic, central populations are highly polymorphic). This pattern might be present in D. pratensis, which is certainly the most complex Robertsonian polymorphism system in the present study. However, L. argentina and C. aquaticum do not display this pattern. This issue is open to further research. Since C. aquaticum is soon to be released in South Africa as a biological control, the latitudinal pattern found in South America may repeat there. This experiment's outcome is open and deserves to be followed. PMID:23909914

  12. Micro-evolution in grasshoppers mediated by polymorphic Robertsonian translocations.

    PubMed

    Colombo, Pablo C

    2013-01-01

    This review focuses on grasshoppers that are polymorphic for Robertsonian translocations because in these organisms the clarity of meiotic figures allows the study of both chiasma distribution and the orientation of trivalents and multivalents in metaphase I. Only five species of such grasshoppers were found in the literature, and all of them were from the New World: Oedaleonotus enigma (Scudder) (Orthoptera: Acrididae), Leptysma argentina Bruner, Dichroplus pratensis Bruner, Sinipta dalmani Stål, and Cornops aquaticum Bruner. A general feature of these species (except O. enigma) is that fusion carriers suffer a marked reduction of proximal and interstitial (with respect to the centromere) chiasma frequency; this fact, along with the reduction in the number of linkage groups with the consequent loss of independent segregation, produces a marked decrease of recombination in fusion carriers. This reduction in recombination has led to the conclusion that Robertsonian polymorphic grasshopper species share some properties with inversion polymorphic species of Drosophila, such as the central-marginal pattern (marginal populations are monomorphic, central populations are highly polymorphic). This pattern might be present in D. pratensis, which is certainly the most complex Robertsonian polymorphism system in the present study. However, L. argentina and C. aquaticum do not display this pattern. This issue is open to further research. Since C. aquaticum is soon to be released in South Africa as a biological control, the latitudinal pattern found in South America may repeat there. This experiment's outcome is open and deserves to be followed.

  13. Polymorphisms in neuropeptide genes and bone mineral density in Korean postmenopausal women.

    PubMed

    Chun, Eun Hee; Kim, Hoon; Suh, Chang Suk; Kim, Jong Hak; Kim, Dong Yeon; Kim, Jung Gu

    2015-11-01

    The purpose of this study was to investigate the association between single nucleotide polymorphisms in neuropeptide genes and bone mineral density (BMD) in Korean postmenopausal women. Twenty polymorphisms in NMU (neuromedin U; two polymorphisms), NMU2R (NMU receptor 2; six polymorphisms), CART (cocaine- and amphetamine-regulated transcript; three polymorphisms), NPY (neuropeptide Y; four polymorphisms), NPY2R (NPY type 2 receptor; two polymorphisms), NOS1 (neuronal nitric oxide synthase; two polymorphisms), and MC4R (melanocortin 4 receptor; one polymorphism) genes were analyzed in 482 Korean postmenopausal women. BMD at the lumbar spine and femoral neck was also examined. Effects of polymorphisms on BMD were evaluated after adjusting for potential confounding factors using analysis of covariance. Odds ratios and 95% CIs for osteoporosis were estimated using χ2 test or Fisher's exact test. Among the polymorphisms measured, the AG genotype of CART rs2239670 had the highest BMD at the lumbar spine. Furthermore, osteoporosis at the lumbar spine was more frequently observed in the GG genotype of NPY rs17149106 polymorphism and in the CC genotype of NPY rs16123 polymorphism and was less frequently observed in the TT-TT genotype identified by a combined polymorphism in the NPY2R gene, compared with the other genotypes. The AA genotype of NOS1 rs1279104 polymorphism was found to have a 3.68-fold higher prevalence of osteoporosis at the femoral neck compared with the GG genotype (95% CI, 1.29-10.50; P = 0.02). Results suggest that CART rs2239670 polymorphism may be one of the genetic factors affecting lumbar spine BMD in Korean postmenopausal women and that NPY rs17149106, NPY rs16123, NOS1 rs1279104, and combined (rs2880415 and rs6857715) polymorphisms in the NPY2R gene may be useful in identifying women at risk for osteoporosis.

  14. Geographic variation in animal colour polymorphisms and its role in speciation.

    PubMed

    McLean, Claire A; Stuart-Fox, Devi

    2014-11-01

    Polymorphic species, in which multiple variants coexist within a population, are often used as model systems in evolutionary biology. Recent research has been dominated by the hypothesis that polymorphism can be a precursor to speciation. To date, the majority of research regarding polymorphism and speciation has focused on whether polymorphism is maintained within a population or whether morphs within populations may diverge to form separate species (sympatric speciation); however, the geographical context of speciation in polymorphic systems is likely to be both diverse and complex. In this review, we draw attention to the geographic variation in morph composition and frequencies that characterises many, if not most polymorphic species. Recent theoretical and empirical developments suggest that such variation in the number, type and frequency of morphs present among populations can increase the probability of speciation. Thus, the geographical context of a polymorphism requires a greater research focus. Here, we review the prevalence, causes and evolutionary consequences of geographic variation in polymorphism in colour-polymorphic animal species. The prevalence and nature of geographic variation in polymorphism suggests that polymorphism may be a precursor to and facilitate speciation more commonly than appreciated previously. We argue that a better understanding of the processes generating geographic variation in polymorphism is vital to understanding how polymorphism can promote speciation.

  15. Characterization of crystal polymorphs of the organic semiconductor non-peripheral octa-hexyl phthalocyanine

    NASA Astrophysics Data System (ADS)

    Yoneya, Makoto; Miyamoto, Ayano; Shimizu, Yo; Ohmori, Masashi; Fujii, Akihiko; Ozaki, Masanori

    2017-08-01

    The carrier-transport and thermodynamic properties of two crystal polymorphs, i.e., bulk and needle polymorphs, of non-peripheral octa-hexyl substituted phthalocyanine were investigated using density functional theory calculations and molecular dynamics simulations. The calculated results show that the bulk and needle polymorphs have hole mobilities of the same order of magnitude and that the hole mobility of the bulk polymorph was approximately twice that of the needle polymorph. For ideal one-dimensional transport along π stacking columns, the difference in mobility between the two polymorphs was larger by a factor of approximately 8. Therefore, we can expect the bulk polymorph to have 2 (or 8) times higher mobility than the values for the needle polymorph. These results predict that the bulk polymorph has the potential to show higher device performance than the needle polymorph. We also obtained the results that imply that a needle-polymorph-like phase with uniform (monoclinic) phthalocyanine-core tilting (instead of the alternative tilting of the needle polymorph) could be a new polymorph in this crystal system.

  16. The Y Alu polymorphism in southern African populations and its relationship to other Y-specific polymorphisms

    SciTech Connect

    Spurdle, A.B.; Jenkins, T. ); Hammer, M.F. )

    1994-02-01

    Y-linked polymorphisms were studied in a number of African populations. The frequency of the alleles of a Y-specific Alu insertion polymorphism, termed the [open quotes]Y Alu polymorphism,[close quotes] was determined in 889 individuals from 23 different African population groups. A trend in frequency was observed, with the insert largely absent in Caucasoid populations, at intermediate frequency in the Khoisan, and at high frequency in Negroids. The insert predates diversification of Homo sapiens, since it occurs in all groups. The Alu insertion is believed to result from a unique mutation event, and comparisons between this and several other Y-linked polymorphisms were carried out in an attempt to validate their usefulness in population and evolutionary studies. The p21A1/Taql and pDP31/EcoRI polymorphisms and 49a/TaqI alleles were all shown to have arisen on more than one occasion, and evidence exists for a preraciation crossover event between the Y-linked pseudoautosomal XY275 locus and the Y chromosome pseudoautosomal boundary. 33 refs., 4 figs., 5 tabs.

  17. The Y Alu polymorphism in southern African populations and its relationship to other Y-specific polymorphisms.

    PubMed Central

    Spurdle, A. B.; Hammer, M. F.; Jenkins, T.

    1994-01-01

    Y-linked polymorphisms were studied in a number of African populations. The frequency of the alleles of a Y-specific Alu insertion polymorphism, termed the "Y Alu polymorphism," was determined in 889 individuals from 23 different African population groups. A trend in frequency was observed, with the insert largely absent in Caucasoid populations, at intermediate frequency in the Khoisan, and at high frequency in Negroids. The insert predates diversification of Homo sapiens, since it occurs in all groups. The Alu insertion is believed to result from a unique mutation event, and comparisons between this and several other Y-linked polymorphisms were carried out in an attempt to validate their usefulness in population and evolutionary studies. The p21A1/TaqI and pDP31/EcoRI polymorphisms and 49a/TaqI alleles were all shown to have arisen on more than one occasion, and evidence exists for a preraciation crossover event between the Y-linked pseudoautosomal XY275 locus and the Y chromosome pseudoautosomal boundary. PMID:8304348

  18. Catecholaminergic polymorphic ventricular tachycardia: a rare cause of recurrent syncope

    PubMed Central

    Azevedo, Ana Isabel; Dias, Adelaide; Teixeira, Madalena; Gama Ribeiro, Vasco

    2015-01-01

    Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia characterized by adrenergically induced polymorphic or bidirectional ventricular tachycardia (VT). Although a rare disease, its recognition is important because of its high mortality rate when left untreated. We report an index case of a 32-year-old woman who presented with recurrent syncope. The diagnosis was confirmed by exercise-induced polymorphic ventricular premature beats and episodes of non-sustained VT, in the absence of structural heart abnormalities. She remained event free with beta-blocker therapy. CPVT is a potentially life-threatening disease and should be considered in the case of recurrent syncope, in young individuals. Diagnosis is based on clinical history and exercise testing, which is the gold standard. Therapy is mandatory in all diagnosed individuals. Exercise testing in first-degree relatives is recommended, even in the case of a mutation-negative index patient. PMID:26512332

  19. Hepatitis-related hepatocellular carcinoma: Insights into cytokine gene polymorphisms.

    PubMed

    Dondeti, Mahmoud Fathy; El-Maadawy, Eman Anwar; Talaat, Roba Mohamed

    2016-08-14

    Hepatocellular carcinoma (HCC) is a primary liver cancer, which is one of the most prevalent cancers among humans. Many factors are involved in the liver carcinogenesis as lifestyle and environmental factors. Hepatitis virus infections are now recognized as the chief etiology of HCC; however, the precise mechanism is still enigmatic till now. The inflammation triggered by the cytokine-mediated immune response, was reported to be the closest factor of HCC development. Cytokines are immunoregulatory proteins produced by immune cells, functioning as orchestrators of the immune response. Genes of cytokines and their receptors are known to be polymorphic, which give rise to variations in their genes. These variations have a great impact on the expression levels of the secreted cytokines. Therefore, cytokine gene polymorphisms are involved in the molecular mechanisms of several diseases. This piece of work aims to shed much light on the role of cytokine gene polymorphisms as genetic host factor in hepatitis related HCC.

  20. Polymorphisms of candidate genes in Slovak autistic patients.

    PubMed

    Kelemenova, Silvia; Schmidtova, Eva; Ficek, Andrej; Celec, Peter; Kubranska, Aneta; Ostatnikova, Daniela

    2010-08-01

    Autism is one of the most genetically influenced neuropsychiatric disorders. However, its detailed genetic basis is far from being clear. Genome-wide association studies have revealed a number of candidate genes, mostly related to synaptogenesis and various neuroendocrine pathways. In our study we have focused on oxytocin (OT), oxytocin receptor (OXTR), GABA receptor gamma 3 (GABRG3), neuroligin (NLGN4X), and reelin (RELN). After signed consent, 90 autistic boys and 85 healthy controls were enrolled in the study. Polymorphisms of OT (rs2740204), OXTR (rs2228485), GABRG3 (rs28431127), and NLGN4X (rs5916338) were analyzed using restriction fragment length polymorphism. (GGC)n STR polymorphism in the 5' UTR of the RELN gene was genotyped using fragment analysis. The only significant association in autistic boys in Slovakia was found with higher number of GGC repeats in the RELN gene (P=0.001) potentially explaining lower RELN levels in blood and brain of autistic patients.

  1. High-pressure polymorphism of acetylsalicylic acid (aspirin): Raman spectroscopy

    NASA Astrophysics Data System (ADS)

    Crowell, Ethan L.; Dreger, Zbigniew A.; Gupta, Yogendra M.

    2015-02-01

    Micro-Raman spectroscopy was used to elucidate the high-pressure polymorphic behavior of acetylsalicylic acid (ASA), an important pharmaceutical compound known as aspirin. Using a diamond anvil cell (DAC), single crystals of the two polymorphic phases of aspirin existing at ambient conditions (ASA-I and ASA-II) were compressed to 10 GPa. We found that ASA-I does not transform to ASA-II, but instead transforms to a new phase (ASA-III) above ∼2 GPa. It is demonstrated that this transformation primarily introduces structural changes in the bonding and arrangement of the acetyl groups and is reversible upon the release of pressure. In contrast, a less dense ASA-II shows no transition in the pressure range studied, though it appears to exhibit a disordered structure above 7 GPa. Our results suggest that ASA-III is the most stable polymorph of aspirin at high pressures.

  2. The epidemiology of Plasmodium vivax circumsporozoite protein polymorphs in Thailand.

    PubMed

    Suwanabun, N; Sattabongkot, J; Wirtz, R A; Rosenberg, R

    1994-04-01

    Enzyme-linked immunosorbent assays (ELISAs) highly specific for the characteristic repeat units of the circumsporozoite proteins of the VK 247 and VK 210 polymorphs of Plasmodium vivax were used to test sporozoites produced by feeding mosquitoes on 1,711 human volunteers presenting at four locations in Thailand over five years. There was no evidence for the existence of any polymorph other than the two already described. Based on the ELISAs, the overall prevalence of the VK 247 type was 29.5%, including those found mixed with VK 210. Relative proportions of VK 210 and VK 247 differed between collection sites. At all places, the ratio of VK 210 to VK 247 was significantly higher at the end of the nontransmission season than it was later during the annual monsoon, suggesting that there may be intrinsic biological differences between the polymorphs that affect their survival.

  3. Vitamin D receptor (VDR) polymorphisms and skin cancer

    PubMed Central

    Denzer, Nicole; Vogt, Thomas

    2011-01-01

    Skin cancer is the most common cancer in humans. There are several types of skin cancer that include basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and malignant melanoma (MM). The associations of vDr polymorphisms with skin cancer risk are not well characterized so far. Only a few epidemiologic studies have directly addressed the relationship between VDR polymorphisms and the incidence and prognosis of MM. To make the most of the available information on VDR polymorphisms and skin cancer (MM, BCC and SCC), we undertook a systematic review of published studies. In conclusion, data summarized in this review support the concept that the vitamin D endocrine system (VDES) is of importance for pathogenesis and progression of MM and other types of skin cancer. PMID:22110781

  4. Hepatitis-related hepatocellular carcinoma: Insights into cytokine gene polymorphisms

    PubMed Central

    Dondeti, Mahmoud Fathy; El-Maadawy, Eman Anwar; Talaat, Roba Mohamed

    2016-01-01

    Hepatocellular carcinoma (HCC) is a primary liver cancer, which is one of the most prevalent cancers among humans. Many factors are involved in the liver carcinogenesis as lifestyle and environmental factors. Hepatitis virus infections are now recognized as the chief etiology of HCC; however, the precise mechanism is still enigmatic till now. The inflammation triggered by the cytokine-mediated immune response, was reported to be the closest factor of HCC development. Cytokines are immunoregulatory proteins produced by immune cells, functioning as orchestrators of the immune response. Genes of cytokines and their receptors are known to be polymorphic, which give rise to variations in their genes. These variations have a great impact on the expression levels of the secreted cytokines. Therefore, cytokine gene polymorphisms are involved in the molecular mechanisms of several diseases. This piece of work aims to shed much light on the role of cytokine gene polymorphisms as genetic host factor in hepatitis related HCC. PMID:27570418

  5. [Pathogenic mutation or polymorphism? (How to find criteria)].

    PubMed

    Kochański, Andrzej

    2006-01-01

    The classification of amino-acid substitutions into pathogenic mutations and harmless polymorphisms should be revised. In the recent years it was shown that some amino-acid substitutions considered as pathogenic mutations were polymorphisms. Similarly, some 'harmless' polymorphisms have been shown to be pathogenic mutations. Functional analysis considered as a good method to estimate the pathogenic nature of mutations is also limited. The selection of DNA samples for the control group is also difficult. Due to the molecular mechanism mediated by recently discovered exonic splicing enhancers and silencers (ESE and ESS) it is hard to predict a pathogenic effect of some mutations. In addition, the phenotype variability observed between unrelated patients harboring the same mutation may reflect the effects of modifying genes as well as the lack of association between mutation and "its" phenotype. The aim of this study is to describe the problem of the pathogenic effect of mutations.

  6. Compositions and methods for detecting single nucleotide polymorphisms

    DOEpatents

    Yeh, Hsin-Chih; Werner, James; Martinez, Jennifer S.

    2016-11-22

    Described herein are nucleic acid based probes and methods for discriminating and detecting single nucleotide variants in nucleic acid molecules (e.g., DNA). The methods include use of a pair of probes can be used to detect and identify polymorphisms, for example single nucleotide polymorphism in DNA. The pair of probes emit a different fluorescent wavelength of light depending on the association and alignment of the probes when hybridized to a target nucleic acid molecule. Each pair of probes is capable of discriminating at least two different nucleic acid molecules that differ by at least a single nucleotide difference. The methods can probes can be used, for example, for detection of DNA polymorphisms that are indicative of a particular disease or condition.

  7. NQR investigation and characterization of cocrystals and crystal polymorphs

    NASA Astrophysics Data System (ADS)

    Seliger, Janez; Žagar, Veselko; Asaji, Tetsuo

    2013-05-01

    The application of 14N NQR to the study of cocrystals and crystal polymorphs is reviewed. In ferroelectric and antiferroelectric organic cocrystals 14N NQR is used to determine proton position in an N-H...O hydrogen bond and proton displacement below TC. In cocrystal isonicitinamide - oxalic acid (2:1) 14N NQR is used to distinguish between two polymorphs and to determine the type of the hydrogen bond (N-...H-O). The difference in the 14N NQR spectra of cocrystal formers and cocrystal is investigated in case of carbamazepine, saccharin and carbamazepine - saccharin (1:1). The experimental resolution allows an unambiguous distinction between the 14N NQR spectrum of the cocrystal and the 14N NQR spectra of the cocrystal formers. The possibility of application of NQR and double resonance for the determination of the inhomogeneity of the sample and for the study of the life time of an unstable polymorph is discussed.

  8. Structural and Physicochemical Studies of Olopatadine Hydrochloride Conformational Polymorphs.

    PubMed

    Łaszcz, Marta; Trzcińska, Kinga; Witkowska, Anna; Ciesielska, Agnieszka; Badowska-Rosłonek, Katarzyna; Kuziak, Krzysztof

    2016-08-01

    Crystal and molecular structures of 2 conformational polymorphs (forms I and II) of olopatadine hydrochloride, an antiallergic agent, are presented. Both crystal modifications crystallize in the monoclinic crystal system with 1 olopatadine hydrochloride molecule in the Z configuration in the asymmetric unit. Molecules are arranged into the centrosymmetric association through the interactions of the intermolecular strong and weak hydrogen bonds of N-H…Cl, O-H…Cl and C-H…Cl, C-H…O types. Conformational change between polymorphs is proved by calculations of a maximum torsion angle deviation (max[Δθ]) and a root-mean-square deviation between the atomic positions (rmsd[r]). The physicochemical characterization of polymorphs is performed by X-ray powder diffraction, infrared and Raman spectroscopy, differential scanning calorimetry. The comparison of the melting points and heats of fusions shows that the forms are monotropically related. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  9. Sequence polymorphisms cause many false cis eQTLs.

    PubMed

    Alberts, Rudi; Terpstra, Peter; Li, Yang; Breitling, Rainer; Nap, Jan-Peter; Jansen, Ritsert C

    2007-07-18

    Many investigations have reported the successful mapping of quantitative trait loci (QTLs) for gene expression phenotypes (eQTLs). Local eQTLs, where expression phenotypes map to the genes themselves, are of especially great interest, because they are direct candidates for previously mapped physiological QTLs. Here we show that many mapped local eQTLs in genetical genomics experiments do not reflect actual expression differences caused by sequence polymorphisms in cis-acting factors changing mRNA levels. Instead they indicate hybridization differences caused by sequence polymorphisms in the mRNA region that is targeted by the microarray probes. Many such polymorphisms can be detected by a sensitive and novel statistical approach that takes the individual probe signals into account. Applying this approach to recent mouse and human eQTL data, we demonstrate that indeed many local eQTLs are falsely reported as "cis-acting" or "cis" and can be successfully detected and eliminated with this approach.

  10. Sampling Polymorphs of Ionic Solids using Random Superlattices.

    PubMed

    Stevanović, Vladan

    2016-02-19

    Polymorphism offers rich and virtually unexplored space for discovering novel functional materials. To harness this potential approaches capable of both exploring the space of polymorphs and assessing their realizability are needed. One such approach devised for partially ionic solids is presented. The structure prediction part is carried out by performing local density functional theory relaxations on a large set of random supperlattices (RSLs) with atoms distributed randomly over different planes in a way that favors cation-anion coordination. Applying the RSL sampling on MgO, ZnO, and SnO_{2} reveals that the resulting probability of occurrence of a given structure offers a measure of its realizability explaining fully the experimentally observed, metastable polymorphs in these three systems.

  11. DNA polymorphism analysis of hereditary multiple exostoses in horses.

    PubMed

    Li, J K; Moloney, B K; Shupe, J L; Gardner, E J; Leone, N C; Elsner, Y

    1989-06-01

    Genomic DNA polymorphisms obtained by restriction fragment-length polymorphism from healthy horses and horses with hereditary multiple exostoses were analyzed. These DNA were digested by 12 restriction enzymes and were hybridized against 6 isotopically labeled oncogene probes. Hybridization was not detected with the viral oncogene, v-ras, which indicated this oncogene was absent in the equine genome. Oncogenes (c-raf-1, c-fes, c-myb, c-myc, and c-sis) were present and had similar hybridization patterns and signal intensities in DNA from healthy horses and horses with hereditary multiple exostoses. Unique and distinct restriction fragment-length polymorphisms were detected with the c-raf-1 probe only in BamHI- and PstI-digested equine DNA.

  12. Mu opioid receptor polymorphism, early social adversity, and social traits.

    PubMed

    Carver, Charles S; Johnson, Sheri L; Kim, Youngmee

    2016-10-01

    A polymorphism in the mu opioid receptor gene OPRM1 (rs1799971) has been investigated for its role in sensitivity to social contexts. Evidence suggests that the G allele of this polymorphism is associated with higher levels of sensitivity. This study tested for main effects of the polymorphism and its interaction with a self-report measure of childhood adversity as an index of negative environment. Outcomes were several personality measures relevant to social connection. Significant interactions were obtained, such that the negative impact of childhood adversity on personality was greater among G carriers than among A homozygotes on measures of agreeableness, interdependence, anger proneness, hostility, authentic pride, life engagement, and an index of (mostly negative) feelings coloring one's world view. Findings support the role of OPRM1 in sensitivity to negative environments. Limitations are noted, including the lack of a measure of advantageous social environment to assess sensitivity to positive social contexts.

  13. Disappearing and reappearing polymorphs. The benzocaine:picric acid system.

    PubMed

    Henck, J O; Bernstein, J; Ellern, A; Boese, R

    2001-03-07

    The low-melting polymorphic modification of the 1:1 complex of benzocaine (BC) and picric acid (PA) had earlier been reported to be an example of a "disappearing polymorph". The BC:PA system has been reinvestigated by thermomicroscopy, calorimetry, solid-state NMR, and X-ray crystallography. The phase diagram has been derived, and robust procedures for the crystallization of the two 1:1 complexes, a hydrate of the 1:1 complex, and a 2:1 complex have been devised. The structures of all four phases have been determined and compared using graph set analysis to characterize the hydrogen-bonding patterns. It is shown that the thorough microscopic investigation of the thermal behavior, combined with calorimetric methods, can lead to the development of strategies to crystallize metastable polymorphic forms which may be difficult to obtain once their stable congeners have been obtained.

  14. Collagen polymorphism in idiopathic chronic pulmonary fibrosis.

    PubMed Central

    Seyer, J M; Hutcheson, E T; Kang, A H

    1976-01-01

    diminished, ranging from 12 to 24% in different patients. These results indicate that an alteration in tissue collagen polymorphism as well as subtle variations in the collagen structure accompany the fibrotic process in the diseased state, and suggest that these alterations may have possible pathogenetic implications. PMID:777026

  15. The association between IGF-1 polymorphisms and high myopia

    PubMed Central

    Zhang, Xiaoyu; Zhou, Xingtao; Qu, Xinhua

    2015-01-01

    Background: The potential association between IGF-1 polymorphisms and high myopia has been investigated in previous studies, but the actual relationship remains controversial. Accordingly, we conducted a meta-analysisincludingcase-control and cohort studies to assess the existing relationship between high myopia and IGF-1 polymorphisms. We searched MEDLINE, EMBASE, and OVID. Odds ratios (OR) with 95% confidence intervals (CI) were derived for single-nucleotide polymorphisms (SNPs) involved in the studies obtained from the retrospective database search. Analyses of heterogeneity, sensitivity, and publication bias were also conducted. The findings from this meta-analysis were based on approximately 2,187 high myopia cases and 1,183 controls, and were used to assess the association between three IGF-1 genetic polymorphisms (rs6214, rs12423791, and rs5742632) and high myopia risks. We investigated the association of the IGF-1 gene SNP rs6214, but no statistical association was observed in the resulting odds ratios (OR) in the allelic (OR = 1.06, 95% CI = 0.89-1.25), dominant (OR = 1.07, 95% CI = 0.90-1.27), or recessive models (OR = 1.06, 95% CI = 0.89-1.26), or in the homozygote (OR = 1.12, 95% CI = 0.91-1.38) and heterozygote comparisons (OR = 1.06, 95% CI = 0.88-1.27). Simultaneously, two other selected SNPs, rs12423791 and rs5742632, were also studied, but similarly, no statistical association existed between these polymorphisms and the risk of high myopia. In conclusions, no statistical association between IGF-1 polymorphisms (rs6214, rs12423791, and rs5742632) and the risk of high myopia was observed following the reported meta-analysis. PMID:26309715

  16. Endothelin-1 Pathway Polymorphisms and Outcomes in Pulmonary Arterial Hypertension

    PubMed Central

    Gomberg-Maitland, Mardi; Demarco, Teresa; Frost, Adaani E.; Torbicki, Adam; Langleben, David; Pulido, Tomas; Correa-Jaque, Priscilla; Passineau, Michael J.; Wiener, Howard W.; Tamari, Mayumi; Hirota, Tomomitsu; Kubo, Michiaki; Tiwari, Hemant K.

    2015-01-01

    Rationale: Pulmonary arterial hypertension (PAH) is a progressive fatal disease. Variable response and tolerability to PAH therapeutics suggests that genetic differences may influence outcomes. The endothelin pathway is central to pulmonary vascular function, and several polymorphisms and/or mutations in the genes coding for endothelin (ET)-1 and its receptors correlate with the clinical manifestations of other diseases. Objectives: To examine the interaction of ET-1 pathway polymorphisms and treatment responses of patients with PAH treated with ET receptor antagonists (ERAs). Methods: A total of 1,198 patients with PAH were prospectively enrolled from 45 U.S. and Canadian pulmonary hypertension centers or retrospectively from global sites participating in the STRIDE (Sitaxsentan To Relieve Impaired Exercise) trials. Comprehensive objective measures including a 6-minute-walk test, Borg dyspnea score, functional class, and laboratory studies were completed at baseline, before the initiation of ERAs, and repeated serially. Single-nucleotide polymorphisms from ET-1 pathway candidate genes were selected from a completed genome-wide association study performed on the study cohort. Measurements and Main Results: Patient efficacy outcomes were analyzed for a relationship between ET-1 pathway polymorphisms and clinical efficacy using predefined, composite positive and negative outcome measures in 715 European descent samples. A single-nucleotide polymorphism (rs11157866) in the G-protein alpha and gamma subunits gene was significantly associated, accounting for multiple testing, with a combined improvement in functional class and 6-minute-walk distance at 12 and 18 months and marginally significant at 24 months. Conclusions: ET-1 pathway associated polymorphisms may influence the clinical efficacy of ERA therapy for PAH. Further prospective studies are needed. PMID:26252367

  17. Catalog of microRNA seed polymorphisms in vertebrates.

    PubMed

    Zorc, Minja; Skok, Dasa Jevsinek; Godnic, Irena; Calin, George Adrian; Horvat, Simon; Jiang, Zhihua; Dovc, Peter; Kunej, Tanja

    2012-01-01

    MicroRNAs (miRNAs) are a class of non-coding RNA that plays an important role in posttranscriptional regulation of mRNA. Evidence has shown that miRNA gene variability might interfere with its function resulting in phenotypic variation and disease susceptibility. A major role in miRNA target recognition is ascribed to complementarity with the miRNA seed region that can be affected by polymorphisms. In the present study, we developed an online tool for the detection of miRNA polymorphisms (miRNA SNiPer) in vertebrates (http://www.integratomics-time.com/miRNA-SNiPer) and generated a catalog of miRNA seed region polymorphisms (miR-seed-SNPs) consisting of 149 SNPs in six species. Although a majority of detected polymorphisms were due to point mutations, two consecutive nucleotide substitutions (double nucleotide polymorphisms, DNPs) were also identified in nine miRNAs. We determined that miR-SNPs are frequently located within the quantitative trait loci (QTL), chromosome fragile sites, and cancer susceptibility loci, indicating their potential role in the genetic control of various complex traits. To test this further, we performed an association analysis between the mmu-miR-717 seed SNP rs30372501, which is polymorphic in a large number of standard inbred strains, and all phenotypic traits in these strains deposited in the Mouse Phenome Database. Analysis showed a significant association between the mmu-miR-717 seed SNP and a diverse array of traits including behavior, blood-clinical chemistry, body weight size and growth, and immune system suggesting that seed SNPs can indeed have major pleiotropic effects. The bioinformatics analyses, data and tools developed in the present study can serve researchers as a starting point in testing more targeted hypotheses and designing experiments using optimal species or strains for further mechanistic studies.

  18. Polymorphism of the DNA Base Excision Repair Genes in Keratoconus

    PubMed Central

    Wojcik, Katarzyna A.; Synowiec, Ewelina; Sobierajczyk, Katarzyna; Izdebska, Justyna; Blasiak, Janusz; Szaflik, Jerzy; Szaflik, Jacek P.

    2014-01-01

    Keratoconus (KC) is a degenerative corneal disorder for which the exact pathogenesis is not yet known. Oxidative stress is reported to be associated with this disease. The stress may damage corneal biomolecules, including DNA, and such damage is primarily removed by base excision repair (BER). Variation in genes encoding BER components may influence the effectiveness of corneal cells to cope with oxidative stress. In the present work we genotyped 5 polymorphisms of 4 BER genes in 284 patients and 353 controls. The A/A genotype of the c.–1370T>A polymorphism of the DNA polymerase γ (POLG) gene was associated with increased occurrence of KC, while the A/T genotype was associated with decreased occurrence of KC. The A/G genotype and the A allele of the c.1196A>G polymorphism of the X-ray repair cross-complementing group 1 (XRCC1) were associated with increased, and the G/G genotype and the G allele, with decreased KC occurrence. Also, the C/T and T as well as C/C genotypes and alleles of the c.580C>T polymorphism of the same gene displayed relationship with KC occurrence. Neither the g.46438521G>C polymorphism of the Nei endonuclease VIII-like 1 (NEIL1) nor the c.2285T>C polymorphism of the poly(ADP-ribose) polymerase-1 (PARP-1) was associated with KC. In conclusion, the variability of the XRCC1 and POLG genes may play a role in KC pathogenesis and determine the risk of this disease. PMID:25356504

  19. Computational Approach for Epitaxial Polymorph Stabilization through Substrate Selection

    SciTech Connect

    Ding, Hong; Dwaraknath, Shyam S.; Garten, Lauren; Ndione, Paul; Ginley, David; Persson, Kristin A.

    2016-05-04

    With the ultimate goal of finding new polymorphs through targeted synthesis conditions and techniques, we outline a computational framework to select optimal substrates for epitaxial growth using first principle calculations of formation energies, elastic strain energy, and topological information. To demonstrate the approach, we study the stabilization of metastable VO 2 compounds which provides a rich chemical and structural polymorph space. Here, we find that common polymorph statistics, lattice matching, and energy above hull considerations recommends homostructural growth on TiO 2 substrates, where the VO 2 brookite phase would be preferentially grown on the a-c TiO 2 brookite plane while the columbite and anatase structures favor the a-b plane on the respective TiO 2 phases. Overall, we find that a model which incorporates a geometric unit cell area matching between the substrate and the target film as well as the resulting strain energy density of the film provide qualitative agreement with experimental observations for the heterostructural growth of known VO 2 polymorphs: rutile, A and B phases. The minimal interfacial geometry matching and estimated strain energy criteria provide several suggestions for substrates and substrate-film orientations for the heterostructural growth of the hitherto hypothetical anatase, brookite, and columbite polymorphs. Our criteria serve as a preliminary guidance for the experimental efforts stabilizing new materials and/or polymorphs through epitaxy. The current screening algorithm is being integrated within the Materials Project online framework and data and hence publicly available.

  20. Catalog of MicroRNA Seed Polymorphisms in Vertebrates

    PubMed Central

    Calin, George Adrian; Horvat, Simon; Jiang, Zhihua; Dovc, Peter; Kunej, Tanja

    2012-01-01

    MicroRNAs (miRNAs) are a class of non-coding RNA that plays an important role in posttranscriptional regulation of mRNA. Evidence has shown that miRNA gene variability might interfere with its function resulting in phenotypic variation and disease susceptibility. A major role in miRNA target recognition is ascribed to complementarity with the miRNA seed region that can be affected by polymorphisms. In the present study, we developed an online tool for the detection of miRNA polymorphisms (miRNA SNiPer) in vertebrates (http://www.integratomics-time.com/miRNA-SNiPer) and generated a catalog of miRNA seed region polymorphisms (miR-seed-SNPs) consisting of 149 SNPs in six species. Although a majority of detected polymorphisms were due to point mutations, two consecutive nucleotide substitutions (double nucleotide polymorphisms, DNPs) were also identified in nine miRNAs. We determined that miR-SNPs are frequently located within the quantitative trait loci (QTL), chromosome fragile sites, and cancer susceptibility loci, indicating their potential role in the genetic control of various complex traits. To test this further, we performed an association analysis between the mmu-miR-717 seed SNP rs30372501, which is polymorphic in a large number of standard inbred strains, and all phenotypic traits in these strains deposited in the Mouse Phenome Database. Analysis showed a significant association between the mmu-miR-717 seed SNP and a diverse array of traits including behavior, blood-clinical chemistry, body weight size and growth, and immune system suggesting that seed SNPs can indeed have major pleiotropic effects. The bioinformatics analyses, data and tools developed in the present study can serve researchers as a starting point in testing more targeted hypotheses and designing experiments using optimal species or strains for further mechanistic studies. PMID:22303453

  1. Cytokine production in patients with cirrhosis and TLR4 polymorphisms

    PubMed Central

    Nieto, Juan Camilo; Sánchez, Elisabet; Román, Eva; Vidal, Silvia; Oliva, Laia; Guarner-Argente, Carlos; Poca, Maria; Torras, Xavier; Juárez, Cándido; Guarner, Carlos; Soriano, German

    2014-01-01

    AIM: To analyze the cytokine production by peripheral blood cells from cirrhotic patients with and without TLR4 D299G and/or T399I polymorphisms. METHODS: The study included nine patients with cirrhosis and TLR4 D299G and/or T399I polymorphisms, and 10 wild-type patients matched for age, sex and degree of liver failure. TLR4 polymorphisms were determined by sequence-based genotyping. Cytokine production by peripheral blood cells was assessed spontaneously and also after lipopolysaccharide (LPS) and lipoteichoic acid (LTA) stimulation. RESULTS: Patients with TLR4 polymorphisms had a higher incidence of previous hepatic encephalopathy than wild-type patients (78% vs 20%, P = 0.02). Spontaneous production of interleukin (IL)-6 and IL-10 was lower in patients with TLR4 polymorphisms than in wild-type patients [IL-6: 888.7 (172.0-2119.3) pg/mL vs 5540.4 (1159.2-26053.9) pg/mL, P < 0.001; IL-10: 28.7 (6.5-177.1) pg/mL vs 117.8 (6.5-318.1) pg/mL, P = 0.02]. However, the production of tumor necrosis factor-α, IL-6 and IL-10 after LPS and LTA stimulation was similar in the two groups. CONCLUSION: TLR4 polymorphisms were associated with a distinctive pattern of cytokine production in cirrhotic patients, suggesting that they play a role in the development of cirrhosis complications. PMID:25516666

  2. The relationship between ACE polymorphism and panic disorder.

    PubMed

    Gulec-Yılmaz, Seda; Gulec, Huseyın; Dalan, Altay Burak; Cetın, Bugra; Tımırcı-Kahraman, Ozlem; Ogut, Dıcle Bılge; Atasoy, Hande; Dırımen, Gulız Arikan; Gultekın, Guldal Inal; Isbır, Turgay

    2014-01-01

    The angiotensin converting enzyme (ACE) gene, which has been found to have an insertion and deletion polymorphism (I/D), is of increasing interest in etiology and treatment of various psychiatric disorders such as panic disorder. The present study aimed to investigate the relationship between ACE polymorphism and panic disorder. In this study, 43 patients diagnosed with panic disorder at the Erenköy Mental and Neurological Diseases Training and Research Hospital, Istanbul and 41 healthy controls were enrolled. The ACE gene insertion/deletion polymorphism of exon 16 was evaluated using the polymerase chain reaction method. There was a significant association between I/D genotype and panic disorder (p=0.003). However, the frequency of the I allele was found to be significantly higher in patients compared to controls (p=0.002). In addition, we recognized a significant association between I/D polymorphism and respiratory-type panic disorder in patients. Carriers of the D allele also had an increased risk of respiratory type panic disorder patients (p=0.034). Moreover, the result of Spearman correlation analysis showed an association with ACE D allele and severity of panic disorder (p<0.001). We suggest that the I/D polymorphism of the ACE gene is associated with panic disorder and particularly respiratory-type panic disorder in patients. The I/D polymorphism of the ACE gene seems to influence therapeutic outcome in patients suffering from panic disorder. Our results indicate that ACE D allele is associated with the severity of panic disorder. Copyright © 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  3. Cisplatin pharmacogenetics, DNA repair polymorphisms, and esophageal cancer outcomes.

    PubMed

    Bradbury, Penelope A; Kulke, Matthew H; Heist, Rebecca S; Zhou, Wei; Ma, Clement; Xu, Wei; Marshall, Ariela L; Zhai, Rihong; Hooshmand, Susanne M; Asomaning, Kofi; Su, Li; Shepherd, Frances A; Lynch, Thomas J; Wain, John C; Christiani, David C; Liu, Geoffrey

    2009-08-01

    Genetic variations or polymorphisms within genes of the nucleotide excision repair (NER) pathway alter DNA repair capacity. Reduced DNA repair (NER) capacity may result in tumors that are more susceptible to cisplatin chemotherapy, which functions by causing DNA damage. We investigated the potential predictive significance of functional NER single nucleotide polymorphisms in esophageal cancer patients treated with (n = 262) or without (n = 108) cisplatin. Four NER polymorphisms XPD Asp312Asn; XPD Lys751Gln, ERCC1 8092C/A, and ERCC1 codon 118C/T were each assessed in polymorphism-cisplatin treatment interactions for overall survival (OS), with progression-free survival (PFS) as a secondary endpoint. No associations with ERCC1 118 were found. Polymorphism-cisplatin interactions were highly significant in both OS (P = 0.002, P = 0.0001, and P < 0.0001) and PFS (P = 0.006, P = 0.008, and P = 0.0007) for XPD 312, XPD 751, and ERCC1 8092, respectively. In cisplatin-treated patients, variant alleles of XPD 312, XPD 751, and ERCC1 8092 were each associated with significantly improved OS (and PFS): adjusted hazard ratios of homozygous variants versus wild-type ranged from 0.22 [95% confidence interval (CI): 0.1-0.5] to 0.31 (95% CI: 0.1-0.7). In contrast, in patients who did not receive cisplatin, variant alleles of XPD 751 and ERCC1 8092 had significantly worse survival, with adjusted hazard ratios of homozygous variants ranging from 2.47 (95% CI: 1.1-5.5) to 3.73 (95% CI: 1.6-8.7). Haplotype analyses affirmed these results. DNA repair polymorphisms are associated with OS and PFS, and if validated may predict for benefit from cisplatin therapy in patients with esophageal cancer.

  4. Polymorphic phases of sp3-hybridized carbon under cold compression.

    PubMed

    Zhou, Rulong; Zeng, Xiao Cheng

    2012-05-02

    It is well established that graphite can be transformed into superhard carbons under cold compression (Mao et al. Science 2003, 302, 425). However, structure of the superhard carbon is yet to be determined experimentally. We have performed an extensive structural search for the high-pressure crystalline phases of carbon using the evolutionary algorithm. Nine low-energy polymorphic structures of sp(3)-hybridized carbon result from the unbiased search. These new polymorphic carbon structures together with previously reported low-energy sp(3)-hybridized carbon structures (e.g., M-carbon, W-carbon, and Cco-C(8) or Z-carbon) can be classified into three groups on the basis of different ways of stacking two (or more) out of five (A-E) types of buckled graphene layers. Such a classification scheme points out a simple way to construct a variety of sp(3)-hybridized carbon allotropes via stacking buckled graphene layers in different combinations of the A-E types by design. Density-functional theory calculations indicate that, among the nine low-energy crystalline structures, seven are energetically more favorable than the previously reported most stable crystalline structure (i.e., Cco-C(8) or Z-carbon) in the pressure range 0-25 GPa. Moreover, several newly predicted polymorphic sp(3)-hybridized carbon structures possess elastic moduli and hardness close to those of the cubic diamond. In particular, Z-carbon-4 possesses the highest hardness (93.4) among all the low-energy sp(3)-hybridized carbon structures predicted today. The calculated electronic structures suggest that most polymorphic carbon structures are optically transparent. The simulated X-ray diffraction (XRD) spectra of a few polymorphic structures are in good agreement with the experimental spectrum, suggesting that samples from the cold-compressed graphite experiments may consist of multiple polymorphic phases of sp(3)-hybridized carbon.

  5. A new polymorph of triphenylmethylamine: the effect of hydrogen bonding.

    PubMed

    Khrustalev, Victor N; Borisova, Irina V; Zemlyansky, Nikolai N; Antipin, M Yu

    2009-02-01

    Crystallization of the hexane reaction mixture after treatment of LiGe(OCH(2)CH(2)NMe(2))(3) with Ph(3)CN(3) gives rise to a new triclinic (space group P\\overline{1}) polymorph of triphenylmethylamine, C(19)H(17)N, (I), containing dimers formed by N-H...N hydrogen bonds, whereas the structure of the known orthorhombic (space group P2(1)2(1)2(1)) polymorph of this compound, (II), consists of isolated molecules. While the dimers in (I) lie across crystallographic inversion centres, the molecules are not truly related by them. The centrosymmetric structure is due to the statistical disordering of the amino H atoms participating in the N-H...N hydrogen-bonding interactions, and thus the inversion centre is superpositional. The conformations and geometric parameters of the molecules in (I) and (II) are very similar. It was found that the polarity of the solvent does not affect the capability of triphenylmethylamine to crystallize in the different polymorphic modifications. The orthorhombic polymorph, (II), is more thermodynamically stable under normal conditions than the triclinic polymorph, (I). The experimental data indicate the absence of a phase transition in the temperature interval 120-293 K. The densities of (I) (1.235 Mg m(-3)) and (II) (1.231 Mg m(-3)) at 120 K are practically equal. It would seem that either the kinetic factors or the effects of the other products of the reaction facilitating the hydrogen-bonded dimerization of triphenylmethylamine molecules are the determining factor for the isolation of the triclinic polymorph (I) of triphenylmethylamine.

  6. Emergence of polymorphic mating strategies in robot colonies.

    PubMed

    Elfwing, Stefan; Doya, Kenji

    2014-01-01

    Polymorphism has fascinated evolutionary biologists since the time of Darwin. Biologists have observed discrete alternative mating strategies in many different species. In this study, we demonstrate that polymorphic mating strategies can emerge in a colony of hermaphrodite robots. We used a survival and reproduction task where the robots maintained their energy levels by capturing energy sources and physically exchanged genotypes for the reproduction of offspring. The reproductive success was dependent on the individuals' energy levels, which created a natural trade-off between the time invested in maintaining a high energy level and the time invested in attracting mating partners. We performed experiments in environments with different density of energy sources and observed a variety in the mating behavior when a robot could see both an energy source and a potential mating partner. The individuals could be classified into two phenotypes: 1) forager, who always chooses to capture energy sources, and 2) tracker, who keeps track of potential mating partners if its energy level is above a threshold. In four out of the seven highest fitness populations in different environments, we found subpopulations with distinct differences in genotype and in behavioral phenotype. We analyzed the fitnesses of the foragers and the trackers by sampling them from each subpopulation and mixing with different ratios in a population. The fitness curves for the two subpopulations crossed at about 25% of foragers in the population, showing the evolutionary stability of the polymorphism. In one of those polymorphic populations, the trackers were further split into two subpopulations: (strong trackers) and (weak trackers). Our analyses show that the population consisting of three phenotypes also constituted several stable polymorphic evolutionarily stable states. To our knowledge, our study is the first to demonstrate the emergence of polymorphic evolutionarily stable strategies within a

  7. Aspirin-induced peptic ulcer and genetic polymorphisms.

    PubMed

    Shiotani, Akiko; Sakakibara, Takashi; Nomura, Maki; Yamanaka, Yoshiyuki; Nishi, Ryuji; Imamura, Hiroshi; Tarumi, Ken-ichi; Kamada, Tomoari; Hata, Jiro; Haruma, Ken

    2010-05-01

    There are a few studies of the association between genetic polymorphisms and the risks of acetylsalicylic acid (aspirin)-induced ulcer or its complications. Two single nucleotide polymorphisms (SNP) of cyclooxygenase-1 (COX-1), A-842G and C50T, exhibited increased sensitivity to aspirin and had lower prostaglandin synthesis capacity, lacking statistical significance in the association with bleeding peptic ulcer. A recent Japanese study indicated that the number of COX-1-1676T alleles was a significant risk factor for peptic ulcer in users of non-steroidal anti-inflammatory drugs (NSAIDs). There are some genetic polymorphisms for aspirin resistance, such as platelet membrane glycoproteins, thromboxane A2 (TXA2) receptor, platelet activating factor acetylhydrolase and coagulation factor XIII; however, data on the frequency of gastrointestinal (GI) events in these variants are lacking. Carrying the CYP2C9 variants is reported a significantly increased risk of non-aspirin NSAID-related GI bleeding. The polymorphisms of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) have been associated with development of peptic ulcer or gastric cancer. In a recent investigation, carriage of the IL-1beta-511 T allele was significantly associated with peptic ulcer among low-dose aspirin users. Hypoacidity in corpus gastritis related to polymorphisms of pro-inflammatory cytokines seems to reduce NSAIDs or aspirin-related injury. Data on which polymorphisms are significant risk factors for GI events in aspirin users are still lacking and further large-scale clinical studies are required.

  8. IL7RA polymorphisms are not associated with AIDS progression.

    PubMed

    Medrano, Luz María; Jiménez, José Luis; Jiménez-Sousa, María A; Fernández-Rodíguez, Amanda; Gutiérrez-Rivas, Mónica; Bellón, José María; Blanco, José Ramón; Inciarte, Alexy; Muñoz-Fernández, Mª Ángeles; Resino, Salvador

    2017-08-10

    Our aim was to determine whether α-chain of the IL-7 receptor (IL7RA) polymorphisms (rs10491434, rs6897932 and rs987106) are associated with the clinical pattern of AIDS progression in ART-naïve HIV-infected patients. We carried out a cross-sectional study in 673 HIV-infected patients who were classified into three groups according to the clinical pattern of AIDS progression (188 long-term nonprogressors (LTNPs), 334 moderate progressors (MPs) and 151 rapid progressors (RPs)). Additionally, 134 healthy blood donors participated as a Control-group. We selected three IL7RA polymorphisms located at three regulatory regions [rs6897932 (exon 6), rs987106 (intronic region) and rs10491434 (3'UTR)]. DNA genotyping was performed using Sequenom's MassARRAY platform. The Control-group and all HIV-infected patients had similar age and percentage of males. LTNP-group was older at HIV diagnosis and at the inclusion in the study and had higher percentage of intravenous drug users (IDU) (P < 0·001). Besides, LTNP-group had lower proportion of male patients and homosexual HIV transmission than MP and RP groups (P < 0·001). Moreover, similar values of allelic, genotypic and haplotype frequencies for IL7RA polymorphisms were found between healthy controls and HIV-infected patients (P > 0·05), and among different subgroups of HIV patients according to AIDS progression (LTNPs, MPs and RPs) (P > 0·05). The adjusted logistic regression did not show any significant association between IL7RA polymorphisms and AIDS progression. IL7RA polymorphisms (rs6897932, rs987106 and rs10491434) were not associated with AIDS progression in Spanish population. Therefore, IL7RA polymorphisms do not seem to help us to understand HIV pathogenesis in untreated HIV-infected patients with different clinical evolution. © 2017 Stichting European Society for Clinical Investigation Journal Foundation.

  9. Emergence of Polymorphic Mating Strategies in Robot Colonies

    PubMed Central

    Elfwing, Stefan; Doya, Kenji

    2014-01-01

    Polymorphism has fascinated evolutionary biologists since the time of Darwin. Biologists have observed discrete alternative mating strategies in many different species. In this study, we demonstrate that polymorphic mating strategies can emerge in a colony of hermaphrodite robots. We used a survival and reproduction task where the robots maintained their energy levels by capturing energy sources and physically exchanged genotypes for the reproduction of offspring. The reproductive success was dependent on the individuals' energy levels, which created a natural trade-off between the time invested in maintaining a high energy level and the time invested in attracting mating partners. We performed experiments in environments with different density of energy sources and observed a variety in the mating behavior when a robot could see both an energy source and a potential mating partner. The individuals could be classified into two phenotypes: 1) forager, who always chooses to capture energy sources, and 2) tracker, who keeps track of potential mating partners if its energy level is above a threshold. In four out of the seven highest fitness populations in different environments, we found subpopulations with distinct differences in genotype and in behavioral phenotype. We analyzed the fitnesses of the foragers and the trackers by sampling them from each subpopulation and mixing with different ratios in a population. The fitness curves for the two subpopulations crossed at about 25% of foragers in the population, showing the evolutionary stability of the polymorphism. In one of those polymorphic populations, the trackers were further split into two subpopulations: (strong trackers) and (weak trackers). Our analyses show that the population consisting of three phenotypes also constituted several stable polymorphic evolutionarily stable states. To our knowledge, our study is the first to demonstrate the emergence of polymorphic evolutionarily stable strategies within a

  10. rs1801275 Interleukin-4 receptor alpha polymorphism in familial hypercholesterolemia.

    PubMed

    Sánchez Muñoz-Torrero, Juan F; Rivas, Maria D; Zamorano, Jose; Alonso, Rodrigo; Joya-Vazquez, Pedro; Padró, Teresa; Mata, Pedro

    2014-01-01

    Interleukin-4 (IL-4) has been linked with atherogenic effects and some single nucleotide polymorphisms (SNPs) of the IL4/13 receptors (ILR4/13) have been associated with enhanced response to IL-4. We investigated the frequency of SNP ILR4/13 in patients with familial hypercholesterolemia (FH) compared with control relatives without FH and their possible association with cardiovascular disease (CVD). ILR4/13 polymorphisms were studied in 626 subjects included in the Spanish FH cohort, 408 patients with FH and 218 healthy relative control subjects. Logistic regression was used to assess the relation between SNP, clinical data, and CVD. A total of 143 (35%) FH patients had rs1801275 polymorphisms (AG or GG) of the IL-4Rα, whereas only 52 (24%) of the control group had these polymorphisms, P = .002. No differences were observed between the groups when the IL13RA2 rs638376 polymorphisms were analyzed. The multivariate analysis found association (odds ratio: 95% confidence interval) between CVD and smoking history (2.22: 1.30-3.80), low levels of high-density lipoprotein cholesterol (1.72: 1.07-2.75), hypertension (2.25: 1.32-3.85), age > 60 years (2.50: 1.52-4.07), and FH diagnosis (13.1: 6.65-26), but not with IL-4Rα rs1801275 polymorphisms. Our data suggest that SNP of IL-4Rα is more frequent in FH patients than in the relative controls. Conversely to the general population, IL-4 does not seems to play a role in the risk of developing CVD in FH patients. Copyright © 2014 National Lipid Association. Published by Elsevier Inc. All rights reserved.

  11. Genomic and genotyping characterization of haplotype-based polymorphic microsatellites in Prunus

    USDA-ARS?s Scientific Manuscript database

    Efficient utilization of microsatellites in genetic studies remains impeded largely due to the unknown status of their primer reliability, chromosomal location, and allele polymorphism. Discovery and characterization of microsatellite polymorphisms in a taxon will disclose the unknowns and gain new ...

  12. Combined crystal structure prediction and high-pressure crystallization in rational pharmaceutical polymorph screening

    NASA Astrophysics Data System (ADS)

    Neumann, M. A.; van de Streek, J.; Fabbiani, F. P. A.; Hidber, P.; Grassmann, O.

    2015-07-01

    Organic molecules, such as pharmaceuticals, agro-chemicals and pigments, frequently form several crystal polymorphs with different physicochemical properties. Finding polymorphs has long been a purely experimental game of trial-and-error. Here we utilize in silico polymorph screening in combination with rationally planned crystallization experiments to study the polymorphism of the pharmaceutical compound Dalcetrapib, with 10 torsional degrees of freedom one of the most flexible molecules ever studied computationally. The experimental crystal polymorphs are found at the bottom of the calculated lattice energy landscape, and two predicted structures are identified as candidates for a missing, thermodynamically more stable polymorph. Pressure-dependent stability calculations suggested high pressure as a means to bring these polymorphs into existence. Subsequently, one of them could indeed be crystallized in the 0.02 to 0.50 GPa pressure range and was found to be metastable at ambient pressure, effectively derisking the appearance of a more stable polymorph during late-stage development of Dalcetrapib.

  13. Asymmetric Dispersal Can Maintain Larval Polymorphism: A Model Motivated by Streblospio benedicti

    PubMed Central

    Zakas, Christina; Hall, David W.

    2012-01-01

    Polymorphism in traits affecting dispersal occurs in a diverse variety of taxa. Typically, the maintenance of a dispersal polymorphism is attributed to environmental heterogeneity where parental bet-hedging can be favored. There are, however, examples of dispersal polymorphisms that occur across similar environments. For example, the estuarine polychaete Streblospio benedicti has a highly heritable offspring dimorphism that affects larval dispersal potential. We use analytical models of dispersal to determine the conditions necessary for a stable dispersal polymorphism to exist. We show that in asexual haploids, sexual haploids, and in sexual diploids in the absence of overdominance, asymmetric dispersal is required in order to maintain a dispersal polymorphism when patches do not vary in intrinsic quality. Our study adds an additional factor, dispersal asymmetry, to the short list of mechanisms that can maintain polymorphism in nature. The region of the parameter space in which polymorphism is possible is limited, suggesting why dispersal polymorphisms within species are rare. PMID:22576818

  14. 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

  15. Replicators in a Fine-Grained Environment: Adaptation and Polymorphism

    NASA Astrophysics Data System (ADS)

    Allahverdyan, Armen E.; Hu, Chin-Kun

    2009-02-01

    Selection in a time-periodic environment is modeled via the two-player replicator dynamics. For sufficiently fast environmental changes, this is reduced to a multiplayer replicator dynamics in a constant environment. The two-player terms correspond to the time-averaged payoffs, while the three- and four-player terms arise from the adaptation of the morphs to their varying environment. Such multiplayer terms can induce a stable polymorphism. The establishment of the polymorphism in partnership games [genetic selection] is accompanied by decreasing mean fitness of the population.

  16. Novel polymorphs of the anti-Trypanosoma cruzi drug benznidazole.

    PubMed

    Honorato, Sara Braga; Mendonça, Jorge Souza; Boechat, Nubia; Oliveira, Alcemira Conceição; Mendes Filho, Josué; Ellena, Javier; Ayala, Alejandro Pedro

    2014-01-24

    Benznidazole (N-benzyl-2-(2-nitro-1H-imidazol-1-yl)acetamide), is a nitro-heterocyclic drug used in the treatment of Chagas disease. Despite the fact that this drug was released more than 30 years ago, little information about its solid state properties is available in the literature. In this study, it was verified that this drug exhibits three polymorphs, which were characterized in situ by X-ray powder diffraction, thermal analysis, hot stage microscopy and infrared spectroscopy. The thermodynamic relationships among these polymorphs were also discussed.

  17. Segregating random amplified polymorphic DNAs (RAPDs) in Betula alleghaniensis.

    PubMed

    Roy, A; Frascaria, N; Mackay, J; Bousquet, J

    1992-11-01

    Molecular markers are currently being developed for Betula alleghaniensis Britton using random amplified polymorphic DNA (RAPD). Arbitrarily designed 11-mer primers were tested on three intraspecific controlled crosses for which more than 15 full-sibs were available. Using two of these primers, we were able to genetically characterize a total of nine polymorphic RAPD markers. Segregation of these markers was consistent with a biparental diploid mode of inheritance, and all appeared dominant. RAPDs were valuable in detecting contaminants and, therefore, in assessing the validity of controlled crosses. Limitations of the technique are discussed in relation to the determination of parental genotypes and construction of linkage maps for hardwood species.

  18. The Pressure-Induced Polymorphic Transformations in Fluconazole.

    PubMed

    Gorkovenko, Ekaterina A; Kichanov, Sergey E; Kozlenko, Denis P; Belushkin, Alexandr V; Wąsicki, Jan; Nawrocik, Wojciech; Mielcarek, Jadwiga; Dubrovinsky, Leonid S; Lathe, Christian; Savenko, Boris N

    2015-12-01

    The structural properties and Raman spectra of fluconazole have been studied by means of X-ray diffraction and Raman spectroscopy at pressures up to 2.5 and 5.5 GPa, respectively. At a pressure of 0.8 GPa, a polymorphic phase transition from the initial form I to a new triclinic form VIII has been observed. At higher pressure of P = 3.2 GPa, possible transformation into another new polymorphic form IX has been detected. The unit cell parameters and volumes, and vibration modes as functions of pressure have been obtained for the different forms of fluconazole. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  19. Novel polymorphs of the anti-Trypanosoma cruzi drug benznidazole

    NASA Astrophysics Data System (ADS)

    Honorato, Sara Braga; Mendonça, Jorge Souza; Boechat, Nubia; Oliveira, Alcemira Conceição; Mendes Filho, Josué; Ellena, Javier; Ayala, Alejandro Pedro

    2014-01-01

    Benznidazole (N-benzyl-2-(2-nitro-1H-imidazol-1-yl)acetamide), is a nitro-heterocyclic drug used in the treatment of Chagas disease. Despite the fact that this drug was released more than 30 years ago, little information about its solid state properties is available in the literature. In this study, it was verified that this drug exhibits three polymorphs, which were characterized in situ by X-ray powder diffraction, thermal analysis, hot stage microscopy and infrared spectroscopy. The thermodynamic relationships among these polymorphs were also discussed.

  20. New epsilon-Bi2O3 metastable polymorph.

    PubMed

    Cornei, Nicoleta; Tancret, Nathalie; Abraham, Francis; Mentré, Olivier

    2006-06-26

    The new metastable epsilon-Bi2O3 polymorph has been prepared by hydrothermal treatment and structurally characterized. It shows strong relationships with the room temperature alpha form and the metastable beta form through rearrangements of [Bi2O3] columns formed by edge-sharing OBi4 tetrahedra. Its fully ordered crystal structure yields an ionic insulating character. It irreversibly transforms at 400 degrees C to the alpha form. The chemical analysis indicates its undoped bismuth oxide nature, then leading to the fifth characterized Bi2O3 polymorph to date.

  1. Serotonin transporter gene (5-HTT) polymorphisms and compulsive buying.

    PubMed

    Devor, E J; Magee, H J; Dill-Devor, R M; Gabel, J; Black, D W

    1999-04-16

    We examined a panel of 21 patients diagnosed with compulsive buying for two DNA sequence polymorphisms found in the gene that encodes the serotonin transport (5-HTT). One polymorphism, found in the promoter region of the 5-HTT gene, involves a 44-base pair (bp) deletion, and the other, found in the second intron, is due to variable numbers of a repeat sequence. We also typed a panel of 38 psychiatrically normal controls for both 5-HH markers. When compared to this control panel, no significant differences were seen for either 5-HTT marker among the compulsive buyers.

  2. Polymorphisms in the Human SNAIL (SNAI1) gene.

    PubMed

    Okajima, K; Paznekas, W A; Burstyn, T; Jabs, E W

    2001-02-01

    The human SNAIL is an important developmental protein involved in the formation of mesoderm and neural crest. The protein contains three classic and one atypical zinc-finger motif. The SNAI1 gene is composed of three exons. We have identified three SNPs in non-coding regions, two in the 5'UTR and one in intron 1, which can be detected by PCR followed by restriction enzyme digestion. We also identified a GGG/GGGG polymorphism in intron 1. We screened CEPH DNAs for these polymorphisms. Copyright 2001 Academic Press.

  3. Time-resolved FRET for single-nucleotide polymorphism genotyping

    NASA Astrophysics Data System (ADS)

    Andreoni, Alessandra; Nardo, Luca; Bondani, Maria

    2009-05-01

    By tens-of-picosecond resolved fluorescence detection (TCSPC, time-correlated single-photon counting) we study Förster resonance energy transfer between a donor and a black-hole-quencher acceptor bound at the 5'- and 3'-positions of a synthetic DNA oligonucleotide. This dual labelled oligonucleotide is annealed with either the complementary sequence or with sequences that mimic single-nucleotide polymorphic gene sequences: they differ in one nucleotide at positions near either the ends or the center of the oligonucleotide. We find donor fluorescence decay times whose values are definitely distinct and discuss the feasibility of single nucleotide polymorphism genotyping by this method.

  4. 4,4'-Dimethoxy-benzophenone: a triclinic polymorph.

    PubMed

    Fun, Hoong-Kun; Franklin, S; Jebas, Samuel Robinson; Balasubramanian, T

    2008-06-13

    The title compound, C(15)H(14)O(3), has been found to crystallize as a new triclinic polymorph. The asymmetric unit of the present structure, as in the previously reported monoclinic structure [Norment & Karle (1962 ▶). Acta Cryst. 15, 873-878], contains two independent mol-ecules, which differ slightly in the orientations of the two benzene rings. The crystal packing of the triclinic polymorph is stabilized by inter-molecular C-H⋯O hydrogen bonds and C-H⋯π inter-actions.

  5. Kappa-casein polymorphisms among cattle breeds and bison herds

    USGS Publications Warehouse

    Cronin, M.A.; Cockett, N.

    1993-01-01

    We identified the HindIII restriction site polymorphism Of kappa-casein in cattle reported by Pinder et al. (Animal Genetics 22, 11, 1991) and found an additonal polymorphism (RsaI) in cattle and bison. The Hin dIII and Rsa I restriction sites were mapped and three haplotypes (alleles) were identified. Preliminary screening of 39 cattle and 71 bison revealed one allele restricted to cattle, one restricted to bison, and one shared by the species. No fixed allelic differences were observed among cattle breeds or among bison herds or subspecies.

  6. Molecular Docking Study of Conformational Polymorph: Building Block of Crystal Chemistry

    PubMed Central

    Dubey, Rashmi; Tewari, Ashish Kumar; Singh, Ved Prakash; Singh, Praveen; Dangi, Jawahar Singh; Puerta, Carmen; Valerga, Pedro; Kant, Rajni

    2013-01-01

    Two conformational polymorphs of novel 2-[2-(3-cyano-4,6-dimethyl-2-oxo-2H-pyridin-1-yl)-ethoxy]-4,6-dimethyl nicotinonitrile have been developed. The crystal structure of both polymorphs (1a and 1b) seems to be stabilized by weak interactions. A difference was observed in the packing of both polymorphs. Polymorph 1b has a better binding affinity with the cyclooxygenase (COX-2) receptor than the standard (Nimesulide). PMID:24250264

  7. Large number of replacement polymorphisms in rapidly evolving genes of Drosophila. Implications for genome-wide surveys of DNA polymorphism.

    PubMed Central

    Schmid, K J; Nigro, L; Aquadro, C F; Tautz, D

    1999-01-01

    We present a survey of nucleotide polymorphism of three novel, rapidly evolving genes in populations of Drosophila melanogaster and D. simulans. Levels of silent polymorphism are comparable to other loci, but the number of replacement polymorphisms is higher than that in most other genes surveyed in D. melanogaster and D. simulans. Tests of neutrality fail to reject neutral evolution with one exception. This concerns a gene located in a region of high recombination rate in D. simulans and in a region of low recombination rate in D. melanogaster, due to an inversion. In the latter case it shows a very low number of polymorphisms, presumably due to selective sweeps in the region. Patterns of nucleotide polymorphism suggest that most substitutions are neutral or nearly neutral and that weak (positive and purifying) selection plays a significant role in the evolution of these genes. At all three loci, purifying selection of slightly deleterious replacement mutations appears to be more efficient in D. simulans than in D. melanogaster, presumably due to different effective population sizes. Our analysis suggests that current knowledge about genome-wide patterns of nucleotide polymorphism is far from complete with respect to the types and range of nucleotide substitutions and that further analysis of differences between local populations will be required to understand the forces more completely. We note that rapidly diverging and nearly neutrally evolving genes cannot be expected only in the genome of Drosophila, but are likely to occur in large numbers also in other organisms and that their function and evolution are little understood so far. PMID:10581279

  8. A twinned triclinic polymorph of dibromidotetrakis(tetrahydrofuran-kappaO)magnesium(II).

    PubMed

    Lorbach, Andreas; Lerner, Hans Wolfram; Bolte, Michael

    2007-04-01

    The title compound, [MgBr(2)(C(4)H(8)O)(4)], forms crystals which appear to be monoclinic but are actually twinned triclinic. The current form is a new triclinic polymorph, with Z'= 2, in addition to the already known tetragonal polymorph. Although the geometric parameters of the two polymorphs agree well, their packing patterns are completely different.

  9. [MOLECULAR-GENETIC POLYMORPHISM OF chs_H1 GENE IN UKRAINIAN HOP VARIETIES].

    PubMed

    Venzer, A M; Volkova, N E; Sivolap, Yu M

    2015-01-01

    Polymorphism of chs_H1 gene encoding the "true" chalcone synthase was determined by alignment of sequences. The polymorphism associates with single nucleotide changes, insertions or deletions (indels) in the promoter, exons, intron, 3'-untranslated region. The molecular-genetic polymorphism in gene chs_H1 different regions of hop varieties of Polessye Agriculture Institute' breeding NAAS was analyzed.

  10. Analysis of gene-derived SNP marker polymorphism in wheat (Triticum aestivum L.)

    USDA-ARS?s Scientific Manuscript database

    In this study, we analyzed 359 single nucleotide polymorphisms (SNPs) previously discovered in intron sequences of wheat genes to evaluate SNP marker polymorphism in common wheat (Triticum aestivum L.). These SNPs showed an average polymorphism information content (PIC) of 0.181 among 20 US wheat c...

  11. Vitiligo susceptibility and catalase gene (CAT) polymorphisms in sicilian population.

    PubMed

    Caputo, Valentina; Niceta, Marcello; Fiorella, Santi; La Vecchia, Marco; Bastonini, Emanuela; Bongiorno, Maria R; Pistone, Giuseppe

    2017-02-15

    Catalase gene (CAT) polymorphisms were analyzed as responsible for the deficiency of catalase enzyme activity and concomitant accumulation of excessive hydrogen peroxide in Vitiligo patients. Catalase is a well known oxidative stress regulator that could play an important role in the pathogenesis of Vitiligo. This study was conducted to evaluate three CAT gene polymorphisms (-89A/T, 389C/T, 419C/T) and their association with Vitiligo susceptibility in Sicilian population. 60 out of 73 Sicilian patients with Vitiligo were enrolled and submitted to CAT gene analysis. Contrary to the Northern part of Europe but likewise to the Mediterranean area, the frequency of the CAT genotypes in Sicily is equally distributed. Out of all CAT genotypes, only CAT -89 T/T frequency was found to be significantly higher amongst Vitiligo patients than controls. Despite the involvement of the CAT enzyme in the pathogenesis of Vitiligo, the biological significance of CAT gene polymorphisms is still controversial. With the only exception for CAT variant -89A/T, the other studied CAT gene polymorphisms (389C/T and 419C/T) might not to be associated with Vitiligo in Sicilian population.

  12. Polymorphous low-grade adenocarcinoma of the nasal fossa.

    PubMed

    González-Lagunas, Javier; Alasà-Caparrós, Cristian; Vendrell-Escofet, Gerard; Huguet-Redecilla, Pere; Raspall-Martin, Guillermo

    2005-01-01

    An unusual case of a T4N2CMx polymorphous low grade adenocarcinoma located in the nasal fossae and extending to the pterygoid area is presented. The primary tumor was excised through a Lefort I maxillotomy and the neck was managed with a supraomohyoid neck dissection. Adjuntive postoperative radiotherapy was also administered to the patient.

  13. [DRD4 polymorphism and the association with mental disorders].

    PubMed

    Aguirre-Samudio, Ana Julia; Nicolini, Humberto

    2005-01-01

    The dopamine D4 receptor (DRD4) is the most important gene in psychiatric genetics since its involvement in the physiology of behavior, pharmacology response and psychopathology. DRD4's sequence gene present some polymorphism such as in the exon 3 constituted from 2 to 10 copies of repetitive sequences of 48 base pair (bp), from class variable number tandem repeats (VNTR). An additional genetic variant in the exon 1 presents polymorphisms to 12 bp VNTR, and the variation -521 C by T of the promoter region. The -521 T allele can reduce the efficiency of the gene expression in comparison with the C allele. The DRD4 gene codes a protein transmembranal of 7 domains, distributed in front cortex, striatum, hypothalamus and hippocampus. This review discusses the biological significance of DRD4 gene and its perspective with emphasis on the impact of association studies in some illness mental and behavioral traits. The DRD4 polymorphism has been studied in association with illnesses like schizophrenia, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive with tics, bipolar manic-depressive disorder, in addition behavioral traits such as novelty seeking. The DRD4 gene is a genetic marker that could play a role in etiology of different mental illness, and behavioral traits, and its polymorphism can be used in association studies, epigenetic and pharmacogenomic analysis for help to understand the genetics basis of both mental disorders and traits.

  14. Sleep and COMT Polymorphism in ADHD Children: Preliminary Actigraphic Data

    ERIC Educational Resources Information Center

    Gruber, Reut; Grizenko, Natalie; Schwartz, George; Amor, Leila Ben; Gauthier, Julie; de Guzman, Rosherrie; Joober, Ridha

    2006-01-01

    Objective: To examine whether COMT (catechol-O-methyltransferase) polymorphism modulates aspects of sleep in children diagnosed with attention-deficit/hyperactivity disorder (ADHD). Method: Nightly sleep actigraphic recordings during a double-blind, placebo-controlled, crossover clinical study (1 week of 0.5 mg/kg MPH; 1 week of placebo) were…

  15. Single Nucleotide Polymorphisms Predict Symptom Severity of Autism Spectrum Disorder

    ERIC Educational Resources Information Center

    Jiao, Yun; Chen, Rong; Ke, Xiaoyan; Cheng, Lu; Chu, Kangkang; Lu, Zuhong; Herskovits, Edward H.

    2012-01-01

    Autism is widely believed to be a heterogeneous disorder; diagnosis is currently based solely on clinical criteria, although genetic, as well as environmental, influences are thought to be prominent factors in the etiology of most forms of autism. Our goal is to determine whether a predictive model based on single-nucleotide polymorphisms (SNPs)…

  16. Vitamin D Receptor Gene Polymorphisms Associated with Childhood Autism.

    PubMed

    Cieślińska, Anna; Kostyra, Elżbieta; Chwała, Barbara; Moszyńska-Dumara, Małgorzata; Fiedorowicz, Ewa; Teodorowicz, Małgorzata; Savelkoul, Huub F J

    2017-09-09

    Autism spectrum disorder (ASD) is a group of heterogeneous, behaviorally defined disorders whereby currently no biological markers are common to all affected individuals. A deregulated immune response may be contributing to the etiology of ASD. The active metabolite of vitamin D₃ has an immunoregulatory role mediated by binding to the vitamin D receptor (VDR) in monocyte, macrophages, and lymphocytes. The effects of vitamin D and interaction with the VDR may be influenced by polymorphism in the VDR gene. Genetic association of four different VDR polymorphisms (Apa-I, Bsm-I, Taq-I, Fok-I) associated with susceptibility to the development of autism in children was investigated. We uniquely found an association between the presence of the T allele at position Taq-I and presence of the a allele at position Apa-I of the VDR gene with decreased ASD incidence. There was also an association between female gender and the presence of the T allele. We found no statistical significant correlation between VDR single nucleotide polymorphisms (SNPs) and vitamin D₃ concentration in serum of ASD children. Genetic polymorphism in two SNP in VDR may be correlated with development of ASD symptoms by influencing functionality of vitamin D₃ metabolism, while vitamin D₃ levels were not significantly different between ASD and non-ASD children.

  17. Genetic polymorphisms for vascular endothelial growth factor in perinatal complications.

    PubMed

    Bányász, Ilona; Bokodi, Géza; Vásárhelyi, Barna; Treszl, András; Derzbach, László; Szabó, András; Tulassay, Tivadar; Vannay, Adám

    2006-12-01

    Low birth weight (LBW) infants have increased susceptibility to perinatal complications. An immature and impaired vascular system may possibly participate in these complications. There is evidence that supports the notion that vascular endothelial growth factor (VEGF), which is an essential regulator of embryonic angiogenesis, plays a central role in the pathogenesis of perinatal complications. We aimed to test whether functional genetic polymorphisms of VEGF are associated with the risk of preterm birth or perinatal morbidity. We enrolled 128 LBW infants (< or = 1500 grams). VEGF T-460C, VEGF C-2578A and VEGF G+405C polymorphisms were determined by real-time PCR or PCR-RFLP, respectively. Their genotypes were compared with VEGF genotypes of 200 healthy, term neonates. The prevalence of the VEGF+405 C allele was higher in LBW infants than in healthy, term neonates (OR [95% CI]: 1.29 [1.01-1.65]). Carrier state for the VEGF -2578A allele was an independent risk factor for enterocolitis necrotisans (NEC) (adjusted OR [95% CI]: 2.77 [1.00-7.65]). The carrier state for the VEGF -2578AA genotype was associated with a decreased risk of acute renal failure (ARF) (adjusted OR [95% CI]: 0.2 [0.05-0.78]). These results suggest that VEGF G+405C polymorphism might be associated with a higher risk of preterm birth and that VEGF C-2578A polymorphism may participate in the development of perinatal complications such as NEC and ARF.

  18. Polymorphism and Divergence at a Drosophila Pseudogene Locus

    PubMed Central

    Pritchard, J. K.; Schaeffer, S. W.

    1997-01-01

    The larval cuticle protein (Lcp) cluster in Drosophila melanogaster contains four functional genes and a closely related pseudogene. A 630-bp fragment including the larval cuticle pseudogene locus (Lcpψ) was nucleotide sequenced in 10 strains of D. melanogaster and a 458-bp Lcpψ fragment from D. simulans was also sequenced. We used these data to test the hypotheses that the rates of synonymous and nonsynonymous substitution are equal, that the absolute levels of variation are higher than in functional genes, and that intraspecific polymorphism is correlated with interspecific divergence. As predicted, synonymous and nonsynonymous substitution rates were equivalent, and overall nucleotide divergence between D. melanogaster and D. simulans (Jukes-Cantor distance = 0.149 +/- 0.150) was extremely high. However, within-species DNA sequence comparisons at Lcpψ revealed lower levels of polymorphism ( & = 0.001 +/- 0.001) than at many functional loci in D. melanogaster. Using the HUDSON, KREITMAN, and AGUADE (HKA) test, we show that the level of polymorphism in Lcpψ within D. melanogaster is lower than expected given the amount of divergence between D. melanogaster and D. simulans when the pseudogene data are compared to the Adh 5' flanking region. Because the Lcpψ lies in a region of relatively infrequent recombination, we suggest that the low level of within-species polymorphism is the result of background selection. PMID:9286680

  19. The role of glucocorticoid receptor (GR) polymorphisms in human erythropoiesis.

    PubMed

    Varricchio, Lilian; Migliaccio, Anna Rita

    2014-01-01

    Glucocorticoids are endogenous steroid hormones that regulate several biological functions including proliferation, differentiation and apoptosis in numerous cell types in response to stress. Synthetic glucocorticoids, such as dexamethasone (Dex) are used to treat a variety of diseases ranging from allergy to depression. Glucocorticoids exert their effects by passively entering into cells and binding to a specific Glucocorticoid Receptor (GR) present in the cytoplasm. Once activated by its ligand, GR may elicit cytoplasmic (mainly suppression of p53), and nuclear (regulation of transcription of GR responsive genes), responses. Human GR is highly polymorphic and may encode > 260 different isoforms. This polymorphism is emerging as the leading cause for the variability of phenotype and response to glucocorticoid therapy observed in human populations. Studies in mice and clinical observations indicate that GR controls also the response to erythroid stress. This knowledge has been exploited in-vivo by using synthetic GR agonists for treatment of the erythropoietin-refractory congenic Diamond Blackfan Anemia and in-vitro to develop culture conditions that may theoretically generate red cells in numbers sufficient for transfusion. However, the effect exerted by GR polymorphism on the variability of the phenotype of genetic and acquired erythroid disorders observed in the human population is still poorly appreciated. This review will summarize current knowledge on the biological activity of GR and of its polymorphism in non-hematopoietic diseases and discuss the implications of these observations for erythropoiesis.

  20. Nestling polymorphism in a cuckoo-host system.

    PubMed

    Sato, Nozomu J; Tanaka, Keita D; Okahisa, Yuji; Yamamichi, Masato; Kuehn, Ralph; Gula, Roman; Ueda, Keisuke; Theuerkauf, Jörn

    2015-12-21

    Virulence of avian brood parasites can trigger a coevolutionary arms race, which favours rejection of parasitic eggs or chicks by host parents, and in turn leads to mimicry in parasite eggs or chicks [1-7]. The appearance of host offspring is critical to enable host parents to detect parasites. Thus, increasing accuracy of parasites' mimicry can favour a newly emerged host morph to escape parasites' mimicry. If parasites catch up with the hosts with a newly acquired mimetic morph, host polymorphism should be maintained through apostatic (negative frequency-dependent) selection, which favours hosts rarer morphs [1-3,7]. Among population-wide polymorphism, uniformity of respective host morphs in single host nests stochastically prevents parasites from targeting any specific morph of hosts and thus helps parents detect parasitism. Polymorphism in such a state is well-known in egg appearances of hosts of brood parasitic birds [2,3,7], which might also occur in chick appearances when arms races escalate. Here, we present evidence of polymorphism in chick skin coloration in a cuckoo-host system: the fan-tailed gerygone Gerygone flavolateralis and its specialist brood parasite, the shining bronze-cuckoo Chalcites lucidus in New Caledonia (Figure 1A-C).

  1. Serotonin transporter gene polymorphisms and hyperserotonemia in autistic disorder

    PubMed Central

    Betancur, Catalina; Corbex, Marylis; Spielewoy, Cécile; Philippe, Anne; Laplanche, Jean-Louis; Launay, Jean-Marie; Gillberg, Christopher; Mouren-Simeoni, Marie-Christine; Hamon, Michel; Giros, Bruno; Nosten-Bertrand, Marika; Leboyer, Marion

    2002-01-01

    Previous studies have provided conflicting evidence regarding the association of the serotonin transporter (5-HTT) gene with autism. Two polymorphisms have been identified in the human 5-HTT gene, a VNTR in intron 21 and a functional deletion/insertion in the promoter region (5-HTTLPR) with short and long variants.2 Positive associations of the 5-HTTLPR polymorphism with autism have been reported by two family-based studies, but one found preferential transmission of the short allele3 and the other of the long allele.4 Two subsequent studies failed to find evidence of transmission disequilibrium at the 5-HTTLPR locus.5,6 These conflicting results could be due to heterogeneity of clinical samples with regard to serotonin (5-HT) blood levels, which have been found to be elevated in some autistic subjects.7–9 Thus, we examined the association of the 5-HTTLPR and VNTR polymorphisms of the 5-HTT gene with autism, and we investigated the relationship between 5-HTT variants and whole-blood 5-HT. The transmission/disequilibrium test (TDT) revealed no linkage disequilibrium at either loci in a sample of 96 families comprising 43 trios and 53 sib pairs. Furthermore, no significant relationship between 5-HT blood levels and 5-HTT gene polymorphisms was found. Our results suggest that the 5-HTT gene is unlikely to play a major role as a susceptibility factor in autism. PMID:11803447

  2. Single Nucleotide Polymorphisms Predict Symptom Severity of Autism Spectrum Disorder

    ERIC Educational Resources Information Center

    Jiao, Yun; Chen, Rong; Ke, Xiaoyan; Cheng, Lu; Chu, Kangkang; Lu, Zuhong; Herskovits, Edward H.

    2012-01-01

    Autism is widely believed to be a heterogeneous disorder; diagnosis is currently based solely on clinical criteria, although genetic, as well as environmental, influences are thought to be prominent factors in the etiology of most forms of autism. Our goal is to determine whether a predictive model based on single-nucleotide polymorphisms (SNPs)…

  3. Gelatinization temperature of rice explained by polymorphisms in starch synthase.

    PubMed

    Waters, Daniel L E; Henry, Robert J; Reinke, Russell F; Fitzgerald, Melissa A

    2006-01-01

    The cooking quality of rice is associated with the starch gelatinization temperature (GT). Rice genotypes with low GT have probably been selected for their cooking quality by humans during domestication. We now report polymorphisms in starch synthase IIa (SSIIa) that explain the variation in rice starch GT. Sequence analysis of the eight exons of SSIIa identified significant polymorphism in only exon 8. These single nucleotide polymorphisms (SNPs) were determined in 70 diverse genotypes of rice. Two SNPs could classify all 70 genotypes into either high GT or low GT types which differed in GT by 8 degrees C. 'A' rather than 'G' at base 2412 determined whether a methionine or valine was present at the corresponding amino acid residue in SSIIa, whilst two adjacent SNPs at bases 2543 and 2544 coded for either leucine (GC) or phenylalanine (TT). Rice varieties with high GT starch had a combination of valine and leucine at these residues. In contrast, rice varieties with low GT starch had a combination of either methionine and leucine or valine and phenylalanine at these same residues. At least two distinct polymorphisms have apparently been selected for their desirable cooking qualities in the domestication of rice.

  4. Relationship between horn fly infestation and polymorphisms in cytochrome

    USDA-ARS?s Scientific Manuscript database

    Individual animal variation occurs regarding external parasite infestation in beef cattle. Our objective was to determine if horn flies infestations present on beef cattle are associated with the single nucleotide polymorphism (SNP; T-318C) in the cytochrome P450 gene (CYP3A28) and the prolactin (PR...

  5. Acquisition of plumage polymorphism in white-throated sparrows

    Treesearch

    Carter T. Atkinson; C. John Ralph

    1980-01-01

    The White-throated Sparrow (Zonotrichia albicollis) was thought to be polymorphic in breeding plumage, having distinct white and tan phases that are bimodal in distribution and independent of sex. Vardy (1971), however, submitted evidence that plumage type is determined primarily by age, sex, and molt cycle. We reexamined this question by measuring plumage...

  6. Determination of alpha-2-MRAP gene polymorphisms in nephrolithiasis patients.

    PubMed

    Mehde, Atheer Awad; Mehdi, Wesen Adel; Yusof, Faridah; Raus, Raha Ahmed; Abidin, Zaima Azira Zainal; Ghazali, Hamid; Rahman, Azlina Abd

    2017-07-29

    The intron 5 insertion/deletion polymorphism of Alpha-2-macroglobulin receptor-associated protein gene (Alpha-2-MRAP) has been implicated in numerous diseases. The current study was designed to analyze the association of intron 5 insertion/deletion polymorphism of Alpha-2-MRAP with nephrolithiasis patients. PCR was conducted on genomic DNA of patients and control to look for Alpha-2-MRAP insertion/deletion polymorphism. Besides that, serum level of Alpha-2-MRAP, oxidative stress marker myeloperoxidase, Malondialdehyde (MDA),